tag:blogger.com,1999:blog-32057721965633660122024-03-08T00:05:55.752-05:00HCV AwarenessThis is my own personal Blog on what is happening today with HCV Awareness and additional info on Hepatitis and HIV co-infection. I will try to post weekly news on what is going on with treatments available today and in the near future. Additionally I will now and then add a soup recipe or a juicing recipe or a motivational quote. I can be contacted by email at ScottWeinstein@Verizon.net or at MrWeinstein007@gmail.comScott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.comBlogger847125tag:blogger.com,1999:blog-3205772196563366012.post-46460916008091604772010-09-27T16:28:00.002-04:002010-09-27T16:29:13.157-04:00Merck Significantly Expands its Patient Assistance Program Offerings to Provide Access to More Medicines for People in NeedMerck Significantly Expands its Patient Assistance Program Offerings to Provide Access to More Medicines for People in Need<br />Survey shows more than one third of uninsured, unemployed Americans have skipped or incorrectly taken their prescribed medications to save money, yet many may qualify for free medicine<br /><br />WHITEHOUSE STATION, N.J., Sep 22, 2010 (BUSINESS WIRE) -- Today, Merck announced that it has significantly expanded the number of Merck medicines available through its Merck Helps(TM) patient assistance programs, which include the Merck Patient Assistance Program, the Merck Vaccine Patient Assistance Program, the ACT Program for Oncology and Hepatitis C medicines, and the SUPPORT(R) Program for HIV/AIDS medicines. The Merck Helps programs provide Merck medicines and vaccines free of charge to eligible individuals, primarily the uninsured, who earn up to 400 percent of the federal poverty level who, without assistance, cannot afford needed Merck medicines.<br /><br />To help increase awareness of all patient assistance programs, the Merck Company Foundation has provided a grant to NeedyMeds, a nonprofit organization with a mission to help people who cannot afford medicine or healthcare costs by making information about these programs available at no cost. NeedyMeds will be using the grant to translate its website into Spanish as well as working closely with various healthcare clinics to increase knowledge of and access to patient assistance programs.<br /><br />"Merck has historically recognized the critical need for people to have access to the prescription medicines and vaccines they require, even if they lose their insurance," said Michael Rosenblatt, M.D., executive vice president and chief medical officer at Merck. "Our patient assistance programs now provide access to even more medicines for chronic conditions like asthma, diabetes and high blood pressure, allowing us to reach more people in need."<br /><br />A recent telephone survey of more than 2,000 Americans, conducted by Harris Interactive on behalf of Merck(1), found that more than one third (35%) of those who are uninsured and unemployed did not buy or refill medicines they were prescribed, cut their dosage in half, or took expired medicine as a way to save money. Furthermore, while 32 percent of U.S. adults are potentially eligible for patient assistance programs, 79 percent of those who are uninsured and unemployed are somewhat or not at all aware that such programs exist.<br /><br />"Unfortunately, many patients don't know that there are patient assistance programs available if they can't afford their prescriptions, and the need is great," said Richard Sagall, MD, co-founder of NeedyMeds. "That's why we are pleased to partner with Merck to help further raise awareness of these programs."<br /><br />"With an uncertain economy and near double-digit unemployment, more patients are struggling to pay for their medicines than ever before," said Emmanuel Durham, director of Community Healthcare Network -- Helen B. Atkinson Health Center, New York, NY. "I have seen firsthand how the Merck Helps programs can keep needed medicines in reach."<br /><br />About Merck Helps<br /><br />For more than 50 years, Merck has helped millions of patients gain access to medicines for chronic conditions like asthma, diabetes and high blood pressure through the Merck Patient Assistance Program. As a global healthcare leader working to help the world be well, Merck provides its medicines and adult vaccines for free to people who do not have prescription drug or health insurance coverage and qualify for a Merck Helps program. Merck Helps programs include:<br /><br />-- The Merck Patient Assistance Program, which helps eligible patients who earn up to 400 percent of the federal poverty level gain access to Merck medicines for chronic conditions like asthma and diabetes.<br /><br />-- The Merck Vaccine Patient Assistance Program, which provides free vaccines to adults over age 19 who do not have health insurance coverage for vaccines and who earn up to 400 percent of the federal poverty level.<br /><br />-- The ACT Program for Oncology and Hepatitis C medicines, which provides free reimbursement support services and refers appropriate patients to a patient assistance program for eligible individuals who earn up to 500 percent of the federal poverty level.<br /><br />-- The SUPPORTProgram for HIV/AIDS, which provides free reimbursement support services and refers appropriate patients to a patient assistance program for eligible individuals who earn up to 500 percent of the federal poverty level.<br /><br />All Merck Helps programs are confidential and patients may qualify for the Merck Patient Assistance Program and the Merck Vaccine Patient Assistance Program if they have a household income of $43,320 or less for individuals, $58,280 or less for couples, or $88,200 or less for a family of four, even if the financial situation is temporary due to unemployment or other reasons. Patients may qualify for The ACT Program and the SUPPORT Program if they have a household income of $54,150 or less for individuals, $72,800 or less for couples, or $110,250 or less for a family of four. With the Merck Helps programs, there are no application fees, no co-payments and a simple enrollment process. Many medicines can be delivered to a patient's home or doctor's office at no charge. Patients in need of information should visit www.MerckHelps.com or call (800) PAP-5400.<br /><br />About NeedyMeds<br /><br />NeedyMeds is a non-profit organization founded in 1997 as a resource for people who need help with the cost of medicine. The mission of NeedyMeds has been, since its inception, to make comprehensive and reliable information about assistance programs available to low-income patients and their advocates at no cost. NeedyMeds' website is visited by over 14,000 people each workday.<br /><br />About Merck<br /><br />Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.<br /><br />(1) This telephone survey was conducted by Harris Interactive on behalf of Merck from August 20 to 23, 2010 among 2,012 U.S. adults of whom 549 do not have any prescription drug benefits and 131 do not have any prescription drug benefits and are not employed.<br /><br />SOURCE: Merck<br /><br />Media Contact: <br />Merck <br />Ron Rogers, 908-423-6449Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com41tag:blogger.com,1999:blog-3205772196563366012.post-24517112945969441092010-09-27T16:28:00.001-04:002010-09-27T16:28:28.073-04:00Mistakes in Genotyping 1, which may occur more in IDUs, becomes more important now with resistance a concern associated with new HCV oral drugsMistakes in Genotyping 1, which may occur more in IDUs, becomes more important now with resistance a concern associated with new HCV oral drugs, activity & development of resistance appears to perhaps differ between genotypes 1a and 1b, as well mistakes in genotyping 1 vs 2 or 3 appears to occur<br /><br /> Evaluation of Versant Hepatitis C Virus Genotype Assay (LiPA) 2.0 - pdf attached - (09/21/10)<br /> <br />Concerns About HCV Genotyping: Hepatitis C Virus (HCV) Genotype 1 Subtype Identification in New HCV Drug Development and Future Clinical Practice - pdf attached - (09/20/10)<br /><br />Methods based on the sole analysis of the 5'NCR, namely Trugene HCV Genotyping Kit and INNO-LiPA HCV 1.0, failed to correctly identify HCV subtype 1a in 22.8% and 29.5% of cases, and HCV subtype 1b in 9.5% and 8.7% of cases, respectively (Table 1)...... The results clearly show that, although they are by far the most widely used techniques in new HCV drug development trials, genotyping techniques based on the sole analysis of the 5'NCR should be avoided, as they mistype approximately 25% and 10% of HCV subtype 1a and 1b strains, respectively......INNO-LiPA HCV 2.0 displays the same 5'NCR oligonucleotide probes as INNO-LiPA HCV 1.0, plus core-encoded oligonucleotide probes aimed at better discriminating between HCV subtypes 1a and 1b. With INNO-LiPA HCV 2.0, subtype identification was corrected in 64 of the 70 subtypes 1a that were incorrectly typed with INNO-LiPA HCV 1.0. Five samples could not be PCR-amplified in the core-coding region and the result was not interpretable with INNO-LiPA HCV 2.0 in the remaining case (Table 1). INNO-LiPA HCV 2.0 also corrected subtype identification in 13 of 23 subtypes 1b that were incorrectly typed with INNO-LiPA HCV 1.0. Eight samples could not be PCR-amplified in the core-coding region and the result was not interpretable with INNO-LiPA HCV 2.0 in the remaining two cases (Table 1). Overall, the second-generation line probe assay correctly classified 97.5% of subtype 1a and 96.2% of subtype 1b strains. When only samples that could be PCR-amplified with the assay procedure were taken into account, correct subtype determination was achieved in 99.6% and 99.2% of cases, respectively (Table 1)The real-time PCR-based assay targeting both the 5'NCR and the NS5B region, Abbott RealTime HCV Genotype II assay, correctly identified 93.2% of subtype 1a and 88.9% of subtype 1b strains. Only 2 HCV subtype 1b samples could not be PCR-amplified with this method (Table 1)......Novel assays have been recently developed that aim at better discriminating among the different HCV genotype 1 subtypes and between genotypes 1 and 6. Abbott RealTime HCV Genotype II assay is a real-time PCR method using several sets of genotype- and subtype-specific primers and probes located in both the 5'NCR and the NS5B-coding region. As shown in Table 1, adding a second target region for analysis led to substantially improving HCV genotype 1 subtype identification compared to methods targeting the sole 5'NCR. However, in contrast with a previous report [33], we found that this assay failed to correctly identify HCV genotype 1 subtype in approximately 10% of cases"Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com2tag:blogger.com,1999:blog-3205772196563366012.post-7422745387568989692010-09-27T16:27:00.001-04:002010-09-27T16:27:43.966-04:00Santaris Pharma A/S Advances miravirsen, the First microRNA-Targeted Drug to Enter Clinical TrialsSantaris Pharma A/S Advances miravirsen, the First microRNA-Targeted Drug to Enter Clinical Trials, Into Phase 2 to Treat Patients Infected With Hepatitis C Virus<br />- Santaris Pharma A/S initiates Phase 2a clinical trial with miravirsen (SPC3649) to assess safety and tolerability in treatment-naive patients with chronic Hepatitis C<br /><br />By: PR Newswire<br />Sep. 22, 2010 07:15 AM<br /><br />Therapeutic Silencing of MicroRNA-122 by SPC3649 in Primates with ...<br />Science Mag, Dec 3, 2009 ... Here, we investigated the potential of miR-122 antagonism by SPC3649 as ... We next assessed the in vivo antagonism of miR-122 in chimpanzee ...<br /><br />www.natap.org/2009/HCV/011009_01.htm<br /><br />HOERSHOLM, Denmark and SAN DIEGO, September 22, 2010 /PRNewswire/ -- Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, today announced that it has advanced miravirsen (SPC3649), the first microRNA-targeted drug to enter clinical trials, into Phase 2 studies to assess the safety and tolerability of the drug in treatment-naive patients infected with the Hepatitis C virus (HCV).<br /><br />Paving the way to conduct the first clinical trials of a microRNA-targeted drug in the United States, Santaris Pharma A/S also received acceptance of its Investigational New Drug (IND) application from the U.S. Food and Drug Administration (FDA). In addition to the United States, the Phase 2a clinical trials will be conducted in the Netherlands, Germany, Poland, Romania, and Slovakia.<br /><br />The World Health Organization estimates about 3% of the world's population has been infected with HCV and that some 170 million are chronic carriers at risk of developing liver cirrhosis and/or liver cancer(2). Approximately 3-4 million Americans are chronically infected with an estimated 40,000 new infections per year(1). In Europe, there are about 4 million carriers(2). The current standard of care, pegylated interferon in combination with ribavirin, is effective in only about 50% of those treated(1).<br /><br />Developed using Santaris Pharma A/S proprietary Locked Nucleic Acid (LNA) Drug Platform, miravirsen is a specific inhibitor of miR-122, a liver specific microRNA that the Hepatitis C virus requires for replication. Miravirsen is designed to recognize and sequester miR-122, making it unavailable to the Hepatitis C virus. As a result, the replication of the virus is effectively inhibited and the level of Hepatitis C virus is reduced.<br /><br />"Advancing miravirsen, the first microRNA-targeted drug to enter clinical trials, into Phase 2 studies in patients with Hepatitis C demonstrates Santaris Pharma A/S leadership in developing RNA-targeted medicines," said Arthur A. Levin, Ph.D., Vice President, Chief Development Officer and President, US Operations. "Receiving IND acceptance from the FDA to conduct the first clinical trials with a microRNA-targeted drug in the United States brings Santaris Pharma A/S one step closer to potentially providing a growing number of patients chronically infected with HCV with a more effective and better tolerated treatment option."<br /><br />The LNA Drug Platform is the only technology with both mRNA and microRNA targeted drugs in clinical trials, reinforcing the broad utility of the platform. The unique combination of small size and very high affinity, which is only achievable with LNA-based drugs, allows this new class of drugs to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. LNA-based drugs are a promising new type of therapy that enables scientists to develop drugs to attack previously inaccessible pathways.<br /><br />"Using our LNA Drug Platform to advance the first microRNA-targeted therapy into human clinical trials was certainly a scientific breakthrough," said Henrik Oerum, Ph.D., Vice President and Chief Scientific Officer of Santaris Pharma A/S. "We are extremely pleased with the results of the Phase I trials and excited to progress miravirsen into Phase 2 clinical trials. Because of its unique mechanism of action and tolerability profile, miravirsen has the potential to be an effective treatment option for patients with HCV."<br /><br />The randomized, double-blind, placebo-controlled, ascending multiple-dose Phase 2a study will assess the safety and tolerability of miravirsen and is designed to enroll up to 55 treatment-naïve patients with chronic Hepatitis C virus genotype 1 infection. Secondary endpoints include pharmacokinetics of miravirsen and its effect on viral load. Miravirsen will be given as subcutaneous injections weekly or every other week for four weeks.<br /><br />Data from Phase 1 clinical studies with miravirsen in healthy volunteers show that the drug is well tolerated. A recent study published in Science demonstrated that miravirsen successfully inhibited miR-122 and dramatically reduced Hepatitis C virus in the liver and in the bloodstream in chimpanzees chronically infected with the Hepatitis C virus(3). Miravirsen provided continued efficacy in the animals up to several months after the treatment period with no adverse events and no evidence of viral rebound or resistance.<br /><br />In addition to miravirsen, Santaris Pharma A/S has a robust product pipeline targeting mRNAs and microRNAs both internally as well as in partnerships and collaborations with miRagen Therapeutics (cardiovascular diseases), Shire plc (rare genetic disorders), Pfizer (undisclosed therapeutic areas), GlaxoSmithKline (viral disease) and Enzon Pharmaceuticals (oncology).<br /><br />About microRNAs<br /><br />MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are associated with many disease processes. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets for controlling many biologic and disease processes.<br /><br />About Locked Nucleic Acid (LNA) Drug Platform<br /><br />The LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the Company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver potent single-stranded LNA-based drug candidates against RNA targets, both mRNA and microRNA, for a range of diseases including metabolic disorders, infectious and inflammatory diseases, cancer and rare genetic disorders. The LNA Drug Platform overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The unique combination of small size and very high affinity, which is only achievable with LNA-based drugs, allows this new class of drugs to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. LNA-based drugs are a promising new type of therapy that enables scientists to develop drugs to attack previously inaccessible clinical pathways. The most important features of LNA-based drugs include excellent specificity, providing optimal targeting; increased affinity to targets providing improved potency; and strong pharmacology upon systemic delivery without complicated delivery vehicles.<br /><br />About Santaris Pharma A/S<br /><br />Santaris Pharma A/S is a privately held clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies. The Locked Nucleic Acid (LNA) Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combine the Company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The Company's research and development activities focus on infectious diseases and metabolic disorders, while partnerships with major pharmaceutical companies include a range of therapeutic areas including cancer, cardiovascular disease, infectious and inflammatory diseases, and rare genetic disorders. The Company has strategic partnerships with miRagen Therapeutics, Shire plc, Pfizer, GlaxoSmithKline, and Enzon Pharmaceuticals. As part of its broad patent estate, the Company holds exclusive worldwide rights to all therapeutic uses of LNA. Santaris Pharma A/S, founded in 2003, is headquartered in Denmark with operations in the United States. Please visit http://www.santaris.com for more information.<br /><br /> <br /> (1) American Association for the Study of Liver Diseases -<br /> http://www.aasld.org/patients/Pages/LiverFastFactsHepC.aspx<br /><br /> (2) World Health Organization -<br /> http://www.who.int/csr/disease/hepatitis/Hepc.pdf<br /><br /> (3) Science. 2010 Jan 8; 327(5962):198-201. Epub 2009 Dec 3Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com2tag:blogger.com,1999:blog-3205772196563366012.post-67576691678879592082010-09-27T16:24:00.000-04:002010-09-27T16:25:13.803-04:00HCV: Health Danger of Parties PastHCV: Health Danger of Parties Past<br /><br />Wall Street Journal<br />Sept 20 2010<br /><br />Most people think their wild-child past is just that—in the past. But some former party animals may be carrying a harmful reminder of their youth and not know it.<br /><br /><br />People who used intravenous drugs, snorted cocaine with a shared straw, or had an unsterile tattoo or body piercing could be infected with hepatitis C and not realize it. The virus, which spreads via blood-to-blood contact, can cause no symptoms for decades while silently destroying the liver.<br /><br /><br />Some people may have innocently been infected if they had a blood transfusion before 1992, when the blood supply began to be screened for the virus. Others may have contracted the virus simply by sharing a toothbrush or a razor. More than three million Americans have been diagnosed with hep C, and health experts say at least that many more are unaware that they have it.<br /><br /><br />"There's a huge reservoir of people who made a few bad decisions many years ago. Now they're successful business people, lawyers, doctors, school principals, and they don't know they are carrying this," says Joseph Galati, medical director of the Center for Liver Disease and Transplantation at Houston's Methodist Hospital. In the meantime, he says, "they could be doing things like drinking alcohol that accelerate the disease or transmitting it to other people."<br /><br /><br />Hep C, first identified in 1989, is today the leading reason for liver transplants and causes about 12,000 deaths in the U.S. each year. In most cases, the infection becomes chronic, inflaming the liver for years, but often with no apparent symptoms unless the inflammation becomes severe. In about 20% of cases, it progresses to cirrhosis, a severe scarring that shuts down liver function. And about 20% of those cirrhosis cases become liver cancer.<br /><br /><br />About 20,000 people are diagnosed with hepatitis C each year, and some two-thirds of those are middle-aged, having contracted the disease 20 or 30 years ago.<br /><br /><br />There is no vaccine against hep C, unlike for hepatitis A and B, which are liver diseases caused by different viruses. Hep C can be cured with a year-long course of chemotherapy drugs, but only about 50% of patients respond to them. A host of new medications now in clinical trials could work faster, and raise the cure rate as high as 80%, according to early results.<br /><br /><br />Hep C can be diagnosed with an inexpensive blood test that checks for antibodies—if doctors think to look for it. If that test is positive, another test can determine if the virus is still active. (In about 15% of hep C cases, the virus goes away on its own, although the antibodies may still be present.)<br /><br /><br />A regular annual checkup may reveal elevated liver enzymes. But many people with hep C have normal enzyme levels, and only vague symptoms like fatigue or joint pain, until the damage is well advanced.<br /><br /><br />"I never had any symptoms. I've had major surgery twice and nobody picked up on this," says a Houston nurse who was diagnosed with hep C in December at age 59. She thinks she was exposed to the virus in 1980, when she was accidentally stuck with a needle while caring for a patient. Her hep C was only found because a new job required the test for hep C antibodies. By then, 35% of her liver was damaged from cirrhosis. She is currently undergoing treatment in a clinical trial with Dr. Galati.<br /><br /><br />Even minute blood drops—from borrowing a toothbrush or piercing several friends' ears with the same needle—can transmit the virus. "Any blood-to-blood transition route can spread it, no matter how microscopic," says Melissa Palmer, medical director at New York University's Hepatology Associates in Plainview, NY.<br /><br /><br />"People may have done something once and forgotten about it, like share a $1 or a $100 bill to snort cocaine. The blood vessels in the nose are very weak and could bleed a little, and then the blood gets passed to the next person," says Dr. Palmer.<br /><br /><br />For now, the standard course of treatment for hep C is two chemotherapy drugs—interferon in weekly injections and ribavirin as pills three times a day—for either 24 or 48 weeks, an arduous regime that can cost more than $50,000 a year. Side effects can include fatigue, weakness, muscle and joint pain, hair loss, nausea and depression. Some patients need additional drugs to boost their red and white blood cells, which the chemo drugs deplete. Some have to stop the treatment because it can be so debilitating.<br /><br />----------------------------------<br /><br />Hepatitis A Through E<br /><br /><br />Hepatitis is an inflammation of the liver, generally caused by viruses, with symptoms ranging from slight to severe. Versions A through C are the most common.<br /><br /><br /> * Hep A: Transmitted via contaminated water or food, particularly in countries with poor hygiene. Symptoms include fatigue, fever, abdominal pain, depression and jaundice. Permanent liver damage is rare. Vaccine recommended for all children at 1 year.<br /><br /> * Hep B: Two billion people world-wide have been infected with hep B, mostly through infected blood or body fluids. It can become chronic and lead to cirrhosis and liver cancer, but most adults clear the virus without treatment and are then immune. Vaccination is now required for many college students and healthcare workers.<br /><br /> * Hep C: Spread by blood-to-blood transmission, with few symptoms either in early stages or for decades later. About 20% of chronic cases develop into cirrhosis or liver cancer. Curable in about 50% of cases by chemotherapy.<br /><br /> * Hep D: Caused by a small RNA virus that only propagates in the presence of hep B, greatly increasing the chance of cancer, cirrhosis and death. Hep B vaccine will prevent illness from D.<br /><br /> * Hep E: Transmitted by fecal-oral contamination in unsanitary conditions. Patients are generally very ill for the first few weeks of infection then the virus usually clears on it own. Vaccine is being tested.<br /><br /><br />Source: WSJ Reporting<br />---------------------------------------<br /><br /><br />"I was really, really sick for a while—I had to hide under the wedding gowns so I could nap," says Sidney Merry, 53, who works for a bridal retailer in Houston. Routine blood tests spotted her hep C, which she thinks she got from a blood transfusion in the 1970s, and later started treatment with Dr. Galati. Ms. Merry stuck with the program and is now free of the virus. She helps counsel other patients undergoing treatment.<br /><br /><br />Ms. Merry says two of her friends died of hep C they declined to treat, and her own mother died of liver cancer at age 53, from what Ms. Merry suspects may also have been hep C. "This touches many lives—but it's so unspoken about and misunderstood," she says.<br /><br /><br />Two new drugs on the horizon—boceprevir by Merck & Co. and telaprevir by Vertex Pharmaceuticals Inc.—are protease inhibitors similar to those in AIDS drugs. They could win approval by the Food and Drug Administration next year. Other companies are studying different approaches to fight hep C.<br /><br /><br />In July, the FDA approved a synthetic form of interferon, called Infergen, by Three Rivers Pharmaceuticals LLC, for use in daily injections for patients who don't respond to the first course of treatment.<br /><br /><br />In some cases, doctors are advising hep C patients to postpone treatment until the new drugs come on the market. But Dr. Galati, who has been the principal investigator for several industry-sponsored clinical trials, notes that the new drugs will be in addition to the current ones, so waiting for the new regimes won't allow patients to avoid the side effects.<br /><br /><br />Unborn babies can acquire hep C from infected mothers. Kathryn Maloney had complained of fatigue for years before she was diagnosed with hep C in 2005. "Turns out I had it my whole life and didn't know," says Ms. Maloney, 29, an accountant in Houston.<br /><br /><br />Since there was no obvious source of her infection, Dr. Galati suggested that her mother, Pamela Grant, be tested too. She tested positive as well, though she has no idea when or where she was exposed. She and her daughter underwent treatment together. They also took part in a clinical trial for one of the new medications and are now free of the virus.<br /><br /><br />Some patients opt to forgo treatment, since only about 20% progress to cirrhosis. But doctors can't tell in advance which cases will progress. Meanwhile, drinking alcohol, smoking cigarettes and carrying excess weight make cirrhosis more likely.<br /><br /><br />Some health experts are urging that the general public be screened for hep C; the blood test for antibodies costs only about $12. Short of that, liver specialists urge anyone who might have been exposed, no matter how or how long ago or how well they feel now, to tell their doctors and be tested.<br /><br /><br />Since hep C can carry a lingering stigma of past drug use, even though there are many other ways to contract it, Dr. Galati says some primary-care physicians routinely hand patients a list of risk factors and say, "If you fit into any of these categories, you should get tested. You don't need to tell me which one."Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com1tag:blogger.com,1999:blog-3205772196563366012.post-45297256959175612572010-09-27T16:21:00.002-04:002010-09-27T16:22:06.627-04:00Evaluation of Versant Hepatitis C Virus Genotype AssayEvaluation of Versant Hepatitis C Virus Genotype Assay (LiPA) 2.0 - pdf attached<br /><br /><br />Journal of Clinical Microbiology, June 2008, p. 1901-1906, Vol. 46, No. 6<br /><br />doi:10.1128/JCM.02390-07<br /><br />"The reliability of genotyping methods highly depends on the amount of information (i.e., the number of informative sites) that is utilized for the discrimination of genetic variants......Our results indicate that Versant HCV genotype assay (LiPA) 2.0 yielded an interpretable genotype result for 96.0% of the samples and that 99.4% of the interpretable results agreed with the reference method, rendering it an accurate and reliable assay suitable for large-scale genotyping. This new assay outperforms the previous version of the line probe assay, since Versant HCV genotype assay (LiPA) 1.0 has an overall accuracy of 74%, taking subtype i nformation into account (8, 23).....In conclusion, Versant HCV genotype assay (LiPA) 2.0 provides a rapid, sensitive, and accurate means of HCV genotyping and can be used as a routine tool to distinguish between the different HCV genotypes and subtypes. Considering the importance of genotype determination in understanding the epidemiology of the virus and in the management of hepatitis C treatment strategies, efficient genotyping tools are indispensable in clinical diagnostic settings."<br /><br /><br />Jannick Verbeeck,1 Mark J. Stanley,2 Jen Shieh,2 Linda Celis,3 Els Huyck,3 Elke Wollants,1 Judy Morimoto,2 Alice Farrior,2 Erwin Sablon,3 Margaret Jankowski-Hennig,4 Carl Schaper,4 Pamela Johnson,4 Marc Van Ranst,1* and Marianne Van Brussel3<br /><br /><br />Laboratory of Clinical Virology, Rega Institute for Medical Research, Leuven, Belgium,1 Department of Microbiology, Kaiser Permanente, TPMG Regional Laboratory, Berkeley, California,2 Innogenetics NV, Gent, Belgium,3 Siemens Healthcare Diagnostics, Berkeley, California4<br /><br />ABSTRACT<br /><br /> <br /><br />Hepatitis C virus (HCV) genotyping is a tool used to optimize antiviral treatment regimens. The newly developed Versant HCV genotype assay (LiPA) 2.0 uses sequence information from both the 5' untranslated region and the core region, allowing distinction between HCV genotype 1 and subtypes c to l of genotype 6 and between subtypes a and b of genotype 1. HCV-positive samples were genotyped manually using the Versant HCV genotype assay (LiPA) 2.0 system according to the manufacturer's instructions. For the comparison study, Versant HCV genotype assay (LiPA) 1.0 was used. In this study, 99.7% of the samples could be amplified, the genotype of 96.0% of samples could be determined, and the agreement with the reference method was 99.4% when a genotype was determined. The reproducibility study showed no significant differences in performance across sites (P = 0.43) or across lots (P = 0.88). In the comparison stud y, 13 samples that were uninterpretable or incorrectly genotyped with Versant HCV genotype assay (LiPA) 1.0 were correctly genotyped by Versant HCV genotype assay (LiPA) 2.0. Versant HCV genotype assay (LiPA) 2.0 is a sensitive, accurate, and reliable assay for HCV genotyping. The inclusion of the core region probes in Versant HCV genotype assay (LiPA) 2.0 results in a genotyping success rate higher than that of the current Versant HCV genotype assay (LiPA) 1.0.<br /><br /><br />INTRODUCTION<br /><br /> <br /><br />Hepatitis C virus (HCV) is a leading cause of chronic liver disease and has already infected at least 170 million people worldwide. Each year, 3 to 4 million people are newly infected. HCV creates an extensive disease burden, since it accounts for 20 to 30% of cases of acute hepatitis, 70 to 80% of cases of chronic hepatitis, 40% of cases of end-stage cirrhosis, 50 to 76% of cases of hepatocellular carcinoma, and 30 to 40% of liver transplants (15, 33, 34).<br /><br /><br />HCV belongs to the family of the Flaviviridae and can be divided into different genotypes based on phylogenetic analysis of full-length or partial sequences of HCV strains. The most current consensus proposal distinguishes six genotypes based on phylogenetic cluster analysis of complete genomes. The genotype formerly designated as 10a has been reassigned as genotype 3, subtype k. Genotypes 7, 8, 9, and 11, belonging to clade 6, have been reassigned to genotype 6, subtypes c to l (25, 26, 27). These six HCV genotypes have different geographical distributions (21, 30, 32).<br /><br /><br />Treatment options for chronic HCV infections are poor. At the moment, the only accepted antiviral therapy with proven effectiveness is a combination therapy of (peg)interferon alpha and ribavirin. The overall success rate of this antiviral treatment ranges from 50% to 90% (11). According to a National Institutes of Health (NIH) 2002 panel, several factors are associated with successful treatment response, including lower baseline HCV RNA levels, lower fibrosis and inflammation scores upon liver biopsy, lower body weight, and lower body surface area, but the most important predicting factor is HCV genotype (24). Patients infected with HCV genotype 1 respond least to therapy, while patients infected with genotypes 2 and 3 show the best responses (14, 17, 22). For HCV genotypes 4, 5, and 6, treatment data are scarce, but it is recommended to treat these individuals using the same regimen as for patients infected with genotype 1 (7, 13, 18, 31). Nearly all patients experience side effects with the antiviral therapy. These side effects can be severe and contribute to discontinuation rates of 10 to 14% and dose reductions for 7 to 42% of patients, depending on the type and length of treatment (16). Therefore, it is important that clinicians have the appropriate information to make individual treatment choices in order to maximize the chance of successful treatment outcome for each individual patient, rendering HCV genotyping assays important and useful tools to optimize treatment type, duration, and dose.<br /><br /><br />In this paper, we evaluate Versant HCV genotype assay (LiPA) 2.0 (CE marked in Europe; for research use only; not for use in diagnostic procedures in the United States) (manufactured by Innogenetics, distributed by Siemens Healthcare Diagnostics), which uses sequence information from the core region in addition to sequence information from the 5' untranslated region (5'UTR), allowing an improved and more accurate distinction between HCV genotype 1 and subtypes c to l of genotype 6 and between subtypes a and b of genotype 1.<br /><br />RESULTS<br /><br /> <br /><br />Clinical accuracy study.<br />Table 1 summarizes the results for the 326 specimens that were used for the reference method comparison. Upon initial testing, 93.3% (304/326) of the specimens gave interpretable genotype results, 2.1% (7/326) failed to amplify, and 4.6% (15/326) amplified but gave uninterpretable results. Of the 304 specimens that yielded a genotype result, 99.3% (302/304) gave results that agreed with the reference method. After specimens that yielded no genotype result were retested, 96.0% (313/326) of the specimens gave interpretable genotype results, 3.5% (12/326) amplified but remained uninterpretable, and 0.3% (1/326) failed to amplify. Of the 313 specimens that yielded a genotype result after repeat testing, 99.4% (311/313) gave results that agreed with the reference method. Table 2 shows that the specimens that did not amplify or give interpretable results were distributed across ge notypes. The two specimens that initially gave results that disagreed with those obtained by the reference method were retested, and both gave retest results that agreed with those obtained by the reference method.<br /><br />In order to determine the core amplification efficiency, 156 genotype 1 and genotype 6 (c to l) samples were analyzed. Two samples showed negative AMPL CTRL 1 lines and were excluded from further analysis. Of the remaining 154 genotype 1 and genotype 6 (c to l) samples, 1 sample had a negative AMPL CTRL 2, r esulting in the amplification of 99.4% (153/154) samples.<br /><br /><br />The clinical subtype efficiency for HCV genotypes 1a and 1b was determined using 129 samples that were genotype 1a or 1b based on reference sequencing and genotype 1, 1a, or 1b based on LiPA genotyping; this determination was based on initial testing only, excluding repeat testing of initial amplification failures and uninterpretable results. Three out of 129 samples were indeterminate at the subtype level, resulting in a clinical HCV genotype 1 subtype efficiency of 97.7% after initial testing. Upon repeat testing, all samples gave a correct consensus subtype result. All of the 126 samples that were genotype 1a or 1b by LiPA were concordant with sequencing.<br /><br /><br />In order to check whether Versant HCV genotype assay (LiPA) 2.0 was able to determine the correct genotype for samples with viral loads at the upper limit of detection, 22 samples with viral loads ranging from 4.0 x 106 IU/ml to 8.7 x 106 IU/ml were selected, and the genotype success rate and the percentage of agreement with the reference method for these high-concentration specimens were estimated. For all these samples, Versant HCV genotype assay (LiPA) 2.0 produced the same genotype results as the genotype result determined by NS5b sequencing and phylogenetic analysis, resulting in both a genotype success rate and an agreement with the reference method of 100%.<br /><br /><br />Reproducibility study.<br />Table 3 summarizes the valid, indeterminate, correct, and incorrect genotype results for each reproducibility panel member. In total, 3.3% (16/486) of reactions gave indeterminate results (defined as specimens with either an amplification failure or an uninterpretable result) and 96.7% (LCL, 95.0%) yielded an interpretable genotype result. Of the 470 specimens with interpretable results, 100% (LCL, 99.4%) gave the correct genotype. The indeterminate results occurred at all sites, with all three reagent lots, and in multiple assay runs. There were no significant performance differences seen for the Versant HCV genotype assay (LiPA) 2.0 system across sites/operators (P = 0.43) or across reagent lots (P = 0.88). The genotype success rates at the individual sites were 98.1% for site 1, 97.6% for site 2, and 94.4% for site 3. The genotype success rates for the individual lots were 96.9% using lot 1, 97.5% using lot 2, and 95.7% using lot 3.<br /><br />Comparison study.<br />Table 4 gives an overview of the results of the comparison study after original testing and after repeat testing. Of the 100 specimens tested, 13 specimens initially produced uninterpretable results by either Versant HCV genotype assay (LiPA) 1.0 or Versant HCV genotype assay (LiPA) 2.0 or both assays. The HCV RNA concentrations of these 13 samples ranged from 14,615 to 2,500,000 IU/ml. These specimens were retested using both ass ays. After repeat testing, three specimens remained uninterpretable by both versions of the assay, five remained uninterpretable by Versant HCV genotype assay (LiPA) 1.0, and one remained uninterpretable by Versant HCV genotype assay (LiPA) 2.0. For all six specimens that gave a genotype result by only one version of the assay, the observed genotype result agreed with that obtained by sequencing the NS5b region of the HCV genome. After repeat testing, 83 specimens were concordant by both assays at the genotype level. Of these, 16 specimens had concordant genotypes by both assays, but one of the assays failed to give a subtype, resulting in a total of 67 concordant specimens when the subtype level is taken into account. Results from eight specimens were discordant between the two assays, and results from nine specimens were uninterpretable by at least one of the assays. The total number of interpretable specimens by both assays was 91, of which 83 had concordant results at the genotype level only (91.2%; LCL, 84.7%). Table 5 shows the number o f genotype and subtype results produced by both assays for the 100 specimens tested after repeat testing.<br /><br /><br />The eight samples that showed discordant results were sequenced in the NS5b region of the HCV genome (two samples were HCV genotype 6 subtypes c to l, and six samples were HCV genotype 1a). Results indicated that Versant HCV genotype assay (LiPA) 2.0 gave the correct HCV genotype and subtype, as determined by NS5b sequencing. In contrast, Versant HCV genotype assay (LiPA) 1.0 had misclassified all eight samples as HC V genotype 1b. Of the 96 specimens that were interpretable with Versant HCV genotype assay (LiPA) 2.0, 83 showed concordant results with Versant HCV genotype assay (LiPA) 1.0, while 13 showed improved results over Versant HCV genotype assay (LiPA) 1.0, which leads to 100% concordant or improved results (LCL, 96.9%).<br /><br />DISCUSSION<br /><br /> <br /><br />Phylogenetic analysis of a coding region, or even more, the complete genome, is considered the gold standard for identifying different HCV genotypes (6). However, since this method is expensive and time-consuming, it is impractical for large-scale genotyping projects (8). For this reason, commercial genotyping kits were developed for routine determination of HCV genotypes. Most commercially available HCV genotyping assays, including Versant HCV genotype assay (LiPA) 1.0, use the 5'UTR, since this region is highly conserved and therefore well suited for the development of detection methods. The reliability of genotyping methods highly depends on the amount of information (i.e., the number of informative sites) that is utilized for the discrimination of genetic variants. The 5'UTR is sufficiently variable for discrimination of HCV genotypes 1 to 5 and most subtypes of HCV genotype 6 (12, 28, 29, 32). However, it does not allow discrimination of HCV genotype 6 subtypes c to l from HCV genotype 1 and has only a limited subtyping accuracy (5, 29). To overcome the limitations of the 5'UTR, a new assay which uses additional sequence information from the core region of the HCV genome, Versant HCV genotype assay (LiPA) 2.0, has recently been developed (20). In this study, we evaluated the new assay and compared it with the previous version of the assay.<br /><br /><br />Our results indicate that Versant HCV genotype assay (LiPA) 2.0 yielded an interpretable genotype result for 96.0% of the samples and that 99.4% of the interpretable results agreed with the reference method, rendering it an accurate and reliable assay suitable for large-scale genotyping. This new assay outperforms the previous version of the line probe assay, since Versant HCV genotype assay (LiPA) 1.0 has an overall accuracy of 74%, taking subtype information into account (8, 23).<br /><br /><br />In the comparison study, eight specimens showed discordant results when tested with both assays. The NS5b sequencing results for these samples showed that Versant HCV genotype assay (LiPA) 2.0 gave the correct HCV genotype and subtype and thereby showed an improvement in identifying HCV-positive samples which are subtypes c to l of genotype 6 and in identifying the correct subtype of genotype 1. This improvement can be attributed to the additional information available from the core region of the HCV genome, which can better distinguish between genotype 1 and subtypes c to l of genotype 6 and between subtype a and b of genotype 1. This core information is not available in Versant HCV genotype assay (LiPA) 1.0, and this can lead to misinterpretation. For example, in a study by Chinchai et al., this assay could not discriminate HCV genotype 6a variants from HCV genotype 1b, and two samples found to be genotype 1 by the assay contained genotype 3 core sequences (5). Chen and Weck showed that Versant HCV genotype assay (LiPA) 1.0 cannot accurately distinguish HCV genotypes 1a and 1b, since in most cases, the 5'UTR is not heterogeneous enough for use in determining the HCV subtype (4). Several other studies report on moderate distinction at the subtype level (1, 2, 9, 12, 19). This is not surprising, since the 5'UTR is the most highly conserved region of the HCV genome, and only one or two nucleotide changes distinguish unique subtypes. Assigning correct genotypes and subtypes to HCV specimens is important for several research purposes, including epidemiological, phylogenetic, and natural history studies. Some studies even report that there is a slight difference in treatment outcomes between HCV genotype 1a- and HCV genotype 1b-infected patients, showing that correct subtype assignment is indispensable (3, 10, 30).<br /><br /><br />In conclusion, Versant HCV genotype assay (LiPA) 2.0 provides a rapid, sensitive, and accurate means of HCV genotyping and can be used as a routine tool to distinguish between the different HCV genotypes and subtypes. Considering the importance of genotype determination in understanding the epidemiology of the virus and in the management of hepatitis C treatment strategies, efficient genotyping tools are indispensable in clinical diagnostic settings.Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com2tag:blogger.com,1999:blog-3205772196563366012.post-80338754325970748732010-09-27T16:21:00.001-04:002010-09-27T16:21:29.761-04:00Hepatitis C Virus (HCV) Genotype 1 Subtype Identification in New HCV Drug Development and Future Clinical PracticeHepatitis C Virus (HCV) Genotype 1 Subtype Identification in New HCV Drug Development and Future Clinical Practice - pdf attached<br /><br />PLoS ONE 4(12): e8209. doi:10.1371/journal.pone.0008209<br /><br />Published December 8, 2009<br /><br />"INNO-LiPA HCV 2.0 currently is the best available commercial assay for HCV genotype 1 subtype identification and should be used in clinical trials and practice.....<br /><br />Trugene HCV Genotyping Kit and INNO-LiPA HCV 1.0, failed to correctly identify HCV subtype 1a in 22.8% and 29.5% of cases, and HCV subtype 1b in 9.5% and 8.7% of cases, respectively....<br /><br />The second-generation line probe assay is currently the best commercial assay for determination of HCV genotype 1 subtypes 1a and 1b. It can therefore be used locally in clinical trials to identify the HCV subtype and stratify the patients at inclusion, as well as to interpret efficacy and resistance data. When reporting final data, direct sequence analysis of the NS5B region and/or another coding region (for instance the region encoding the antiviral drug target HCV protein) should always be performed as it may identify mistyping or mis-subtyping with commercial assays, especially in the case of rare subtypes."<br /><br />Stéphane Chevaliez1,2, Magali Bouvier-Alias1,2, Rozenn Brillet2, Jean-Michel Pawlotsky1,2*<br /><br /><br />1 French National Reference Center for Viral Hepatitis B, C and delta, Department of Virology, Hôpital Henri Mondor, Université Paris 12, Créteil, France, 2 INSERM U955, Créteil, France<br /><br />Methods based on the sole analysis of the 5′NCR, namely Trugene HCV Genotyping Kit and INNO-LiPA HCV 1.0, failed to correctly identify HCV subtype 1a in 22.8% and 29.5% of cases, and HCV subtype 1b in 9.5% and 8.7% of cases, respectively (Table 1)......<br /><br />The results clearly show that, although they are by far the most widely used techniques in new HCV drug development trials, genotyping techniques based on the sole analysis of the 5′NCR should be avoided, as they mistype approximately 25% and 10% of HCV subtype 1a and 1b strains, respectively......<br /><br />INNO-LiPA HCV 2.0 displays the same 5′NCR oligonucleotide probes as INNO-LiPA HCV 1.0, plus core-encoded oligonucleotide probes aimed at better discriminating between HCV subtypes 1a and 1b. With INNO-LiPA HCV 2.0, subtype identification was corrected in 64 of the 70 subtypes 1a that were incorrectly typed with INNO-LiPA HCV 1.0. Five samples could not be PCR-amplified in the core-coding region and the result was not interpretable with INNO-LiPA HCV 2.0 in the remaining case (Table 1). INNO-LiPA HCV 2.0 also corrected subtype identification in 13 of 23 subtypes 1b that were incorrectly typed with INNO-LiPA HCV 1.0. Eight samples could not be PCR-amplified in the core-coding region and the result was not interpretable with INNO-LiPA HCV 2.0 in the remaining two cases (Table 1). Overall, the second-generation line probe assay correctly classified 97.5% of subtype 1a and 96.2% of subtype 1b strains. When only samples that could be PCR-amplified with the assay procedure were taken into account, correct subtype determination was achieved in 99.6% and 99.2% of cases, respectively (Table 1)<br /><br />The real-time PCR-based assay targeting both the 5′NCR and the NS5B region, Abbott RealTime HCV Genotype II assay, correctly identified 93.2% of subtype 1a and 88.9% of subtype 1b strains. Only 2 HCV subtype 1b samples could not be PCR-amplified with this method (Table 1)......<br /><br />Novel assays have been recently developed that aim at better discriminating among the different HCV genotype 1 subtypes and between genotypes 1 and 6. Abbott RealTime HCV Genotype II assay is a real-time PCR method using several sets of genotype- and subtype-specific primers and probes located in both the 5′NCR and the NS5B-coding region. As shown in Table 1, adding a second target region for analysis led to substantially improving HCV genotype 1 subtype identification compared to methods targeting the sole 5′NCR. However, in contrast with a previous report [33], we found that this assay failed to correctly identify HCV genotype 1 subtype in approximately 10% of cases.<br /><br /><br />Table 1. Ability of the different molecular methods tested in this study to correctly identify HCV subtypes 1a and 1b in a series of 500 patients infected by one or the other of these subtypes.<br />Screen shot 2010-09-18 at 7.38.55 AM.png<br /><br />Abstract <br /><br />Background<br /><br /><br />With the development of new specific inhibitors of hepatitis C virus (HCV) enzymes and functions that may yield different antiviral responses and resistance profiles according to the HCV subtype, correct HCV genotype 1 subtype identification is mandatory in clinical trials for stratification and interpretation purposes and will likely become necessary in future clinical practice. The goal of this study was to identify the appropriate molecular tool(s) for accurate HCV genotype 1 subtype determination.<br /><br />Methodology/Principal Findings<br /><br /><br />A large cohort of 500 treatment-naïve patients eligible for HCV drug trials and infected with either subtype 1a or 1b was studied. Methods based on the sole analysis of the 5′ non-coding region (5′NCR) by sequence analysis or reverse hybridization failed to correctly identify HCV subtype 1a in 22.8%–29.5% of cases, and HCV subtype 1b in 9.5%–8.7% of cases. Natural polymorphisms at positions 107, 204 and/or 243 were responsible for mis-subtyping with these methods. A real-time PCR method using genotype- and subtype-specific primers and probes located in both the 5′NCR and the NS5B-coding region failed to correctly identify HCV genotype 1 subtype in approximately 10% of cases. The second-generation line probe assay, a reverse hybridization assay that uses probes targeting both the 5′NCR and core-coding region, correctly identified HCV subtypes 1a and 1b in more than 99% of cases.<br /><br />Conclusions/Significance<br /><br /><br />In the context of new HCV drug development, HCV genotyping methods based on the exclusive analysis of the 5′NCR should be avoided. The second-generation line probe assay is currently the best commercial assay for determination of HCV genotype 1 subtypes 1a and 1b in clinical trials and practice.<br /><br />Funding: The Trugene HCV 5′NC Genotyping kits and the INNO-LiPA HCV kits were kindly provided by Siemens Medical Solutions Diagnostics. The Abbott RealTime HCV Genotype II kits were kindly provided by Abbott Molecular. This work is part of the activity of the VIRGIL European Network of Excellence on Antiviral Drug Resistance supported by a grant (LSHM-CT-2004-503359) from the Priority 1 “Life Sciences, Genomics and Biotechnology for Health” program in the 6th Framework Program of the European Union. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.<br /><br />Introduction <br /><br /><br />Over 170 million individuals are infected with hepatitis C virus (HCV) worldwide. Phylogenetic analyses have shown that HCV strains can be classified into at least 6 major genotypes (numbered 1 to 6), and a large number of subtypes within each genotype [1]. Genotype 1 is by far the most frequent genotype in chronically infected patients worldwide, with subtypes 1a and 1b representing the vast majority of circulating strains [2], [3], [4].<br /><br /><br />Current treatment of chronic hepatitis C is based on the combination of pegylated interferon (IFN)-α and ribavirin [5]. This treatment fails to eradicate infection in 50%–60% of patients infected with HCV genotype 1 and approximately 20% of those infected with HCV genotypes 2 and 3 [6], [7], [8]. Thus the need for more efficacious therapies is urgent, especially for patients infected with HCV genotype 1. A number of novel antiviral molecules currently are in preclinical or clinical development [9]. The most advanced ones are specific inhibitors of viral enzymes and functions involved in the HCV life cycle. Molecules that have reached clinical development include inhibitors of the nonstructural (NS) 3/4A serine protease and inhibitors of HCV replication that belong to different categories: nucleoside/nucleotide analogue and non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase (RdRp), NS5A inhibitors and cyclophilin inhibitors [9]. These agents have shown potent antiviral efficacy when used alone, and encouraging results have been recently published showing that HCV clearance can be achieved in approximately 70% of cases when a potent NS3/4A inhibitor is used in combination with pegylated IFN-α and ribavirin [10], [11], [12].<br /><br /><br />HCV genotype 1 is generally considered as a homogeneous group. There are however biological differences between the different subtypes of HCV genotype 1, which are related to differences in their nucleotide and amino acid sequences. Importantly, differences between subtype 1a and 1b (by far the most frequently encountered genotype 1 subtypes in clinical practice) include different efficacies of antiviral drugs and different resistance profiles to such drugs. Indeed, several HCV inhibitors appear to have selective activity against different HCV genotype 1 subtypes, both in vitro and in vivo. Differences have been observed in vitro with NS3/4A protease inhibitors, non-nucleoside inhibitors of HCV RdRp and NS5A inhibitors [13], [14], [15], [16], [17]. For instance, BILB 1941, a non-nucleoside inhibitor of HCV RdRp, has been shown to have better antiviral efficacy in patients infected with HCV subtype 1b than in those infected with HCV subtype 1a, a finding reflecting in vitro experiments [13].<br /><br /><br />A major issue that limits the efficacy of direct acting antiviral therapies for HCV is the selection by these drugs of resistant variants upon administration [18]. Recent studies with NS3/4A protease inhibitors have shown that the genetic barrier and resistance profiles substantially differ between the different genotype 1 subtypes. For instance, the Arg to Lys substitution at position 155 of the NS3 protease (R155K) is usually selected in subtype 1a replicons treated with telaprevir, but not in subtype 1b replicons [19]. The reason is that only one nucleotide substitution is needed relative to the subtype 1a sequence to generate this variant, whereas two substitutions are needed relative to the 1b sequence (codon usage bias). Overall, natural polymorphisms at positions R155 and V36 are frequent in subtype 1a, but rare in subtype 1b where substitutions at position A156 are preferentially selected in vitro [19]. This is reflected in vivo by the different resistance profiles in patients infected by HCV subtypes 1a and 1b. In the former, the V36 and R155 substitutions represent the backbone of resistance, whereas in the latter resistance is less frequent as it is preferentially associated with substitutions at position A156 that are associated with a decreased fitness of the variants [19], [20], [21]. Similarly, important differences in the resistance profiles have been described in vitro with HCV-796, a non-nucleoside inhibitor of HCV RdRp. The C316Y amino acid substitution has been reported to be selected in both subtype 1a and 1b replicon cells. However, in genotype 1a replicons, the C316Y substitution has low replication capacity that must be compensated for by additional “compensatory” substitutions, including L392F or M414T, resulting in an increase in replication levels of at least 10-fold [19]. A higher genetic barrier to resistance to HCV-796 and related compounds is therefore expected in patients infected with HCV subtype 1a than 1b. In vivo, HCV-796 monotherapy was however shown to select subtype 1a variants with a single C316Y substitution, whereas the C316Y substitution was associated with a number of additional substitutions in subtype 1b patients [22].<br /><br /><br />As a result of these findings, correct identification of HCV subtypes 1a and 1b is crucial in clinical trials assessing new HCV drugs in order to correctly stratify and interpret efficacy and resistance data. It may also become important in future clinical practice, as tailoring treatment schedules with HCV inhibitors to HCV genotype 1 subtype might become necessary. A variety of molecular methods can be used to identify the HCV genotype and subtype both in clinical trials and practice. Commercial assays have been developed, most of them targeting the 5′ noncoding region (5′NCR) of the HCV genome, although this region is the most conserved one. These methods have been shown to differentiate well the different HCV genotypes (1 to 6), except genotype 1 from genotype 6, a rare HCV genotype in the Western world [23], [24]. The goal of our study was to assess the ability of molecular methods targeting the 5′NCR to correctly identify the HCV genotype 1 subtype in patients eligible for clinical trials, and to identify the best method for this purpose.<br /><br />Results <br /><br />Hepatitis C Virus Genotype and Subtype Determination by Phylogenetic Analysis of a Portion of the NS5B Gene<br /><br /><br />Direct sequence analysis of a sufficiently long portion of the NS5B gene followed by phylogenetic analysis is the reference method for identification of HCV genotype and subtype [1], [25]. It was used to identify the HCV genotype and subtype in 516 treatment-naïve patients included in a multicenter clinical trial assessing different schedules of pegylated IFN-α2a and ribavirin [26]. All of these patients were thought to be infected with HCV genotype 1 at inclusion based on local assessment. In fact, 6 patients were infected with genotype 6, including 2 with subtype 6e, one with subtype 6o, one with subtype 6p, one with subtype 6q and one with subtype 6r. These 6 samples were not considered for further analysis in the present study. The remaining 510 patients were confirmed to be infected with HCV genotype 1: 237 of them (46.5%) were infected with HCV subtype 1a and 263 (51.6%) with subtype 1b (Figure 1). As shown in Figure 1, HCV subtype 1a strains segregated into two distinct clades, that were termed 1a clade I (n = 83, 35.0%) and 1a clade II (n = 154, 65.0%). Eight patients (1.6%) were infected with another HCV genotype 1 subtype, including 4 patients with subtype 1d, 2 with subtype 1e, one with subtype 1i, and one with subtype 1l. The remaining 2 patients (0.3%) were infected with genotype 1 but the subtype could not be determined. The ability of the different molecular methods to correctly identify HCV subtypes 1a and 1b was then tested on the 237 and 263 samples containing HCV subtypes 1a and 1b, respectively.<br /><br />INNO-LiPA HCV 2.0 displays the same 5′NCR oligonucleotide probes as INNO-LiPA HCV 1.0, plus core-encoded oligonucleotide probes aimed at better discriminating between HCV subtypes 1a and 1b. With INNO-LiPA HCV 2.0, subtype identification was corrected in 64 of the 70 subtypes 1a that were incorrectly typed with INNO-LiPA HCV 1.0. Five samples could not be PCR-amplified in the core-coding region and the result was not interpretable with INNO-LiPA HCV 2.0 in the remaining case (Table 1). INNO-LiPA HCV 2.0 also corrected subtype identification in 13 of 23 subtypes 1b that were incorrectly typed with INNO-LiPA HCV 1.0. Eight samples could not be PCR-amplified in the core-coding region and the result was not interpretable with INNO-LiPA HCV 2.0 in the remaining two cases (Table 1). Overall, the second-generation line probe assay correctly classified 97.5% of subtype 1a and 96.2% of subtype 1b strains. When only samples that could be PCR-amplified with the assay procedure were taken into account, correct subtype determination was achieved in 99.6% and 99.2% of cases, respectively (Table 1).<br /><br /><br />The real-time PCR-based assay targeting both the 5′NCR and the NS5B region, Abbott RealTime HCV Genotype II assay, correctly identified 93.2% of subtype 1a and 88.9% of subtype 1b strains. Only 2 HCV subtype 1b samples could not be PCR-amplified with this method (Table 1).<br /><br />5′NCR Sequence Analysis in Misclassified Subtype 1a Strains<br /><br /><br />Among the HCV subtype 1a strains, 47 were misclassified as subtype 1b by Trugene HCV Genotyping Kit and/or INNO-LiPA HCV 1.0, including 33 that were misclassified by both assays, 7 that were misclassified by Trugene HCV Genotyping Kit only, and 7 that were misclassified by INNO-LiPA HCV 1.0 only (Table 2). Figure 2 shows an alignment of their 5′NCR sequences relative to the consensus sequences of the correctly classified strains (including subtype 1a clade I, subtype 1a clade II and subtype 1b). As shown in Figure 2, misclassification of subtype 1a strains into subtype 1b in one or both assays was related to the presence of natural polymorphisms at nucleotide positions 204 and 243, both of which are located within the sequence of an INNO-LiPA HCV 1.0 probe. At position 243, A is the most frequent nucleotide in HCV subtype 1a, in both subtype 1a clade I and clade II. Substitution into a G, the most frequent nucleotide at position 243 in subtype 1b, was found in all cases that were misclassified as subtype 1b by Trugene HCV Genotyping Kit and/or INNO-LiPA HCV 1.0 (Figure 2). At position 204, A is the most frequent nucleotide for subtype 1a clade I, whereas C is the most frequent nucleotide for subtype 1a clade II, and C or T are the most frequent nucleotides for subtype 1b. In spite of the presence of a G at position 243, the presence of an A at position 204 allowed correct identification of subtype 1a with Trugene HCV Genotyping Kit but not with INNO-LiPA HCV 1.0 (Figure 2). The usual presence of a C at position 204 in subtype 1a clade II explains why misclassifications were far more frequent with this clade than with subtype 1a clade I.<br /><br />Among the 12 subtype 1a strains that were classified as genotype 1, indeterminate subtype with Trugene HCV Genotyping Kit, one had a G and 5 had mixed A and G populations at position 243. Two additional patients with an A at position 243 had a C at position 248. In the remaining 4 cases, no explanation was found in the 5′NCR sequence for the failure to identify the HCV subtype (data not shown). Among the 25 subtype 1a strains that were classified as genotype 1, indeterminate subtype with INNO-LiPA HCV 1.0 (including 6 with the same profile in Trugene HCV Genotyping Kit), 4 had a G and 4 had mixed A and G populations at position 243. Three additional patients with an A at position 243 had a C at position 248 (C only in two of them, a mixture of C and T in one). In the 14 remaining cases, no explanation was found in the 5′NCR sequence for the failure to identify the HCV subtype (data not shown).<br /><br />5′NCR Sequence Analysis in Misclassified Subtype 1b Strains<br /><br /><br />Among HCV subtype 1b strains, 8 were misclassified as subtype 1a by Trugene HCV Genotyping Kit and/or INNO-LiPA HCV 1.0, including 3 that were misclassified by both assays, 4 that were misclassified by Trugene HCV Genotyping Kit only, and 1 that was misclassified by INNO-LiPA HCV 1.0 only (Table 2). Figure 3 shows an alignment of their 5′NCR sequences relative to the consensus sequences of the correctly classified subtype 1a and subtype 1b strains. As shown in Figure 3, and as for misclassified subtype 1a strains discussed above, misclassification of subtype 1b strains into subtype 1a was related to the presence of natural polymorphisms at positions 204 and 243. At position 243, G is the most frequent nucleotide in HCV subtype 1b. Substitution into an A, the most frequent nucleotide at position 243 in subtype 1a, was found in all cases that were misclassified as subtype 1a by both Trugene HCV Genotyping Kit and INNO-LiPA HCV 1.0 and by INNO-LiPA HCV 1.0 only, but not in those that were misclassified by Trugene HCV Genotyping Kit only (Figure 3). In the latter, it is the presence of an A at position 204 instead of a C or a T that was responsible for misclassification in all but one case (Figure 3).<br /><br />Among the 11 subtype 1b strains that were classified as genotype 1, indeterminate subtype with Trugene HCV Genotyping Kit, one had an A at position 243. In the remaining cases, no explanation was found in the 5′NCR sequence for the failure to identify the HCV subtype (data not shown). Among the 15 subtype 1b strains that were classified as genotype 1, indeterminate subtype with INNO-LiPA HCV 1.0 (none of which were classified as indeterminate in Trugene HCV Genotyping Kit), one had an A and one harbored mixed A and G populations at position 243. Both of them had a C at position 248 (C only in one of them and a mixture of C and T in the other one). In the remaining 13 cases, no explanation was found in the 5′NCR sequence for the failure to identify the HCV subtype (data not shown).<br /><br />Incorrect Subtyping with Abbott RealTime HCV Genotype II Assay, that Targets Both the 5′NCR and NS5B Region<br /><br /><br />Among the HCV subtype 1a strains, 16 were incorrectly classified by Abbott RealTime HCV Genotype II assay (Table 1): 2 were misclassified as subtype 1b, 12 were classified as genotype 1, indeterminate subtype, one was identified as a mixed 1a/1b infection, and one gave an indeterminate result. In one case, PCR amplification failed, and in one case, not enough serum volume was available for testing.<br /><br /><br />Among the HCV subtype 1b strains, 27 were incorrectly classified by Abbott RealTime HCV Genotype II assay (Table 1): 3 were misclassified as subtype 1a, 18 were classified as genotype 1, indeterminate subtype, 5 were identified as a mixed 1a/1b infection, and one gave an indeterminate result. In 2 cases, PCR amplification failed, and in one case, not enough serum volume was available for testing.Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com5tag:blogger.com,1999:blog-3205772196563366012.post-16762597487237550762010-09-27T16:15:00.001-04:002010-09-27T16:15:27.996-04:00Pegasys Patient Assistance ProgramPegasys Patient Assistance Program<br /><br />has generous provisions for patients who want to start HCV therapy with Pegasys and are uninsured. Since Roche & Genentech merged the Genentech Access Solutions P rogram took over this program starting Sept 1 2010 and as I say it is a generous transparent program. <br /><br />http://www.pegasysaccesssolutions.com<br /><br />866 422-2377Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-31103088841445975572010-09-27T16:14:00.001-04:002010-09-27T16:14:59.114-04:00Healthcare-Associated Infections (HAIs)I've reached out to you in the past about Kimberly-Clark's efforts to lead the fight against Healthcare-Associated Infections (HAIs). I wanted to follow up with some very exciting news. Kimberly-Clark has launched a new online program - the HAI WATCHDOG* Community - where healthcare providers can discuss best practices for defeating HAIs. The goal is to help eliminate these often preventable infections through discussion and education.<br /><br />The HAI WATCHDOG* Community allows members to start discussions, post photos, videos and even enter the 2010 HAI WATCHDOG* Awards. Entering the awards program not only allows healthcare providers to share and learn from each other, but also gives contest participants the opportunity to be rewarded for their efforts with an educational grant.<br /><br />I would love for you to join the community and share this news with the readers of HCV Awareness. I've created a microsite which explains everything:<br /><br />http://haiwatchnews.com<br /><br />If you are able to post about this, I'd love to get the link to your post. Please let me know if you have any questions or need more information.<br /><br />Thank you,<br /><br />Barbara<br /><br />--<br />Barbara Dunn<br />barbara@haiwatchnews.com<br />haiwatch.com<br />haiwatchdog.comScott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-23178122914178403392010-09-27T16:12:00.001-04:002010-09-27T16:12:40.858-04:009-9-10 NYC Hep B & C Advocacy Committee Meeting Highlights9-9-10 NYC Hep B & C Advocacy Committee Meeting Highlights<br />Tuesday, September 14, 2010 5:40 PM<br />From:<br />"Nirah Johnson" <njohnso2@health.nyc.gov><br />View contact details<br />To:<br />undisclosed-recipients<br />Message contains attachments<br />2 Files (8KB) | Download All<br /><br /> * image002.jpgimage002.jpg<br /> * image001.jpgimage001.jpg<br /><br />NYC Hepatitis B & C Advocacy Meeting Highlights<br /><br />September 9th 2010 (10 AM-12) - New York Organ Donor Network: 460 West 34th Street , 15th Floor, New York , NY 10001<br /><br />NYC Hepatitis B & C Advocacy Committee Website<br /><br />Next Meeting: October 21st!<br /><br /> <br /><br />In attendance: see below<br /><br /> <br /><br />Meeting Highlights<br /><br /> * Hepatitis B & C Advocacy Committee Strategic Plan Development Discussion<br /><br />· Wish list<br /><br />o A Community Health Center (FQHC) Comprehensive Hepatitis B & C Program in each borough<br /><br />o NYC DOHMH to provide:<br /><br />§ HBV testing at public health clinics (STD or Immunization)<br /><br />§ Full panel of HBV Tests<br /><br />§ HCV PCR (Confirmatory) Testing<br /><br />o Hepatitis B & C Health Educator Certification<br /><br />o Hepatitis B & C Testing Protocol Package<br /><br />§ Pre & Post Test Counseling Certification<br /><br />§ Referral process protocol<br /><br />o Methadone Clinics, Detox Centers : Enhanced Hepatitis B & C, testing, treatment services and supportive services (case management)<br /><br />o Corrections: Rikers - Enhanced Hepatitis B & C, testing, treatment services and supportive services (case management/discharge planning)<br /><br />o Faith Based Organizations: Integration of Hepatitis B & C into Health Education<br /><br />o 1 minute Hepatitis B & C Public Service Announcement for the General Public. Translated into major languages.<br /><br />o Hepatitis B Patient Advocate cohort who are willing to speak publicly about their experience<br /><br />o HBV Anti-stigma campaign<br /><br /> <br /><br /> * Planning for October 19th Viral Hepatitis Awareness City Council Legislative Breakfast<br /><br />· Advocacy committee members and team leaders will call their Council person and invite to event (not yet – official invites have not gone out)<br /><br />Hepatitis B & C Community Partners,<br /><br />Please register a representative from your organization for this exciting awareness event!<br /><br /> <br /><br />NYC Hepatitis B & C Awareness Breakfast<br /><br />Sponsored by<br /><br />NYC City Council Members<br /><br />Maria del Carmen Arroyo, Margaret Chin & Peter Koo<br /><br />Organized by<br /><br />NYC Hepatitis B Coalition & NYC Hepatitis C Task Force<br /><br />NYC Department of Health & Mental Hygiene - Office of Viral Hepatitis Coordination<br /><br />Tuesday October 19th<br /><br />9 – 10:30 AM<br /><br />Albella - 10 Reade Street, NY 10007 - www.albellanyc.com - map<br /><br />Breakfast buffet will be served<br /><br />Program:<br /><br /> * Introduction by NYC Council<br /> * Information about Hepatitis B & C and how these life threatening chronic diseases impact NYC<br /> * Testimonials by NYC residents affected by Hepatitis B & C<br /> * Networking with NYC residents, community organizations representing the Hepatitis B & C populations and NYC Council Members<br /><br />Please join us in representing the NYC Viral Hepatitis Community by designating one representative from your organization to attend the event! RSVP to: njohnso2@health.nyc.gov as soon as possible.<br /><br /> <br /><br />Updates<br /><br /> * Victory! NY Congressman Charles Rangel signed on to Viral Hepatitis and Liver Cancer Control & Prevention Act (H.R. 3974)! Congratulations NYC Hepatitis B & C Advocacy Committee for your hard work!<br /> * Kerry Introduces Bill to Fight Viral Hepatitis – Senate<br /><br /> o Disrupting a deadly disease - Hepatitis defense can save thousands of lives a year. By Sen. John Kerry and Rep. Michael M. Honda. The Washington Times<br /><br /> <br /><br />In Attendance<br /><br /> * Benjamin Vines, Health Educator – AIDS Service Center of NY<br /> * Daniel Raymond, National Policy Director – Harm Reduction Coalition<br /> * Dara Hunt, Advocate<br /> * Eric Rude, Director Office of Viral Hepatitis Coordination DOHMH<br /> * Fred Wright – VOCAL<br /> * Jacqueline Aguilar Taylor – Bilingual Health Educator, Coney Island<br /> * Joseph Prioleau, Health Educator – AIDS Service Center of NY<br /> * Justina Wu, NYU B FREE CEED<br /> * Kevin Lo - Charles B Wang Community Health Center<br /> * Michael Carden, Project Director – Center for the Study of Hepatitis C<br /> * Nirah Johnson – DOHMH<br /> * Ronni Marks, HCV Support Group Leader & Advocate<br /><br /> <br /><br />**********************************************************************<br />The New York City Department of Health & Mental Hygiene is now offering information important for the health of all New Yorkers. To sign up for these new and valuable updates, log-on to our website at http://www.nyc.gov/health/email and select the NYC DOHMH updates you'd like to receive.<br />IMPORTANT NOTICE: This email is meant only for the use of the intended recipient. It may contain confidential information that is legally privileged or otherwise protected by law. If you have received this communication in error, please notify me immediately by replying to this message and please delete it from your computer. Thank you for your cooperation.Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com2tag:blogger.com,1999:blog-3205772196563366012.post-81767683603570498302010-09-27T16:11:00.001-04:002010-09-27T16:11:37.952-04:00NYC Hepatitis B & C Awareness BreakfastHepatitis B & C Community Partners,<br /><br /> <br /><br />Please register a representative from your organization for this exciting awareness event!<br /><br /> <br /><br /> <br /><br />NYC Hepatitis B & C Awareness Breakfast<br /><br />Sponsored by<br /><br />NYC City Council Members<br /><br />Maria del Carmen Arroyo, Margaret Chin & Peter Koo<br /><br />Organized by<br /><br />NYC Hepatitis B Coalition & NYC Hepatitis C Task Force<br /><br />NYC Department of Health & Mental Hygiene - Office of Viral Hepatitis Coordination<br /><br />Tuesday October 19th<br /><br />9 – 10:30 AM<br /><br />Albella - 10 Reade Street, NY 10007 - www.albellanyc.com - map<br /><br />Breakfast buffet will be served<br /><br />Program:<br /><br /> * Introduction by NYC Council<br /> * Information about Hepatitis B & C and how these life threatening chronic diseases impact NYC<br /> * Testimonials by NYC residents affected by Hepatitis B & C<br /> * Networking with NYC residents, community organizations representing the Hepatitis B & C populations and NYC Council Members<br /><br />Please join us in representing the NYC Viral Hepatitis Community by designating one representative from your organization to attend the event! RSVP to: njohnso2@health.nyc.gov as soon as possible.<br /><br /> <br /><br />**********************************************************************<br />The New York City Department of Health & Mental Hygiene is now offering information important for the health of all New Yorkers. To sign up for these new and valuable updates, log-on to our website at http://www.nyc.gov/health/email and select the NYC DOHMH updates you'd like to receive.<br />IMPORTANT NOTICE: This email is meant only for the use of the intended recipient. It may contain confidential information thaScott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-67245307366399353922010-09-27T16:10:00.001-04:002010-09-27T16:10:44.654-04:00Guidance for Industry Chronic Hepatitis C Virus Infection: Developing Direct- Acting Antiviral Agents for Treatment DRAFT GUIDANCEGuidance for Industry<br />Chronic Hepatitis C Virus<br />Infection: Developing Direct-<br />Acting Antiviral Agents for<br />Treatment<br />DRAFT GUIDANCE<br />This guidance document is being distributed for comment purposes only.<br />Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.<br />For questions regarding this draft document contact Jeffrey Murray at (301) 796-1500.<br />U.S. Department of Health and Human Services<br />Food and Drug Administration<br />Center for Drug Evaluation and Research (CDER)<br />September 2010<br />Clinical Antimicrobial<br />I:\9216dft.doc<br />08/31/10<br />Guidance for Industry<br />Chronic Hepatitis C Virus<br />Infection: Developing Direct-<br />Acting Antiviral Agents for<br />Treatment<br />Additional copies are available from:<br />Office of Communications, Division of Drug Information<br />Center for Drug Evaluation and Research<br />Food and Drug Administration<br />10903 New Hampshire Ave., Bldg. 51, rm. 2201<br />Silver Spring, MD 20993-0002<br />Tel: 301-796-3400; Fax: 301-847-8714; E-mail: druginfo@fda.hhs.gov<br />http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm<br />U.S. Department of Health and Human Services<br />Food and Drug Administration<br />Center for Drug Evaluation and Research (CDER)<br />September 2010<br />Clinical Antimicrobial<br />TABLE OF CONTENTS<br />I.<br />INTRODUCTION<br />.............................................................................................................<br />1<br />II.<br />BACKGROUND<br />...............................................................................................................<br />2<br />III.<br />DEVELOPMENT PROGRAM<br />.......................................................................................<br />4<br />A.<br />General Considerations<br />.................................................................................................................<br />4<br />1.<br />Pharmacology/Toxicology Development Considerations<br />................................................................<br />4<br />2.<br />Nonclinical Virology Development Considerations<br />.........................................................................<br />5<br />a.<br />Mechanism of action<br />.................................................................................................................<br />5<br />b. Antiviral activity in cell culture<br />................................................................................................<br />5<br />c.<br />Resistance and cross-resistance<br />.................................................................................................<br />6<br />d. Combination antiviral activity<br />..................................................................................................<br />6<br />e.<br />Activity in animal models<br />.........................................................................................................<br />6<br />3.<br />Drug Development Population<br />.........................................................................................................<br />7<br />4.<br />Early Phase Clinical Development Considerations<br />.........................................................................<br />7<br />a.<br />First-in-human trials<br />..................................................................................................................<br />7<br />b. Phase 1b (proof-of-concept) trials<br />.............................................................................................<br />8<br />c.<br />Phase 2 trials and dose-finding<br />..................................................................................................<br />8<br />d. Combination therapy with multiple DAAs<br />.............................................................................<br />10<br />e.<br />Other phase 2 trial design considerations<br />................................................................................<br />11<br />5.<br />Efficacy Considerations<br />.................................................................................................................<br />11<br />6.<br />Safety Considerations<br />.....................................................................................................................<br />12<br />B.<br />Specific Efficacy Trial Design Considerations<br />...........................................................................<br />13<br />1.<br />Trial Design<br />...................................................................................................................................<br />13<br />2.<br />Trial Population<br />.............................................................................................................................<br />14<br />a.<br />Patient enrollment definition<br />...................................................................................................<br />14<br />b. Patient enrollment biopsy considerations<br />................................................................................<br />15<br />3.<br />Randomization, Stratification, and Blinding<br />..................................................................................<br />15<br />4.<br />Efficacy Endpoints<br />..........................................................................................................................<br />16<br />5.<br />Trial Procedures and Timing of Assessments<br />................................................................................<br />16<br />6.<br />Statistical Considerations<br />...............................................................................................................<br />16<br />a.<br />Analysis populations<br />...............................................................................................................<br />16<br />b. Efficacy analyses<br />.....................................................................................................................<br />16<br />c.<br />Handling of missing data<br />.........................................................................................................<br />17<br />d. Interim analyses and data monitoring committees<br />..................................................................<br />18<br />e.<br />Statistical analysis plan<br />...........................................................................................................<br />19<br />C.<br />Other Considerations<br />...................................................................................................................<br />19<br />1.<br />Clinical Virology Considerations<br />...................................................................................................<br />19<br />2.<br />PK/PD Considerations<br />...................................................................................................................<br />20<br />3.<br />Special Populations<br />........................................................................................................................<br />21<br />a.<br />Hepatic impairment<br />.................................................................................................................<br />21<br />b. HIV/HCV co-infected patients<br />................................................................................................<br />21<br />c.<br />Patients with decompensated cirrhosis<br />....................................................................................<br />22<br />d. Pediatric populations<br />...............................................................................................................<br />23<br />4.<br />Early Access/Treatment INDs<br />........................................................................................................<br />23<br />GLOSSARY OF ACRONYMS<br />.................................................................................................<br />25<br />REFERENCES<br />............................................................................................................................<br />26<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />1 Guidance for Industry1<br />2 Chronic Hepatitis C Virus Infection: Developing Direct3 Acting Antiviral Agents for Treatment<br />4<br />5<br />6<br />7<br />8<br />This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) 9<br />current thinking on this topic. It does not create or confer any rights for or on any person and 10<br />does not operate to bind FDA or the public. You can use an alternative approach if the approach 11<br />satisfies the requirements of the applicable statutes and regulations. If you want to discuss an 12<br />alternative approach, contact the FDA staff responsible for implementing this guidance. If you 13<br />cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of 14<br />this guidance. 15<br />16 17 18 19 I. INTRODUCTION 20 21 This guidance provides recommendations for the development of direct-acting antiviral 22 agents (DAAs) regulated within the Center for Drug Evaluation and Research at the Food 23 and Drug Administration (FDA) for the treatment of chronic hepatitis C (CHC) infection. 24 For the purpose of this guidance, we define direct-acting hepatitis C virus (HCV) 25 antivirals as agents that interfere with specific steps in the HCV replication cycle through 26 a direct interaction with the HCV polyprotein and its cleavage products. This guidance is 27 intended to serve as a focus for continued discussions among the review divisions, 28 pharmaceutical sponsors, the academic community, and the public.2 The organization of 29 the guidance parallels the development plan for a particular drug or biologic.3 30 31 This guidance does not address the development of immune-based agents for the 32 treatment of HCV infection such as new interferon products. Therapeutics without 33 antiviral mechanisms intended to mitigate or reverse clinical or pathophysiological 34 outcomes of CHC, such as prevention of hepatocellular carcinoma (HCC), reversal of 35 fibrosis, or treatment of acute hepatitis C, are not addressed in this guidance. 36<br />1 This guidance has been prepared by the Division of Antiviral Products in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.<br />2 In addition to consulting guidance documents, sponsors are encouraged to contact the division to discuss specific issues that arise during the development of DAAs.<br />3 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological products unless otherwise specified.<br />1<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />37 Additionally, general issues of clinical trial design or statistical analyses for HCV trials 38 are not addressed in this guidance. Those topics are addressed in the ICH guidances for 39 industry E9 Statistical Principles for Clinical Trials and E10 Choice of Control Group 40 and Related Issues in Clinical Trials.4 This guidance also does not contain details 41 regarding nonclinical safety and toxicology studies. Such studies for direct-acting HCV 42 antivirals generally should be conducted in standard animal models as described in the 43 guidance for industry Nonclinical Safety Evaluation of Drug or Biologic Combinations. 44 45 FDA’s guidance documents, including this guidance, do not establish legally enforceable 46 responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and 47 should be viewed only as recommendations, unless specific regulatory or statutory 48 requirements are cited. The use of the word should in Agency guidances means that 49 something is suggested or recommended, but not required. 50 51 52 II. BACKGROUND 53 54 HCV is a small positive-strand RNA virus in the Flaviviridae family. Six viral 55 genotypes, numbered 1 to 6, have been identified; some have been divided into multiple 56 subtypes (e.g., genotype 1 subtypes 1a and 1b). In the United States, genotype 1 is the 57 most common (70 to 90 percent), followed by genotypes 2 and 3. Other genotypes occur 58 uncommonly in the United States, but may predominate in other parts of the world. 59 60 In the United States, HCV infection causes 20 percent of all cases of acute viral hepatitis 61 and 70 to 90 percent of all cases of HCC. Estimates show nearly 3.2 million Americans 62 are chronically infected with HCV. CHC is currently the leading indication in the United 63 States for liver transplantation, and predictive modeling suggests that without effective 64 treatment interventions significant increases in CHC-associated liver morbidity, 65 mortality, and health care costs are likely (Kim 2002). 66 67 Current treatment of CHC typically is a pegylated interferon administered in combination 68 with ribavirin (Peg-Interferon/RBV), often referred to in hepatitis C clinical trials as 69 standard of care (SOC). The goal of treatment is sustained virologic response (SVR), 70 defined as undetectable plasma HCV RNA at week 24 following treatment cessation 71 (SVR24). Total duration of current treatment depends on genotype, with longer 72 treatment durations needed to achieve SVR for genotypes 1 and 4 and shorter treatment 73 durations needed for genotypes 2 and 3. SVR rates in treatment-naive patients receiving 74 Peg-Interferon/RBV typically are in the range of 40 percent to 45 percent for viral 75 genotype 1 and are 70 percent to 80 percent for genotypes 2 and 3 (Ghany, Stradler, et al.<br />4 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.<br />2<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />76 2009).5 SVR rates for blacks and HIV co-infected patients with genotype 1 HCV are in 77 the range of 20 percent to 30 percent (in some studies less than 20 percent), which is 78 substantially lower than rates for whites and patients who are not co-infected. 79 80 On-treatment virologic measurements at early time points can predict the likelihood of 81 SVR and are often used to guide treatment duration. When treating with interferon-based 82 regimens, health care providers generally stop treatment if patients do not have at least a 83 2 log10 drop from baseline in HCV RNA at week 12 or do not have an undetectable HCV 84 RNA by week 24, because not meeting these interim virologic response criteria results in 85 a low likelihood of SVR. Three terms relating to on-treatment responses used in clinical 86 trials include: (1) rapid virologic response (RVR), meaning an undetectable HCV RNA 87 at 4 weeks of treatment; (2) complete early virologic response, meaning an undetectable 88 HCV RNA at week 12 of treatment; and (3) extended RVR, meaning an undetectable 89 HCV RNA at week 4 that persists through week 12. These measurements are sometimes 90 used to guide treatment duration strategies in clinical trials. 91 92 Even among patients who achieve SVR, liver injury may persist and hepatic 93 complications may occur; although the likelihood of hepatic complications appears to be 94 substantially reduced compared to patients who do not achieve SVR. Multiple 95 observational cohorts show correlations between SVR and improvements in clinical 96 outcomes of interest, such as development of HCC, hepatic events, fibrosis, and all-cause 97 mortality (Yoshida, Shiratori, et al. 1999; Yoshida, Arakawa, et al. 2002; Shiratori, Ito, et 98 al. 2005; Okanoue, Itoh, et al. 1999; Imai, Kawata, et al. 1998; Arase, Ikeda, et al. 2007; 99 Veldt, Heathcote, et al. 2007, Braks, Ganne-Carrie, et al. 2007; Bruno, Stroffolini, et al. 100 2007; Manos, Zhao, et al. 2009). Evaluating clinical outcomes from prospective, 101 randomized controlled clinical trials is challenging because of the difficulty of 102 maintaining patients on a randomized arm without intervening therapy for a sufficient 103 duration (many years) to identify late-occurring clinical events such as HCC. 104 105 Pegylated interferons and RBV are difficult to tolerate and have significant adverse event 106 profiles that limit treatment in many patients or result in substantial morbidity. 107 Therefore, new drugs are needed that increase SVR rates when added to current therapy, 108 that shorten the duration of interferon-based regimens, or that replace components of 109 current therapy in patients who cannot tolerate interferon or RBV. New drugs are also 110 needed to construct regimens in patients with decompensated cirrhosis and in patients 111 undergoing liver transplant. 112 113 Host factors, such as genetic polymorphisms, metabolic parameters, and viral factors 114 (i.e., genomic mutations), are being investigated for their roles in predicting response to 115 treatments for CHC. Recently, a genetic polymorphism near the IL-28B gene, encoding 116 interferon-l-3 (IFN-l-3), has been shown in several studies to predict an approximately 117 two-fold change in response to interferon-based treatment regimens in patients of<br />5 See also labeling information for PegIntron and Pegasys at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?CFID=42688251&CFTOKEN=cea143f9 dc49c115-37E6D01E-0AF3-6971-CCAA04EECE6DE6A7.<br />3<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />118 African-American and European ancestries (Ge, Fellay, et al. 2009). At least one test for 119 the IL-28B polymorphism is now available to physicians and for use in clinical protocols. 120 121 122 III. DEVELOPMENT PROGRAM 123 124 A. General Considerations 125 126 1. Pharmacology/Toxicology Development Considerations 127 128 Pharmacology/toxicology development for single direct-acting HCV antivirals should 129 follow existing guidances for drug development.6 130 131 Guidance suggests conducting nonclinical combination studies to support clinical trials 132 for combination drugs.7 However, similar to the approach used for HIV and oncology 133 drugs, we do not recommend that these nonclinical studies be conducted routinely for the 134 following reasons: 135 136 • In clinical practice, DAAs are likely to be used with multiple hepatitis C drugs, 137 including interferon and RBV and other DAAs, in multiple different 138 combinations; it would not be feasible to conduct animal studies for all potentially 139 relevant combinations 140 141 • Given the difficulty of conducting combination toxicologic studies that may 142 require multiple different drugs and multiple dose combinations, we believe that 143 nonclinical studies would be more interpretable and may offer more useful data 144 by looking at individual agents at multiple and higher doses 145 146 • Single- and multiple-dose drug-interaction trials in humans and in vitro metabolic 147 studies can screen for potential pharmacokinetic (PK) drug interactions that may 148 lead to safety issues 149 150 To support clinical trials evaluating 2 or more investigational DAAs for up to 90 days, we 151 recommend a minimum of 3 months repeat-dose nonclinical toxicity studies in a rodent 152 and nonrodent species for each individual agent. Longer term data on individual agents 153 (6-month rodent, 9-month nonrodent) can support longer duration combination clinical 154 trials, depending on the toxicity profile (see ICH M3(R2)). 155 156 Nonclinical combination studies of an investigational antiviral plus approved SOC (e.g., 157 Peg-Interferon/RBV) may not be needed unless data from nonclinical studies of an<br />6 See the ICH guidances for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals and S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.<br />7 See the guidance for industry Nonclinical Safety Evaluation of Drug or Biologic Combinations.<br />4<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />158 investigational antiviral drug suggest a potential for increased or synergistic toxicity with 159 the approved therapeutic agents. 160 161 2. Nonclinical Virology Development Considerations 162 163 DAAs for the treatment of CHC should be tested in cell culture for antiviral activity 164 before submission of an initial investigational new drug application (IND). Information 165 about pre-investigational new drug testing and information regarding appropriate 166 nonclinical assays is available from the FDA.8 Additional recommendations for general 167 antiviral drug development can be found in the guidance for industry Antiviral Product 168 Development — Conducting and Submitting Virology Studies to the Agency. 169 170 a. Mechanism of action 171 172 The mechanism by which a DAA exhibits anti-HCV activity should be investigated in 173 studies that include evaluation of the effect of the agent on relevant stages of the virus life 174 cycle. Mechanism of action investigations should include appropriate controls for 175 assessing the specificity of anti-HCV activity, which may include assessments of activity 176 against HCV proteins that are not targeted by the candidate agent, relevant host proteins, 177 or other viruses. 178 179 b. Antiviral activity in cell culture 180 181 The antiviral activity of a new agent should be characterized in cell culture to identify a 182 target plasma concentration for evaluation in HCV-infected patients. Antiviral activity of 183 candidate agents targeting nonstructural components should be assessed using HCV 184 genotype 1a- and 1b-derived replicon systems, and a 50 percent effective concentration 185 (EC50) determined. Nonclinical studies should include assessments of antiviral activity 186 against the major HCV genotypes and subtypes. Assessments of antiviral activity against 187 replication models using HCV components derived from multiple clinical isolates are 188 also recommended, because antiviral activity can vary for strains within each subtype. If 189 differences in susceptibility are observed for different clinical isolates within the same 190 viral genotype or subtype, additional genotypic and phenotypic characterizations should 191 be conducted to identify genetic polymorphisms that may affect HCV susceptibility to the 192 new agent. 193 194 The antiviral activity of agents that target HCV entry functions can be evaluated using 195 HCV pseudoparticle systems. Assessments of antiviral activity against HCV grown in 196 cell culture are recommended for any anti-HCV agent when appropriate. The cytotoxic 197 effects of the agent should be quantified directly in the cells used for assessing anti-HCV 198 activity, and a 50 percent cytotoxic concentration (CC50) and a therapeutic index should 199 be calculated. Cytotoxicity should also be assessed using various cell lines and primary 200 cells cultured under proliferating and nonproliferating conditions. Sequestration of the<br />8 See the FDA Web site http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approval Applications/InvestigationalNewDrugINDApplication/Overview/ucm077546.htm.<br />5<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />201 agent by serum proteins should also be assessed and a serum-adjusted EC50 value 202 determined. We recommend evaluation of the agent’s antiviral activity at different 203 concentrations of human serum and extrapolation to a 100 percent human serum EC50 204 value. 205 206 c. Resistance and cross-resistance 207 208 The ability of HCV to develop resistance to a DAA when subjected to drug pressure 209 should be examined in appropriate cell culture models. Amino acid or nucleotide 210 substitutions associated with the development of resistance to the candidate agent should 211 be determined and validated by introducing the changes into the HCV genome and 212 determining the conferred fold-shift in susceptibility using appropriate cell culture and/or 213 biochemical assays. Results from these studies should be used to: (1) determine whether 214 the genetic barrier for resistance development is high or low; (2) predict whether the 215 genetic barrier for resistance may vary as a function of concentration of the new agent; 216 (3) reveal potential resistance pathways and the potential for cross-resistance with other 217 anti-HCV agents; and (4) support the agent’s hypothesized mechanism of action. 218 219 Resistance studies should include evaluation of the potential for cross-resistance, both to 220 approved agents and to agents in development, particularly focusing on those in the same 221 drug class. Although the mechanism of action for RBV remains unclear, RBV should be 222 included in assessments of cross-resistance for inhibitors that target the NS5B RNA223 dependent RNA polymerase. 224 225 d. Combination antiviral activity 226 227 Most, if not all, DAAs for HCV will be used to treat CHC in combination with other 228 approved drugs. Early in development, cell culture combination antiviral activity 229 relationships of the new agent and pegylated interferons and the new agent and RBV 230 should be characterized to determine whether the combination antiviral activity is 231 additive, synergistic, or antagonistic. Additional combination antiviral activity studies 232 with other candidate anti-HCV agents should be conducted if future combination therapy 233 with other agents is anticipated. For all combination antiviral activity assessments, 234 sponsors should provide combination index values when the two agents are combined at 235 or near their individual EC50 values, and studies should include controls for cytotoxicity. 236 Combination antiviral activity relationships for HIV and HCV agents with similar 237 mechanisms of action (e.g., nucleoside analogue polymerase/reverse-transcriptase 238 inhibitors, protease inhibitors) should also be assessed before testing combinations of the 239 agents in HIV/HCV co-infected patients. 240 241 e. Activity in animal models 242 243 Demonstration of anti-HCV activity in an animal model is not needed. However, if such 244 studies are conducted and provided in support of an anti-HCV therapy program, reported 245 data should include the HCV genotype/subtype used, time course plots of viral load data<br />6<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />246 for each animal, and an assessment of resistance development that includes monitoring 247 the persistence of resistant virus in the absence of anti-HCV treatment. 248 249 3. Drug Development Population 250 251 Overall drug development programs should include a broad population as appropriate for 252 the characteristics of the antiviral agent. However, a DAA may have differential activity 253 against different HCV genotypes or subtypes; therefore, development can be targeted to a 254 specific genotype (e.g., genotype 1 versus genotype 2 or 3). We recommend including 255 patients diagnosed with compensated cirrhosis in phase 2 and phase 3 trials. Also, we 256 encourage the study of combinations of direct-acting HCV antivirals in patients with the 257 greatest need for new agents, such as patients who cannot tolerate interferon, patients for 258 whom interferon is contraindicated, transplant patients, and patients with decompensated 259 cirrhosis. DAAs can be studied in combination with other DAAs and with or without 260 SOC in HIV co-infected patients as soon as appropriate based on the availability of data. 261 Trials in the above-mentioned subgroups may need to be supported by preliminary data 262 from trials to define safety and pharmacokinetics, such as hepatic impairment trials and 263 drug-drug interaction trials (e.g., antiretrovirals for HIV, immunosuppresants for 264 transplant). 265 266 CHC is a disease that is present worldwide and clinical trials typically are conducted 267 internationally. However, trials should include adequate U.S. patient representation to 268 ensure applicability of trial results to the U.S. population. An adequate representation of 269 males and females, races, ages, and weights is recommended during drug development, 270 especially in phase 3 trials. Because race (e.g., black, Asian) and ethnicity (e.g., Latino) 271 affect response rates to interferon-based regimens, it is important to ensure that there is 272 sufficient diversity in clinical trial demographics to conduct meaningful analyses of such 273 groups. Furthermore, in addition to viral genotypes, host genotypes are emerging as 274 correlates of clinical response to antivirals and may partially explain differences in 275 response rates by race; therefore, collection of patient DNA is an important 276 consideration.9 277 278 4. Early Phase Clinical Development Considerations 279 280 The early clinical evaluation of new DAAs should follow a rational plan to provide 281 sufficient data to establish preliminary safety and activity to support phase 3 trials. 282 283 a. First-in-human trials 284 285 In general, we recommend single- and/or multiple-ascending-dose trials in healthy adult 286 subjects to assess safety and pharmacokinetics for the first-in-human trials. However, 287 single-dose and short multiple-dose PK trials (see below) can also be conducted in HCV288 infected patients, particularly if nonclinical data suggest a drug may be genotoxic or 289 otherwise unacceptable for studies in healthy volunteers.<br />9 See the guidance for industry Pharmacogenomic Data Submissions.<br />7<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />290 291 b. Phase 1b (proof-of-concept) trials 292 293 The first proof-of-concept trial (meaning a trial in HCV-infected patients that 294 demonstrates initial activity as measured by reductions in HCV RNA from baseline 295 levels) should be a repeat-dose, randomized, dose-ranging, monotherapy trial, of 296 approximately 3 days duration, with collection of intensive PK, safety, and HCV RNA 297 decay data. Doses selected for phase 1b should be predicted to provide plasma drug 298 exposures expected to exceed, by several-fold, the protein binding-adjusted, cell culture 299 EC50 value of the agent for the relevant HCV genotype/subtype. Choice of doses should 300 also take into account safety margins identified in animal toxicology studies and in any 301 trials conducted in healthy volunteers. 302 303 Monotherapy exceeding 3 days is not recommended because data indicate resistant virus 304 is rapidly selected during monotherapy dosing with some DAA drug classes. 305 Furthermore, 3 days of monotherapy with a directly targeting anti-HCV agent is usually 306 sufficient for establishing proof of concept and for initial dose exploration. Selection of 307 resistance may limit the future utility of the new agent as well as other agents with similar 308 resistance pathways. In most cases, longer durations of monotherapy with directly 309 targeting anti-HCV agents are not appropriate because of resistance concerns, but can be 310 considered on a case-by-case basis depending on the characteristics of the individual 311 agent. In addition to limiting the duration of monotherapy, we recommend that phase 1 312 trials of initial activity be conducted in patients with CHC who are naïve to previous anti313 CHC therapy (including the agent under investigation), and who have minimal fibrosis 314 and no significant co-morbidities. Following demonstration of safety and antiviral 315 activity in treatment-naïve patients, sponsors can plan additional trials in treatment316 experienced patients. 317 318 Results from proof-of-concept trials can be used to guide dose selection for subsequent 319 phase 2 trials in which DAAs are studied for longer durations as part of a combination 320 regimen. We recommend that sponsors conduct mechanistic modeling of the 321 concentration-viral kinetics and the concentration-safety profile from phase 1 trials to 322 predict the most active and tolerable doses for study in phase 2. The mechanistic viral 323 kinetic model should describe time-dependent changes in HCV infection and the effect of 324 drug concentrations (Neumann, Lam, et al. 1998). The model should also include 325 components to describe virologic breakthrough, relapse, and long-term viral response 326 (e.g., SVR) to inform dose selection and treatment duration. In general, the model should 327 be used to inform dose selection and to reduce the risk of selecting for resistant virus 328 because of subtherapeutic exposure. 329 330 c. Phase 2 trials and dose-finding 331 332 A goal of early phase 2 trials is to begin to characterize the optimal dose and duration of 333 the DAA as part of combination regimens with regard to both activity and safety. 334<br />8<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />335 The most straight-forward design for early phase 2 is a randomized controlled trial of 336 several doses of a DAA added to Peg-Interferon/RBV compared to a standard-of-care 337 regimen (consisting of Peg-Interferon/RBV). In general, trial patients should receive a 338 full course of treatment with the Peg-Interferon/RBV component (24 to 48 weeks 339 depending on early treatment responses); however, the DAA component can be 340 administered for shorter durations (e.g., 12 weeks, depending on results from phase 1b). 341 The dosing duration of the investigational agent in phase 2 trials should be based on 342 scientific and clinical rationale and not limited in duration only because long-term animal 343 toxicology studies have not been completed. 344 345 The U.S.-approved Peg-Interferon/RBV labels for treatment of HCV genotype 1 HCV 346 recommend 48 weeks of therapy; although in practice many clinicians shorten the course 347 for patients who have HCV RNA levels below the limit of detection at week 4 of 348 treatment. At present, the optimal duration of dosing a third drug in combination with 349 Peg-Interferon/RBV is not known and is likely to vary depending on characteristics of the 350 investigational agent and treatment population. Thus, various durations of treatment can 351 be evaluated in clinical trials. However, we generally recommend that phase 2 trials 352 include at least one treatment arm that evaluates 48 weeks of treatment with all 353 components of a regimen unless antiviral activity or safety data support a rationale for 354 shorter durations of the DAA component of the regimen. Evaluating shorter durations of 355 a regimen or a component of the regimen can also be accomplished by incorporating a 356 second randomization to assess treatment duration in those patients who have 357 demonstrated early virologic suppression. For example, one treatment strategy can allow 358 patients who reach undetectable HCV RNA by week 4 (RVR) and maintain undetectable 359 HCV RNA level at week 12 (extended RVR) to be re-randomized to receive a regimen of 360 24 versus 48 weeks in duration. Patients who do not attain extended RVR would receive 361 48 weeks of therapy in this example. 362 363 We recommend that sponsors conduct their first phase 2 combination trials with Peg364 Interferon/RBV in treatment-naïve patients as opposed to starting dose-finding in 365 treatment-experienced patients. Giving suboptimal doses to treatment-experienced 366 patients can further increase emergence of resistance and incomplete virologic response 367 to a DAA in combination with Peg-Interferon/RBV and this could jeopardize future 368 treatment regimens for those individuals. 369 370 Sustained virologic response should be the primary endpoint of the phase 2 trials; 371 however, analyses of 12 weeks of safety and antiviral activity data from the first 372 combination trial with Peg-Interferon/RBV in treatment-naïve patients can be used to 373 design larger phase 2b dose comparison trials to further characterize optimal dosing in 374 broader populations, including both treatment-naïve and treatment-experienced patients. 375 376 To provide the most meaningful comparisons for further development of a DAA, we 377 recommend phase 2 trial designs allow for direct comparisons between treatment arms 378 with respect to dose, strategy, and duration. For example, if two doses are evaluated, 379 both treatment doses should be evaluated for the same duration of therapy. 380<br />9<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />381 Because the presence of an IL-28B genetic polymorphism has been shown to predict 382 substantial treatment response differences among patients receiving Peg-Interferon/RBV, 383 an effort should be made to collect samples for IL-28B testing at baseline to reduce the 384 potential for confounding in trial analyses. For example, in smaller dose-finding trials, 385 treatment arm imbalances in patients with the IL-28B polymorphism can confound 386 interpretation of trial results if sponsors do not consider the potential effect of this 387 predictive marker on treatment outcome. Sponsors should consider stratifying based on 388 IL-28B when DAAs are combined with Peg-Interferon/RBV in phase 2 and phase 3 389 trials. 390 391 d. Combination therapy with multiple DAAs 392 393 We encourage trials of DAAs with and without Peg-Interferon/RBV, depending on the 394 patient population. Trials of combinations of DAAs in patients who cannot tolerate 395 interferon or for whom interferon is contraindicated may address an unmet medical need. 396 Based on HCV replication dynamics in infected patients (Perelson 2009), the error-prone 397 nature of HCV genome replication, and the fact that the activity of a DAA is often 398 reduced by a single amino acid substitution in the drug target, multiple DAAs are needed 399 to suppress all pre-existing and emerging drug resistant variants to achieve SVR. At 400 present it is not known whether regimens that do not include interferon can produce SVR. 401 402 Ideally, agents with different mechanisms of action should be considered for combination 403 use. The information recommended to support combination trials using DAAs without 404 interferon and RBV includes: 405 406 • Combination antiviral activity data from cell culture 407 408 • Resistance and cross-resistance patterns for each agent in the combination 409 410 • Anti-HCV activity data from clinical trials (from short-term monotherapy trials or 411 from dose-finding in combination with Peg-Interferon/RBV) 412 413 • Some human safety data on each agent 414 415 • Justification for proposed doses based on clinical trials or other sources to indicate 416 doses chosen are likely to provide reasonable anti-HCV activity 417 418 • Drug-drug interaction data if the metabolism profiles suggest an interaction 419 potential between agents in the combination regimen 420 421 Some examples of potential designs for initial trials of combinations of DAAs include but 422 are not limited to the following: 423 424 • Randomized, controlled trials that compare short durations (less than 2 weeks) of 425 multiple DAAs in treatment-naïve patients followed by a full course of Peg426 Interferon/RBV either with or without one or more of the DAAs evaluated in the<br />10<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />427 first 2 weeks. An approved Peg-Interferon/RBV regimen can be used as a control 428 arm. 429 430 • Randomized, controlled trials that compare several different dosing combinations 431 of multiple DAAs given for longer durations in treatment-naïve or -experienced 432 patients. This type of design includes frequent HCV RNA monitoring and 433 stopping rules for loss or lack of antiviral response. When enrolling treatment434 naïve patients or treatment-experienced patients who can tolerate interferon and 435 RBV, protocols can specify adding interferon and RBV to the DAA regimen after 436 a specified time point (e.g., 6 weeks) or at any other time if virologic rebound or 437 lack of complete virologic response is determined. 438 439 • A single-arm trial evaluating multiple doses of combination therapy before liver 440 transplant to study the overall antiviral effect before liver transplant and 441 potentially the effect on preventing infection of the transplanted liver. Response 442 rates can be compared to historical controls because transmission of HCV to a 443 transplanted liver in this setting is universal (Gane 2008), such that demonstrating 444 lack of infection in a substantial proportion of allograft recipients is meaningful. 445 446 Sponsors are encouraged to discuss with the FDA proposed development plans for 447 combination therapy of two or more DAAs. 448 449 e. Other phase 2 trial design considerations 450 451 Phase 2 trials can also be used to explore alternative dosing strategies of a DAA in 452 combination with other agents before confirmation of alternative dosing strategies in 453 larger phase 3 trials. Detailed rationale for an alternative dosing strategy should be 454 included with a phase 2 protocol submission. One example of an alternative dosing 455 strategy is a lead-in period with Peg-Interferon/RBV (before initiation of the new agent 456 as part of a three-drug therapy). One arm containing a lead-in period with Peg457 Interferon/RBV can be compared to another arm in which all drugs in the regimen were 458 started simultaneously. In theory, a lead-in strategy may be beneficial before starting a 459 DAA with a low genetic barrier to resistance because Peg-Interferon/RBV may reach a 460 steady-state by the time the new agent is added, reducing the possibility of combining the 461 agent in the setting of subtherapeutic Peg-Interferon/RBV exposures. The effects of 462 variations in dosing of a combination regimen, such as lead-in periods, can be explored in 463 phase 2 and confirmed in phase 3. 464 465 5. Efficacy Considerations 466 467 We recommend that sponsors analyze and provide summaries of SVR outcome data 468 (SVR12 and SVR24) from phase 2 to demonstrate that treatment responses are durable 469 and to allow for sample size calculations for phase 3 trials. 470 471 Sponsors can submit an NDA to gain approval of a drug in a single population, either 472 treatment-naïve or treatment-experienced patients. Such an application should include at<br />11<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />473 least two adequate and well-controlled trials conducted in the proposed population 474 intended for labeling. Alternatively, sponsors can choose to pursue an indication for both 475 treatment-naïve and -experienced patients. In this circumstance, the NDA should contain 476 at least one adequate and well-controlled phase 3 trial in each patient population, with 477 adequate supporting data from phase 2 trials. 478 479 Trial designs for combinations of investigational DAAs without interferon and RBV 480 should include provisions for demonstrating that each component of the combination 481 therapy contributes to the desired effect. Establishing the contribution of each 482 component can be accomplished using factorial designs or modified factorial designs; 483 however, we acknowledge that factorial designs in which patients are randomized to only 484 one new DAA may not be appropriate because of emergence of resistance. As an 485 alternative to factorial designs, sponsors can show a DAA’s contribution toward efficacy 486 of a multiple DAA combination regimen using other types of data. Examples of data 487 supporting contribution of efficacy include but are not limited to the following: 488 489 • Cell culture data showing that DAA combinations slow or prevent the emergence 490 of resistance compared to single agents. 491 492 • Clinical trial data showing the efficacy of each new DAA in combination with 493 interferon and RBV. 494 495 • Comparisons of viral load reductions of short-term monotherapy trials (e.g., 3-day 496 trials) with viral load reductions of combination therapy in the same trial or across 497 other short-term trials. In this example, short-term viral load reductions in 498 patients given combination therapy with two DAAs should be substantially 499 greater than that observed in patients given the single agents. 500 501 • Early phase 2 clinical trial data showing that DAA combinations prevent or 502 reduce emergence of resistance. 503 504 Sponsors should consult 21 CFR 300.50 regarding combining drug products in a single 505 dosage form. 506 507 HCV treatment development plans may be eligible for consideration under 21 CFR part 508 312, subpart E, Drugs Intended to Treat Life-Threatening and Severely-Debilitating 509 Illnesses, fast track,10 or priority review if the specifics of the development plan justify 510 such an approach. 511 512 6. Safety Considerations 513 514 In general, we recommend that initial marketing applications for drugs intended to treat 515 CHC in patients without decompensated cirrhosis contain a safety database of<br />10 See the guidance for industry Fast Track Drug Development Programs — Designation, Development, and Application Review.<br />12<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />516 approximately 1,000 to 1,500 patients exposed to the proposed dose and duration of 517 treatment. However, if significant safety signals emerge during drug development, the 518 safety database may need to be increased or specific safety studies may need to be 519 conducted. 520 521 For an indication in patients with decompensated cirrhosis or in patients who generally 522 have a high risk of morbidity and few if any treatment options, a safety database of 523 approximately 500 patients administered the DAA for the proposed dose and duration 524 may be sufficient for filing an NDA. We encourage sponsors to discuss their proposed 525 safety database before submitting an NDA. On occasion, specific findings in nonclinical 526 or clinical development may indicate the need for a database that is larger or longer in 527 duration to adequately evaluate potential drug toxicity. 528 529 We recommend that sponsors provide controlled and comparative safety data. Safety 530 data from uncontrolled protocols or treatment IND protocols may be useful, but often 531 lack the degree of detailed reporting obtained in controlled clinical trials. Moreover, the 532 assessment of causal relationships between a drug and an adverse event is more difficult 533 when relying on uncontrolled safety data and spontaneously occurring events or events 534 related to concurrent treatment or underlying illness may be attributed to the new drug. 535 536 B. Specific Efficacy Trial Design Considerations 537 538 1. Trial Design 539 540 Until the first DAA is approved, the recommended, and most straight-forward, design for 541 initial registration of a DAA is demonstration of superiority as an add-on to SOC, Peg542 Interferon/RBV, in a blinded comparison to placebo plus SOC. In the future, a 543 superiority design also can include a new drug as part of a four-agent regimen compared 544 to a three-agent regimen. Alternatively, an active-controlled noninferiority trial design 545 could be appropriate, comparing a new DAA plus Peg-Interferon/RBV to another 546 approved DAA (control) plus Peg-Interferon/RBV. The latter design is dependent on the 547 ability to define the contribution of the new active control to the Peg-Interferon/RBV 548 treatment so that a stringent noninferiority margin can be calculated. Sponsors 549 considering a noninferiority trial design should discuss in advance with the FDA 550 justification of the noninferiority margin, trial design, and the data analysis plan.11 551 552 Patients who achieve SVR should be followed for at least 3 years in larger phase 2 or 553 phase 3 trials to: (1) ensure durability of response; (2) determine whether subsequent 554 detection of HCV RNA represents outgrowth of pre-existing virus versus re-infection; 555 and (3) evaluate development of progressive liver disease and/or HCC. Long-term 556 follow-up can be provided as part of a postmarketing commitment following the initial 557 application.<br />11 For more information, see the draft guidance for industry Non-Inferiority Clinical Trials. When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.<br />13<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />558 559 2. Trial Population 560 561 a. Patient enrollment definition 562 563 To be enrolled in a trial, patients should have CHC as documented by being tested: 564 565 • Positive for anti-HCV antibody, HCV RNA, or an HCV genotype at least 6 566 months before screening, and positive for HCV RNA and anti-HCV antibody at 567 the time of screening; or 568 569 • Positive for anti-HCV antibody and HCV RNA at the time of screening with a 570 liver biopsy consistent with chronic HCV infection (or a liver biopsy performed 571 before enrollment with evidence of CHC disease, such as the presence of fibrosis) 572 573 In addition to documentation of CHC, treatment-experienced patients should have 574 complete documentation of prior treatment history (including but not limited to 575 compliance with previous therapy and reasons for discontinuation), because these factors 576 may affect their response to retreatment. For the purpose of trial enrollment, the 577 following definitions are used to define the treatment experience of CHC patients, which 578 are based on previous responses to Peg-Interferon/RBV.12 579 580 • Naïve: received no prior therapy for HCV (including interferon or pegylated 581 interferon monotherapy) 582 583 • Null Responder13: less than 2 log10 reduction in HCV RNA at week 12 of a Peg584 Interferon/RBV 585 586 • Partial Responder: greater than or equal to 2 log10 reduction in HCV RNA at 587 week 12, but not achieving HCV RNA undetectable at end of treatment with a 588 Peg-Interferon/RBV 589 590 • Responder Relapser: HCV RNA undetectable at end of treatment with a 591 pegylated interferon-based regimen, but HCV RNA detectable within 24 weeks of 592 treatment follow-up 593 594 Note that HCV RNA undetectable for previous treatment response should have 595 been based on an assay that was considered sensitive at the time of treatment.<br />12 Patients who previously received interferon monotherapy or nonpegylated interferons plus RBV will be a diminishing proportion presenting for future trials. These patients can be categorized separately.<br />13 Other definitions for null response have been proposed, such as less than 1 log10 IU/mL decline in HCV RNA at week 4 of treatment. However, failure to achieve a greater than 2 log10 IU/mL HCV RNA decline at week 12 has typically been used as a treatment futility criterion and use of a null response definition of viral reduction less than 1 log10 IU/mL at week 4 causes a gap in classification for individuals with a viral load reduction greater than 1 log10 at week 4 but less than 2 log10 reduction at week 12.<br />14<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />596 597 b. Patient enrollment biopsy considerations 598 599 Baseline biopsies can help to establish CHC diagnosis and can be useful for making 600 correlations between the amount of baseline fibrosis and subsequent treatment outcomes 601 such as SVR and occurrence of treatment-related adverse events. Correlations between 602 baseline fibrosis and efficacy or safety outcomes can provide useful information in 603 labeling. Sponsors should have a sufficient number of baseline biopsies throughout drug 604 development to explore correlations between fibrosis and outcomes. We recommend the 605 following regarding enrollment biopsies throughout drug development: 606 607 • For phase 1 trials in CHC patients and early phase 2 trials intended to evaluate 608 pharmacokinetics/pharmacodynamics (PK/PD) or initial efficacy and safety, a 609 liver biopsy may not be needed as long as patients fulfill the criteria for CHC 610 infection as described in the section above. 611 612 • For later phase 2 trials and phase 3 treatment-naïve trials, we recommend biopsies 613 within 2 to 3 years before enrollment. If cirrhosis has been previously 614 demonstrated on a biopsy, then biopsies obtained more than 3 years before 615 enrollment need not be repeated. 616 617 • For later phase 2 and 3 trials in treatment-experienced patients, a biopsy within 2 618 to 3 years may not be needed for trial enrollment; however, documentation of a 619 prior biopsy showing histological evidence of CHC should be available for 620 review. 621 622 • Biopsies can be waived for patients who would be placed at risk from the 623 procedure, such as patients with bleeding disorders. Inability to do a liver biopsy 624 should not exclude patients from a trial. 625 626 Noninvasive measures of hepatic fibrosis and disease activity assessments using 627 biochemical or scanning measurements are not considered validated and should not be a 628 substitute for the histological information yielded by liver biopsy. 629 630 3. Randomization, Stratification, and Blinding 631 632 We encourage sponsors to conduct double-blind trials whenever feasible. For add-on 633 superiority trials of a new DAA plus SOC compared to SOC alone, patients randomized 634 to SOC should receive a matching DAA placebo. It is appreciated that endpoints in these 635 trials are objective, but other aspects of the trial can be influenced by knowledge of 636 treatment assignment. In open-label protocols, patients may be more likely to drop out of 637 the trial if they know they are not receiving the new treatment or investigators could 638 provide different levels of encouragement to continue. 639 640 Sponsors should consider stratification of patients by important baseline factors such as 641 IL-28B polymorphisms, viral load (high or low), HCV genotype/subtype, and cirrhosis,<br />15<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />642 because these baseline factors are predictive of SVR depending on the regimen and 643 population studied. In international trials, patients should be stratified by geographic 644 area. 645 646 4. Efficacy Endpoints 647 648 The primary endpoint for phase 3 studies should be SVR at 24 weeks after completion of 649 a scheduled course of therapy (SVR24). Viral RNA clearance should be measured using 650 a sensitive and specific quantitative assay. Before initiation of clinical trials, sponsors 651 should provide in their development plans the name and performance data for the assay 652 proposed for measuring HCV RNA viral load. 653 654 5. Trial Procedures and Timing of Assessments 655 656 Recommended key time points for measuring viral RNA are at weeks 4, 12, 24, and 48 or 657 at the end of therapy (which may occur at 24 or 48 weeks). Viral measurements at week 658 12 and 24 have been critical for deciding whether a full course of interferon/RBV is 659 justified. Week 4 and 12 measurements can be used in protocol decision making for 660 determining duration of a DAA or a regimen. 661 662 6. Statistical Considerations 663 664 a. Analysis populations 665 666 All patients who are randomized and receive at least one dose of assigned therapy during 667 the trial should be included in the primary efficacy analysis. If a substantial proportion of 668 patients exit the trial after randomization but before receiving treatment or if there is an 669 imbalance between treatment arms in the number of such patients, then sensitivity 670 analyses can be conducted imputing all or a proportion of those who exited as treatment 671 failures. 672 673 b. Efficacy analyses 674 675 The primary analysis endpoint should be SVR24, which measures the presence or 676 absence of viral RNA 24 weeks after completing a protocol-defined treatment course, and 677 this analysis determines whether effectiveness has been demonstrated.14 The primary 678 analysis should be adjusted for at least one or two of the most important covariates (e.g., 679 baseline HCV genotype, screening HCV RNA or IL-28B polymorphism). The covariates 680 that will be included in the primary analysis should be prespecified in the protocol. 681 682 For subgroup analyses, the analysis of SVR24 should be performed within important 683 demographic and baseline characteristics (e.g., geographic region (U.S., non-U.S.), sex, 684 race, age group, HCV genotype, screening serum HCV RNA, IL-28B status, baseline<br />14 Patients who discontinue therapy, for whatever reason, before the protocol-defined treatment duration can still be considered a responder if they have confirmed absence of HCV RNA 24 weeks after the originally planned treatment duration.<br />16<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />685 weight, baseline body mass index, baseline alanine aminotransferase (ALT), baseline 686 liver histology, baseline fibrosis, and prior response to interferon/RBV-based regimens). 687 The purpose of these subgroup analyses basically is to evaluate the consistency of the 688 SVR24 endpoint result across these subgroups. It is important to recognize, however, 689 that simply by chance a hypothetical drug that has a homogeneous overall effect in a trial 690 population will almost invariably show statistically significant effects in some subgroups 691 and not in others in any given trial. Therefore, such subgroup results should be 692 interpreted with caution. 693 694 For meaningful subgroup analyses in treatment-experienced trials there should be 695 adequate representation from null responders, partial responders, and responder relapsers, 696 as appropriate for each drug based on activity observed in phase 2 data (phase 2 data may 697 suggest that it is futile to study certain categories of nonresponders in phase 3). 698 699 Secondary endpoints can include: 700 701 • Normalization of ALT levels 702 703 • The proportion of patients with RVR (undetectable HCV RNA after 4 weeks of 704 treatment) 705 706 • The proportion of patients with complete early virologic response (undetectable 707 HCV RNA after 12 weeks of treatment) 708 709 • The proportion of patients with undetectable levels of HCV RNA at the end of 710 treatment and 12 weeks after the end of treatment 711 712 • Relapse rates at 12 and 24 weeks after the end of treatment 713 714 However, secondary endpoints are not sufficient to support efficacy in the absence of an 715 effect on the primary endpoint. The protocol should propose a multiple testing strategy 716 for secondary endpoints that adjust for multiplicity to be applied after the result for the 717 primary endpoint is significant. 718 719 Patients who stop treatment because they did not completely suppress HCV RNA or had 720 rebound of HCV RNA after complete suppression should be regarded as failures in all 721 analyses. For patients who discontinue treatment early, sponsors should collect 722 information to determine if these patients switched treatments or added additional 723 therapy. This information can be used to understand reasons for discontinuation and how 724 patients will be included in the analysis. 725 726 c. Handling of missing data 727 728 For the primary analysis, sponsors should consider patients not to have achieved an SVR 729 if the patients discontinue from a trial before the end of the scheduled 24 week follow-up<br />17<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />730 period and if the patients have missing HCV RNA values at the end of the scheduled 24 731 week follow-up period. 732 733 Sponsors should make every attempt to limit loss of patients from the trial, and when the 734 loss is unavoidable, to collect information that can help explain the cause of the loss and 735 the final status of the patient. Analyses excluding patients with missing data or other 736 post-treatment outcomes can be biased because patients who do not complete the trial 737 may differ substantially in both measured and unmeasured ways from patients who 738 remain in the trial. 739 740 A range of sensitivity analyses should be performed to demonstrate that the primary 741 analysis is robust to discontinuation and noncompliance. Sensitivity analyses can be 742 performed using various methods for imputing missing post-treatment virologic results at 743 24 weeks of follow-up. Examples include but are not limited to using results from any 744 available last post-treatment week in place of the 24-week follow-up visit or treating a 745 percentage of missing data as successes or failures based on the overall results in which 746 post-treatment data are available. 747 748 We recommend that sponsors collect detailed data on drug-adherence and confirmation 749 of reasons for discontinuation (e.g., opportunity to enter another trial offering a promising 750 new treatment, death or events leading to death, disease progression, adverse events, loss 751 to follow-up, withdrawal of consent, noncompliance, pregnancy, protocol violations, not 752 discontinued or not known to be discontinued but data were missing at the final visit). 753 The underlying reasons for discontinuation should be interpreted. For example, the 754 statistical analysis should include the number of patients who withdrew consent or were 755 lost to follow-up, or who had adverse events (e.g., nausea and diarrhea) that could have 756 been related to the treatment they were taking. 757 758 d. Interim analyses and data monitoring committees 759 760 If interim (or futility) analyses are performed, these analyses should be specified in the 761 statistical analysis plan (SAP). The purpose of the interim analysis should be stated in 762 the SAP. 763 764 The SAP should include provisions that ensure the interim analysis does not compromise 765 trial integrity. Sponsors should refer to ICH E9 when considering the use of interim 766 analyses in clinical trials. 767 768 Sponsors should consider using a data monitoring committee for phase 3 trials evaluating 769 treatments for CHC, particularly if there are potential safety issues with one or more 770 treatment arms. A detailed charter with the composition of the committee members and 771 the operational details should be provided for review.15 772<br />15 See the guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data Monitoring Committees.<br />18<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />773 e. Statistical analysis plan 774 775 Before initiation of any phase 2b trial (larger phase 2 trial intended to be supportive of 776 efficacy for registration) or phase 3 trial, we recommend sponsors provide a detailed 777 SAP. The SAP can be either a separate document or be within the protocol. The SAP 778 should be considered as part of the protocol and ideally should be finalized together with 779 the protocol before patient enrollment. The SAP should have details on endpoint 780 ordering, the analysis population, the structure of statistical hypotheses to be tested, 781 methods and statistical models of analyses including the mathematical formulations, level 782 of significance or alpha-level, alpha adjustments for multiple comparisons and interim 783 analyses, and any planned covariates for the analyses. It is possible to modify an SAP as 784 long as the trial remains blinded, but sponsors should recognize that a detailed discussion 785 may be needed concerning data access and appropriate firewalls for maintaining the 786 integrity of the blind. 787 788 It is important that the SAP prospectively identify the covariates to be used in the 789 analysis. It is also important that the number of covariates be kept to a minimum and 790 limited to those that are expected to strongly influence outcome. 791 792 Center-by-treatment interaction should be investigated and reported to assess consistency 793 of the efficacy results. 794 795 C. Other Considerations 796 797 1. Clinical Virology Considerations 798 799 Proof-of-concept and efficacy trials should assess the development of HCV genotypic 800 resistance to the investigational agent. Resistance testing should be performed for 801 patients who demonstrate virologic breakthrough (defined as a greater than or equal to 1 802 log10 increase in HCV RNA above nadir, or detectable HCV RNA, while on treatment, 803 after an initial drop to below detection), an incomplete antiviral response (e.g., detectable 804 HCV RNA at end of treatment), a slow or plateau viral load decay phase, or virologic 805 relapse after treatment cessation. Any changes, including mixtures, in the amino acid 806 coding sequence of the targeted genome region present in on-treatment or follow-up 807 samples, but not in the baseline sample, should be reported as having developed during 808 therapy. In addition, baseline samples should be analyzed to identify HCV genetic 809 polymorphisms that are associated with differential antiviral activity with the new agent. 810 811 Viral resistance-associated polymorphisms or substitutions observed in clinical trials but 812 not identified and characterized in nonclinical virology experiments should be evaluated 813 phenotypically by introducing the changes into the HCV genome, and determining the 814 conferred fold-shift in susceptibility to the agent using appropriate cell culture and/or 815 biochemical assays. In addition, phenotypic analyses should be performed using baseline 816 and on-treatment clinical isolates from a subset of trial patients representative of the HCV 817 genetic diversity and virologic responses observed in clinical trials. 818<br />19<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />819 Emerging data with new DAAs suggest resistance-associated substitutions may persist 820 for long periods of time in the absence of drug selection. Because DAAs within the same 821 drug class typically have overlapping resistance profiles, the persistence of resistance822 associated substitutions can significantly limit a patient’s future treatment options. 823 Therefore, patients who have detectable resistance-associated substitutions at treatment 824 cessation or follow-up should be followed for an extended period, preferably at least 1 825 year after treatment cessation, to assess the persistence of resistance-associated 826 substitutions. The potential persistence of resistance-associated substitutions should be 827 characterized for patients enrolled in phase 1 and phase 2 clinical trials so that 828 preliminary long-term follow-up data are obtained by the time of completion of phase 3 829 trials. Genotyping methodology should be capable of assessing the quantity of resistant 830 viruses during the outgrowth of wild-type virus. 831 832 Sponsors should consider genotyping regions outside the direct HCV genome target 833 depending on the characteristics of the antiviral agent and interactions of the target with 834 other viral proteins. In cases when resistance is suspected based on viral RNA kinetics, 835 but genotypic evidence of resistance is not detected, sponsors should also consider 836 performing additional genotypic analyses using a method sufficiently sensitive to detect 837 minority variants.16 838 839 2. PK/PD Considerations 840 841 Trials conducted in HCV-infected patients should include assessment of 842 pharmacokinetics and the relationship between exposure and virologic success and 843 toxicity in all patients. 844 845 Sponsors can use a combination of dense and sparse sampling throughout development to 846 characterize the pharmacokinetics of the investigational agent. For example, a dense 847 sampling schedule should be implemented in monotherapy trials. In longer term trials, 848 however, a dense sampling schedule might not be feasible. Alternatively, sparse 849 sampling from these trials can be combined with dense PK data from earlier trials for 850 analysis. Sparse PK samples should be obtained at the time of key virologic assessments, 851 such as weeks 4, 12, 24, and 48. These data can then be subjected to appropriate 852 population PK analysis.17 PK samples for evaluation of Peg-Interferon/RBV or any other 853 agent in the regimen should also be collected in trials of combination therapy to assist in 854 exposure-response analyses. 855 856 Sponsors can use the following two broad approaches to characterize the relationship 857 between exposure and viral kinetics or virologic success of the investigational agent, 858 depending on the stage of development and purpose of the analysis. Both approaches<br />16 Additional guidance for reporting HCV drug resistance can be found in the guidance for industry<br />Antiviral Product Development — Conducting and Submitting Virology Studies to the Agency: Guidance for Submitting HCV Resistance Data.<br />17 See the guidance for industry Population Pharmacokinetics.<br />20<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />859 allow for exploration of relevant covariates. These analyses should also account for the 860 development of resistance to the investigational agent. 861 862 (1) To aid the design of phase 2b or phase 3 trials, with respect to dose and regimen 863 choice, a mechanistic approach relating drug concentrations and viral kinetics is 864 most appropriate. Specifically, sponsors should develop a viral kinetic model that 865 describes time-dependent changes in HCV infection during treatment, includes a 866 mechanistically appropriate targeted drug effect, and, includes components to 867 describe virologic breakthrough, relapse, and long-term viral response. 868 869 (2) When sufficient SVR12 or SVR24 data are available, a simplified analysis 870 relating proportion of patients with virologic success and appropriate exposure 871 variable (e.g., Cmin or area under curve) can be used to support evidence of 872 effectiveness and justify dose selection.18 873 874 3. Special Populations 875 876 Treatments for patients with hepatic impairment or pre- or post-transplant patients, 877 patients co-infected with HIV and HCV, and patients with decompensated cirrhosis are 878 unmet medical needs. We strongly encourage sponsors to discuss early in development 879 the process to determine appropriate timing for initiating trials in these populations. 880 881 a. Hepatic impairment 882 883 A hepatic impairment trial to inform the need for dose modifications should be conducted 884 early in development so that patients with hepatic impairment can be included in phase 2 885 and 3 trials, as appropriate. These data also can support use in pre- or post-transplant 886 patients. 887 888 b. HIV/HCV co-infected patients 889 890 It is estimated that nearly 30 percent of patients with HIV are co-infected with HCV 891 (Sulkowski 2008). Patients with HIV/HCV co-infection are at higher risk of more rapid 892 progression of liver disease than patients with HCV infection alone. In addition, 893 treatment responses (SVR24) with SOC in co-infection are generally less than responses 894 (SVR24) with HCV infection alone. 895 896 As needed, and based on a particular investigational drug’s metabolic profile, drug-drug 897 interaction trials should be conducted before trials in co-infected patients to support 898 concomitant dosing of a new HCV drug and antiretroviral drugs. 899 900 We strongly suggest that an initial NDA for the treatment of HCV contain some clinical 901 data on the HIV/HCV co-infected population at time of filing, including:<br />18 See the guidance for industry Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications.<br />21<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />902 903 • Drug-drug interaction data with the most commonly used HIV drugs 904 905 • Safety data on a cohort of co-infected patients receiving the drug for the 906 recommended treatment duration 907 908 • Preliminary efficacy data characterizing, at minimum, on-treatment responses 909 910 With the above-mentioned preliminary data, labeling describing drug interactions and 911 preliminary safety data may be appropriate. For more extensive labeling that expands the 912 indication to the HIV co-infected population or includes a description of efficacy in the 913 co-infected population, a clinical trial demonstrating efficacy and safety in at least 300 914 co-infected patients may be appropriate. In some cases, single-arm prospective trials 915 (with historical controls) may be appropriate for the co-infected population if trials in the 916 HCV mono-infected population showed robust and substantial efficacy of the new DAA 917 added to SOC. Trials in co-infected patients should evaluate SVR at 24 weeks after end 918 of therapy as the primary efficacy endpoint. As part of the safety evaluation, loss of HIV 919 efficacy (rebounds in HIV viral RNA) should be assessed. 920 921 c. Patients with decompensated cirrhosis 922 923 SOC, interferon-based regimens are not considered appropriate for patients with 924 decompensated cirrhosis or for most patients pre- or post-liver transplant; therefore, 925 treatment with multiple investigational DAAs is likely to be needed to achieve viral 926 suppression. Because there are currently no HCV treatments in patients with 927 decompensated cirrhosis and because spontaneous resolution of HCV infection in this 928 population is consistently negligible, dose-response trials or historically controlled 929 efficacy and safety trials showing clinically significant SVRs may be appropriate to 930 expand the labeling for this population. However, as more drugs become available for 931 study in combination regimens, we will encourage comparative trials. SVR24 should be 932 the primary efficacy endpoint, but other important endpoints include progression of liver 933 disease, transplantation, and mortality. SVR24 is an important endpoint notwithstanding 934 disease progression requiring transplantation, because SVR24 will likely translate into 935 prevention of infection of a newly transplanted liver. 936 937 The contribution of each agent toward overall efficacy of a regimen should be 938 demonstrated, but can be based on data such as that discussed in section III.B.6, 939 Statistical Considerations. For example, trials showing the efficacy of one new DAA 940 added to Peg-Interferon/RBV in patients with compensated cirrhosis can serve as 941 supportive data for demonstrating contribution toward efficacy in other populations that 942 are more difficult to study. 943 944 Plans for expanded access trials or safety trials should also be considered for this 945 population early in development. 946<br />22<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />947 d. Pediatric populations 948 949 Early trials of DAAs should enroll adult patients only, reserving pediatric exposure until 950 the pharmacokinetics, pharmacodynamics, and safety of the agent are reasonably well951 defined. Sponsors are encouraged to begin discussions of their pediatric formulation and 952 clinical development plan early in development, but pediatric clinical trials should be 953 initiated once phase 2 adult data characterizing the safety profile and initial antiviral 954 efficacy are available. If clinical trials in adults have demonstrated no safety concern 955 specific to a histologic stage, liver biopsies are not recommended for routine entry criteria 956 into pediatric trials. If biopsies are done because they are clinically indicated, biopsy data 957 should be provided. 958 959 4. Early Access/Treatment INDs 960 961 Some hepatitis C-infected patients who have not responded to approved treatments and/or 962 who are at substantial risk of liver disease progression may benefit from access to new 963 therapeutic options before their approval. Treatment INDs or other access protocols for 964 DAAs may be appropriate when sufficient clinical trial data have been generated to 965 characterize a reasonably safe and active dose of an investigational agent. Ideally, the 966 timing of a treatment IND would occur after phase 3 trials were fully enrolled or well 967 underway so as not to interfere with phase 3 drug development. Treatment INDs can 968 provide early access while phase 3 trials are being completed, analyzed, submitted, and 969 reviewed by the FDA. Alternatively, individual patient INDs and treatment access 970 protocols for intermediate size populations may be possible. In contrast to treatment 971 INDs for larger populations during or after phase 3 trials, access for intermediate size 972 populations (approximately 100 patients or fewer), can occur earlier in drug 973 development. 974 975 Historically, early access programs with HIV allowed many people to gain access to life976 saving drugs. However, for some individuals, early access to a drug resulted in what 977 amounted to sequential monotherapy and the emergence of multidrug resistance. 978 Because treatment of CHC requires multiple agents to achieve SVR and to reduce the 979 emergence of drug resistance to single agents or drug classes, treatment INDs that include 980 two or more investigational agents or that allow co-enrollment in several treatment IND 981 programs simultaneously are desirable, particularly for previous null responders or for 982 patients who cannot take interferon-based regimens. However, treatment use of multiple 983 investigational agents should be supported by: 984 985 • Data and rationale that characterize the potential for PK drug interactions and 986 potential for overlapping toxicity. Data to support dose modifications if drug 987 interactions are present. 988 989 • Information suggesting the potential for additive or synergistic activity and no or 990 minimal overlapping resistance profiles. 991<br />23<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />992 Refer to section III.A.4.d., Combination therapy with multiple DAAs, for the data needed 993 to support treatment use of multiple investigational agents. 994<br />24<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />995 GLOSSARY OF ACRONYMS 996 997 CHC chronic hepatitis C 998 DAA direct-acting antiviral agent 999 HCC hepatocellular carcinoma 1000 HCV hepatitis C virus 1001 HCV RNA hepatitis C virus ribonucleic acid 1002 HIV human immunodeficiency virus 1003 IFN interferon 1004 IL interleukin 1005 Peg pegylated 1006 RBV ribavirin 1007 RVR rapid virologic response 1008 SOC standard of care 1009 SVR sustained virologic response 1010 SVR24 sustained virologic response 24 weeks after stopping treatment 1011<br />25<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />1012 REFERENCES 1013 1014 Arase, Y, K Ikeda, F Suzuki, Y Suzuki, S Saitoh, M Kobayashi, N Akuta, T Someya, R 1015 Koyama, T Hosaka, H Sezaki, M Kobayashi, H Kumada, 2007, Long-Term Outcome 1016 After Interferon Therapy in Elderly Patients With Chronic Hepatitis C, Intervirology, 1017 50(1):16-23. 1018 1019 Braks, RE, N Ganne-Carrie, H Fontaine, J Paries, V Grando-Lemaire, M Beaugrand, S 1020 Pol, JC Trinchet, 2007, Effect of Sustained Virological Response on Long-Term 1021 Clinical Outcome in 113 Patients With Compensated Hepatitis C-Related Cirrhosis 1022 Treated By Interferon Alpha and Ribavirin, World J Gastroenterol, Nov 14, 1023 13(42):5648-53. 1024 1025 Bruno, S, T Stroffolini, M Colombo, S Bollani, L Benvegnù, G Mazzella, A Ascione, T 1026 Santantonio, F Piccinino, P Andreone, A Mangia, GB Gaeta, M Persico, S Fagiuoli, 1027 PL Almasio; Italian Association of the Study of the Liver Disease (AISF), 2007, 1028 Sustained Virological Response to Interferon-Alpha Is Associated With Improved 1029 Outcome in HCV-Related Cirrhosis: A Retrospective Study, Hepatology, Mar, 1030 45(3):579-87. 1031 1032 Gane, EJ, 2008, The Natural History of Recurrent Hepatitis C and What Influences This, 1033 Liver Transpl., Suppl2: S36-44. 1034 1035 Ge, D, J Fellay, AJ Thompson, JS Simon, KV Shianna, TJ Urban, EL Heinzen, P Qiu, 1036 AH Bertelsen, AJ Muir, M Sulkowski, JG McHutchison, DB Goldstein, 2009, Genetic 1037 Variation in IL-28B Predicts Hepatitis C Treatment-Induced Viral Clearance, Nature, 1038 461:399-401. 1039 1040 Ghany, MG, DB Strader, DL Thomas, LB Seeff, 2009, Diagnosis, Management, and 1041 Treatment of Hepatitis C: An Update, Hepatology, 49:1335-1374. 1042 1043 Imai, Y, S Kawata, S Tamura, I Yabuuchi, S Noda, M Inada, Y Maeda, Y Shirai, T 1044 Fukuzaki, I Kaji, H Ishikawa, Y Matsuda, M Nishikawa, K Seki, Y Matsuzawa, 1998, 1045 Relation of Interferon Therapy and Hepatocellular Carcinoma in Patients With 1046 Chronic Hepatitis C, Osaka Hepatocellular Carcinoma Prevention Study Group, Ann 1047 Intern Med, Jul 15, 129(2):94-9, PMID: 9669992. 1048 1049 Kim, WR, 2002, The Burden of Hepatitis C in the United States, Hepatology, 1050 36(Suppl):S30-S34. 1051 1052 Manos, MM, WK Zhao, VA Shvachko, N Volkova, CP Quesenberry, Viral Hepatitis 1053 Registry, Kaiser Permanente Division of Research, Oakland, CA, 2009, Long Term 1054 Outcomes in Patients Treated With Peg-Interferon/Ribavirin Therapy for Hepatitis C: 1055 The Substantial Effect of Sustained Viral Response (SVR) on Liver Disease, Mortality 1056 and Diabetes, 13th International Symposium on Viral Hepatitis and Liver Disease, 1057 Abstract PL-3.<br />26<br />Contains Nonbinding Recommendations<br />Draft — Not for Implementation<br />1058 Neumann, AU, NP Lam, H Dahari, DR Gretch, TE Wiley, TJ Layden, AS Perelson, 1059 1998, Hepatitis C Viral Dynamics In Vivo and the Antiviral Efficacy of Interferon1060 alpha Therapy, Science, Oct 2, 282(5386):103-7. 1061 1062 Okanoue, T, Y Itoh, M Minami, S Sakamoto, K Yasui, M Sakamoto, K Nishioji, Y 1063 Murakami, K Kashima, 1999, Interferon Therapy Lowers the Rate of Progression to 1064 Hepatocellular Carcinoma in Chronic Hepatitis C but not Significantly in an Advanced 1065 Stage: A Retrospective Study in 1148 Patients, Viral Hepatitis Therapy Study Group, 1066 J Hepatol, Apr, 30(4):653-9, PMID: 10207807. 1067 1068 Perelson, AS, 2009, HCV Kinetics, 13th International Symposium on Viral Hepatitis and 1069 Liver Disease, Washington, DC. 1070 1071 Shiratori, Y, Y Ito, O Yokosuka, F Imazeki, R Nakata, N Tanaka, Y Arakawa, E 1072 Hashimoto, K Hirota, H Yoshida, Y Ohashi, M Omata; Tokyo-Chiba Hepatitis 1073 Research Group, 2005, Antiviral Therapy for Cirrhotic Hepatitis C: Association With 1074 Reduced Hepatocellular Carcinoma Development and Improved Survival, Ann Intern 1075 Med, Jan 18, 142(2):105-14, PMID: 15657158. 1076 1077 Sulkowski, MS, 2008, Viral Hepatitis and HIV Coinfection, J Hepatol, Feb, 48(2):3531078 67. 1079 1080 Veldt, BJ, EJ Heathcote, H Wedemeyer, J Reichen, WP Hofmann, S Zeuzem, MP 1081 Manns, BE Hansen, SW Schalm, HL Janssen, 2007, Sustained Virologic Response 1082 and Clinical Outcomes in Patients With Chronic Hepatitis C and Advanced Fibrosis, 1083 Ann Intern Med, 147:677-684. 1084 1085 Yoshida, H, Y Arakawa, M Sata, S Nishiguchi, M Yano, S Fujiyama, G Yamada, O 1086 Yokosuka, Y Shiratori, M Omata, 2002, Interferon Therapy Prolonged Life 1087 Expectancy Among Chronic Hepatitis C Patients, Gastroenterology, Aug, 123(2):4831088 91. 1089 1090 Yoshida, H, Y Shiratori, M Moriyama, et al., 1999, Interferon Therapy Reduces the Risk 1091 for Hepatocellular Carcinoma: National Surveillance Program of Cirrhotic and 1092 Noncirrhotic Patients With Chronic Hepatitis C in Japan, IHIT Study Group, 1093 Inhibition of Hepatocarcinogenesis by Interferon Therapy, Ann Intern Med, Aug 3, 1094 131(3):174-81. 1095<br />27Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-23666295126267405402010-09-27T16:08:00.001-04:002010-09-27T16:08:45.089-04:00We are delighted to announce that we will be holding a second “Medicine and Me: Hepatitis C” half-day conference in conjunction with the Royal SocietDear Patient Association Member<br /><br /> <br /><br /> We are delighted to announce that we will be holding a second “Medicine and Me: Hepatitis C” half-day conference in conjunction with the Royal Society of Medicine in May 2011 as part of our tenth anniversary celebrations.<br /><br /> <br /><br /> ‘Medicine and Me’ conferences, initiated and developed by the Royal Society of Medicine, are specifically designed to bring together healthcare professionals and patients, their families, carers and advocates to discuss current management and research issues of a particular condition so that each can learn from the other.<br /><br /> <br /><br /> ‘Medicine and Me: Hepatitis C’ aims to provide an interactive forum in which the patient’s voice is given top priority. The meeting provides an opportunity for healthcare professionals to hear first hand from patients and their families about their experiences and concerns and for patients to hear about the latest treatment and research by questioning the experts in an informal environment.<br /><br /> <br /><br /> Using a mix of both patients and professionals to give their views, some of the themes we are currently considering include:<br /><br /> <br /><br /> · The complexity of the hepatitis C virus, what we do know and what we don’t<br /><br /> · Changes to support and care of patients (eg home delivered care, support meetings at their hospital)<br /><br /> · Preparing for and managing treatment<br /><br /> · Managing life with HCV<br /><br /> · Post treatment challenges<br /><br /> · New treatments on the horizon<br /><br /> <br /><br /> We want to ensure that your voice is heard, so whether you are a patient or a professional, we would love to have your suggestions on topics you would like covered, or speakers you’d be interested to hear and we will do our best to incorporate your ideas. <br /><br /> <br /><br /> If you would like to share your ideas and take advantage of this unique opportunity to contribute to, or take part in, a debate around the latest issues concerning hepatitis C, please email administration@hepctrust.org.uk<br /><br /> or call Karine on 0207 089 6220. Please note we need your contributions by Friday 24th September.<br /><br /> <br /><br /> With best wishes<br /><br /> <br /><br /> The Hepatitis C TrustScott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-20645411109514649892010-09-27T16:07:00.001-04:002010-09-27T16:07:26.725-04:00ZymoGenetics Acquisition Highlights Competitive Hepatitis C Treatment RaceZymoGenetics Acquisition Highlights Competitive Hepatitis C Treatment Race<br /><br /><br />http://www.onemedplace.com<br /><br />Bristol-Myers Squibb Company (BMS) announced Tuesday that it had signed an agreement to acquire biopharmaceutical company ZymoGenetics for $9.75 per share in cash, or approximately $885 million. Under the terms of the agreement, BMS will gain control of ZymoGenetics? product development pipeline, which includes potential treatments for surgical bleeding, metastatic skin cancer, and atopic dermatitis.<br /><br /><br />However, perhaps the biggest prize BMS will acquire in the deal is pegylated-interferon lambda, a novel interferon drug candidate for the treatment of hepatitis C, an infectious disease that affects the liver. Approximately 3.2 million people in the U.S. are chronically infected with hepatitis C, according to the U.S. Centers for Disease Control, and ZymoGenetics? drug candidate has the potential to improve upon the current standard of care, interferon combined with ribavirin. While this drug combination works for many patients, it has to be taken for months and has many potential side effects.<br /><br /><br />According to a report by market research firm Global Data, the global hepatitis C market was worth $4 billion in 2009 and is projected to grow at a compound annual growth rate of 9.8% to reach $8.5 billion by 2016. ZymoGenetics is competing with Vertex Pharmaceuticals, Merck, Anadys Pharmaceuticals, Idenix Pharmaceuticals, and a number of other companies to be the first to market a hepatitis C drug that outperforms the current standard of care.<br /><br /><br />Along with ZymoGenetics, Vertex has been drawing a lot of attention; the Cambridge, Mass.-based company released positive late-stage clinical data on Tuesday. In a study of 662 treatment-resistant hepatitis C patients, 65 percent of patients who took Vertex?s telaprevir were cured, compared to 17 percent of patients who were treated with the current standard of care. The news wasn?t as good for Idenix, which halted trials of two of its experimental hepatitis C drugs over safety concerns after liver abnormalities were discovered in three healthy study participants. Other news from the hepatitis C space: PSI-7977, developed by Pharmasset, recently received fast track designation from the FDA. The drug is currently in Phase 2b clinical trials. With such a significant need for effective hepatitis C treatments, and with so many competitors in the field, the race to commercialization continues to be an interesting one.Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-23626303111844931022010-09-27T16:06:00.001-04:002010-09-27T16:06:15.661-04:00FDA halts Idenix drug studies due to side effectsFDA halts Idenix drug studies due to side effects<br /><br /><br />businessweek.com<br /><br />CAMBRIDGE, Mass.<br /><br /><br />Shares of Idenix Pharmaceuticals were cut nearly in half Tuesday after federal regulators halted development of its two hepatitis drugs due to its potential side effects.<br /><br /><br />The Food and Drug Administration issued a clinical hold after Idenix reported three cases of liver side effects in patients taking IDX-184 and IDX-320, the company said. Both drugs are experimental treatments for hepatitis C, a type of infection that damages the liver.<br /><br /><br />Idenix said liver function in all three patients later returned to normal.<br /><br /><br />Idenix received verbal notice of the FDA's decision Friday. The company had been studying a combination dose of the two drugs in healthy volunteers.<br /><br /><br />"We remain committed to the future potential of these drug candidates" said Idenix Chairman and Chief Executive Jean-Pierre Sommadossi. "We will work closely with independent experts and our external safety committee to better understand the cause of these serious adverse events."<br /><br /><br />Shares of Idenix Pharmaceuticals tumbled $2.87 to $3.12 in midday trading.<br /><br />News Release<br /><br /><br />Idenix Provides Update on HCV Clinical Development Activities<br /><br />Conference call today at 8:30 am ET<br /><br /><br />CAMBRIDGE, Mass., Sept 07, 2010 /PRNewswire via COMTEX/ --<br /><br /><br />Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced that the company received verbal notice on Friday, September 3, 2010 from the U.S. Food and Drug Administration (FDA) that the IDX184 and IDX320 programs have been placed on clinical hold. A clinical hold is an order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. This decision was made after Idenix notified the FDA of three serious adverse events that occurred during a drug-drug interaction study of the combination of IDX184 and IDX320 in healthy volunteers. These observed serious adverse events were elevated liver function tests detected in three subjects during post exposure safety visits. The liver function tests have returned to nearly normal levels in all thr ee subjects during follow-up. All planned studies of IDX184 and IDX320 to date have been completed and there are currently no healthy volunteers or patients receiving IDX184 or IDX320. Idenix will submit full data to the FDA from recently completed preclinical and clinical studies, including 3-month chronic toxicology studies of IDX184, a 14-day study of IDX184 in combination with pegylated interferon/ribavirin (PegIFN/RBV), a 3-day proof-of-concept study of IDX320 in hepatitis C (HCV) infected patients, and the IDX184 and IDX320 drug-drug interaction study in healthy volunteers in order to assess next steps in the development of both compounds.<br /><br /><br />"We have not yet received a formal letter from the FDA, nor has the Agency had an opportunity to review the safety and efficacy data from recently completed clinical trials with IDX184 and IDX320. Based upon our discussions with the Agency, we are primarily focused on three cases of elevated liver function tests observed during our drug-drug interaction study of the combination of IDX184 and IDX320 in healthy volunteers," said Jean-Pierre Sommadossi, Ph.D., Idenix Chairman and Chief Executive Officer. "Based upon the safety and antiviral activity we observed in the IDX184 14-day study and the IDX320 3-day proof-of-concept study, both in HCV-infected patients, we remain committed to the future potential of these drug candidates. We will work closely with independent experts and our external safety committee to better understand the cause of these serious adverse events in the combination study of IDX184 and IDX 320 and to provide the FDA with more information in order to expedite their review and resolve this matter as quickly as possible."<br /><br /><br />Full data presentations of IDX184, IDX320 and IDX375 studies will be presented at the annual meeting of the American Association for the Study of Liver Diseases (AASLD), which will be held at the end of October in Boston.<br /><br /><br />Phase I: IDX184/IDX320 Combination<br /><br /><br />Idenix completed a two-week Phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetic drug-drug interaction between IDX320 and IDX184 in healthy volunteers. Two cohorts were evaluated in the study with 10 subjects in each cohort randomized eight to active drug and two to placebo. Subjects in the first cohort received 400 mg once-daily of IDX320 for the first week, subsequently adding 100 mg once-daily of IDX184 for the second week. Subjects in the second cohort received 100 mg once-daily of IDX184 plus placebo for the first week, subsequently adding 400 mg once-daily of IDX320 for the second week. The combination of IDX184 and IDX320 was generally safe and well tolerated during the 14 days of treatment. Liver function abnormalities deemed to be serious adverse events were detected in three subjects during the post exposure safety visits. Liver function tests in thes e subjects have returned to nearly normal during follow-up. Pharmacokinetic drug-drug interactions between IDX184 and IDX320 were not considered to be clinically significant. Neither the plasma exposure of IDX184 and its metabolite, 2'-methylguanosine, nor IDX320 plasma exposure explain these three serious adverse events.<br /><br /><br />Phase IIa: IDX184, a liver-targeted HCV nucleotide prodrug<br /><br /><br />This 14-day, Phase IIa clinical trial evaluated 50 to 200 mg doses of IDX184 in combination with PegIFN/RBV in treatment-naive HCV genotype 1-infected patients. At Day 14, mean (+/- standard deviation) viral load reductions were 1.5 (+/- 1.3) logs for placebo (n=16), 2.7 (+/- 1.3) logs for 50 mg IDX184 QD (n=16), 4.0 (+/- 1.7) logs for 50 mg IDX184 BID (n=8), 4.2 (+/- 1.9) logs for 100 mg QD (n=8), 4.1 (+/- 1.2), for 150 mg QD (n=15), 4.1 (+/-1.4) logs for 100 mg BID (n=8) and 3.7 (+/- 1.2) logs for 200 mg QD (n=8). In the cohorts of 100 mg, 150 mg, and 200 mg daily doses in combination with PegIFN/RBV, 50%, 40% and 25%, respectively, of patients achieved undetectable virus levels (<15 IU/mL) by Day 14. Liver injury parameters (ALT and AST) improved with all doses of IDX184. The side effect profile of the three drug combination was consistent with the known side effect profile of PegIFN/RBV alone. The most common adverse events reported were fatigue, myalgia, headache and nausea.<br /><br /><br />Phase I/II: IDX 320, an HCV protease inhibitor<br /><br /><br />This randomized, parallel-arm, double-blind, placebo-controlled proof-of-concept trial evaluated the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in treatment-naive HCV genotype 1-infected patients. Thirty patients were randomized equally and received placebo, 50, 100, 200 or 400 mg of IDX320 orally once-a-day for three days. One cohort of eight patients was randomized to receive 200 mg IDX320 BID or placebo. At Day 3, mean (+/- standard deviation) viral load reductions were 0.1 (+/- 0.15) logs for placebo (n=5), 2.6 (+/-0.49) logs for 50 mg IDX320 QD (n=5), 3.1 (+/- 0.29) logs for 100 mg QD (n=6), 3.1 (+/- 0.41) logs for 200 mg QD (n=6) and 3.3 (+/- 0.28) logs for 400 mg QD (n=7). At daily doses of placebo, 50, 100, 200, and 400 mg, 0%, 20%, 67%, 67% and 86%, respectively, of patients achieved greater than or equal to 3 log reduction in HCV RNA at the end of treatment. In the 200 mg IDX 320 BID cohort at Day 3, mean (+/- standard deviation) viral load reductions were 3.8 (+/- 0.52) logs and all patients (100%) achieved greater than or equal to 3 log reduction in HCV RNA. In the 3-day proof-of-concept study, IDX320 was generally safe, well tolerated, and demonstrated potent, dose-related HCV antiviral activity.<br /><br /><br />Phase I: IDX375, an HCV non-nucleoside polymerase inhibitor<br /><br /><br />Idenix has an ongoing Phase I clinical trial in healthy volunteers evaluating single doses of the free acid form of IDX375 ranging from 200 to 1200 mg per day. Overall, IDX375 achieved pharmacologically relevant drug exposure and was well tolerated for doses up to 1200 mg for one day in healthy subjects. In the fourth quarter of 2010, Idenix plans to initiate a 3-day proof-of-concept trial in treatment-naive genotype 1 HCV-infected patients.<br /><br /><br />Conference Call Information<br /><br /><br />Idenix will hold a conference call today at 8:30 a.m. ET. To access the call please dial (800) 471-3635 U.S./Canada or (706) 758-9475 International and enter passcode 99538089. A replay of the conference call and webcast will be available until September 21, 2010. To access the replay, please dial (800) 642-1687 U.S./Canada or (706) 645-9291 International and enter the passcode 99538089.<br /><br /><br />About HCV<br /><br /><br />Hepatitis C virus is a common blood-borne pathogen infecting three to four million people worldwide annually. Currently, an estimated 170 million people are infected worldwide, representing a nearly 5-fold greater prevalence than human immunodeficiency virus.(1)<br /><br /><br />About Idenix<br /><br /><br />Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of patients with chronic hepatitis C infection. For further information about Idenix, please refer to www.idenix.com.<br /><br /><br />Forward-Looking Statements<br /><br /><br />This press release contains "forward-looking statements" for purposes of the safe harbor provisions of The Private Securities Litigation Reform Act of 1995, including but not limited to the statements regarding the company's future business and financial performance. For this purpose, any statements contained herein that are not statements of historical fact may be deemed forward-looking statements. Without limiting the foregoing, the words "expect," "plans," "anticipates," "will," "expects," "goal," "estimates," "projects," "would," "could," "targets," and similar expressions are also intended to identify forward-looking statements, as are expressed or implied statements with respect to the company's clinical development programs or commercialization activities in hepatitis C, or any potential pipeline candidates, including any expressed or implied statements regarding the efficacy and safety of our drug cand idates, the likelihood and success of any future clinical trials involving our drug candidates or successful development of novel combinations of direct-acting antivirals for the treatment of hepatitis C. Actual results may differ materially from those indicated by such forward-looking statements as a result of risks and uncertainties, including but not limited to the following: there can be no guarantees that the company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization; management's expectations could be affected by unexpected regulatory actions or delays, including the current clinical hold on IDX184 and IDX320; uncertainties relating to, or unsuccessful results of, clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the company's ability to obtain additional funding required to conduct its research, deve lopment and commercialization activities; the company's dependence o n its collaborations with Novartis Pharma AG and GlaxoSmithKline; changes in the company's business plan or objectives; the ability of the company to attract and retain qualified personnel; competition in general; and the company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. These and other risks which may impact management's expectations are described in greater detail under the heading "Risk Factors" in each of the company's annual report on Form 10-K for the year ended December 31, 2009 and quarterly report on form 10-Q for the quarter ended June 30, 2010, as filed with the Securities and Exchange Commission (SEC) and in any subsequent p eriodic or current report that the company files with the SEC.<br /><br /><br />All forward-looking statements reflect the company's estimates only as of the date of this release (unless another date is indicated) and should not be relied upon as reflecting the company's views, expectations or beliefs at any date subsequent to the date of this release. While Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if the company's estimates change.<br /><br /><br />(1) Lavanchy (2009) Liver International. 29(s1):74-81<br /><br /><br /> Idenix Pharmaceuticals Contact:<br /><br /> Jonae Barnes (617) 224-4485 (investors)<br /><br /> Kelly Barry (617) 995-9033 (media)Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-89312890393832862532010-09-27T16:05:00.001-04:002010-09-27T16:05:38.848-04:00Vertex, J&J Hepatitis C Drug Works After Others FailVertex, J&J Hepatitis C Drug Works After Others Fail<br /><br />By Ellen Gibson and Elizabeth Lopatto - Bloomberg, Sep 7, 2010 5:16 PM ET<br /><br /><br /><br />Vertex Pharmaceuticals Inc.?s most advanced experimental drug, in development with Johnson & Johnson, worked in patients with hepatitis C who didn?t respond to other treatment, a study found.<br /><br /><br />Vertex?s medicine, telaprevir, added to standard treatments for the infection, cured 65 percent of patients overall compared with 17 percent on the other regimen alone, according to a company-funded study that Vertex reported today in a statement.<br /><br /><br />No proven medicines are available for hepatitis C patients who don?t respond to standard care. If approved by the U.S. Food and Drug Administration, Vertex?s drug may garner $4 billion in global annual sales by 2014, said Phil Nadeau, an analyst at Cowen & Co. Vertex, of Cambridge, Massachusetts, said it will seek U.S. approval of telaprevir in the fourth quarter.<br /><br /><br />“What most physicians have been doing up to now is warehousing those treatment-failed patients,” Nadeau said in a phone interview. “Now they have a real chance of being cured.”<br /><br /><br />Standard hepatitis C treatment -- a combination of the antiviral medicine ribavirin and a pegylated interferon such as Roche Holding AG?s Pegasys -- cures fewer than half of those who take them, and many patients develop serious side effects. With a second round of treatment using the same combination, the success rate drops as low as 10 percent.<br /><br /><br />Shares of Vertex rose 24 cents to $35.25 at 4:49 p.m. New York time in extended trading after closing down 2.9 percent on the Nasdaq Stock Market. Trial results were reported after the close of U.S. markets. The shares fell 3.6 percent in past 12 months.<br /><br /><br />Racing Merck<br /><br /><br />Telaprevir is racing boceprevir from Whitehouse Station, New Jersey-based Merck & Co. to become the first new hepatitis C treatment approved in a decade. Both are in a family of medicines known as protease inhibitors that work by blocking an enzyme that viruses use to copy themselves.<br /><br /><br />“Today?s results give people who haven?t achieved success with prior treatments some real hope for having a cure,” Robert Kauffman, the chief medical officer for Vertex, said today in a telephone interview.<br /><br /><br />About 3.6 million people in the U.S. and 170 million worldwide have hepatitis C, a chronic and potentially fatal infection, according to the World Health Organization, based in Geneva.<br /><br /><br />The virus, which typically spreads through contact with contaminated blood, damages the liver and can cause the organ to fail. While many people with hepatitis C have no symptoms and go undiagnosed, others experience stomach pain, jaundice, fevers and fatigue.<br /><br /><br />Revenue<br /><br /><br />In the U.S., there are 270,000 to 300,000 patients with hepatitis C who failed standard treatments, Vertex Chief Financial Officer Ian Smith said in a presentation to investors in Boston on Aug. 12. The company expects most of telaprevir?s revenue to come from this group during the first three years after the drug is cleared for sale, he said.<br /><br /><br />Today?s study, called Realize, was from the third and final stage of testing generally needed for FDA approval. It involved 662 people who had received prior treatment and weren?t cured, or who relapsed after the course of therapy ended.<br /><br /><br />The trial included three patient groups. One group received telaprevir for 12 weeks, added to ribavirin and interferon, followed by an added 36 weeks on the two older drugs alone. Among those people, 64 percent were cured, meaning the virus was reduced to undetectable levels in a blood test.<br /><br /><br />Study Results<br /><br /><br />A second group received that same 12-week cocktail. This group also got 4 weeks of prior treatment and 32 weeks of follow-up therapy with ribavirin and interferon. For them, the cure rate was 66 percent. (from Jules: see results I emailed yesterday - 31% SVR in null responders, 80+% in relapsers, 57% in prior partial responders)<br /><br /><br />A third set of patients had 48 weeks of treatment with the older drugs alone, and had a cure rate of 17 percent.<br /><br /><br />About 4 percent of patients enrolled in the trial discontinued treatment with telaprevir, interferon and ribaviron, compared with 3 percent in the control arm. With telaprevir, 0.6 percent stopped because of anemia, and 0.4 percent discontinued due to rashes.<br /><br /><br />“The safety profile is comparable to previous studies,” Kauffman said.<br /><br /><br />Previously reported results from two other late-stage trials of telaprevir showed the drug achieved a 75 percent cure rate in patients who had received no prior therapies and that treatment time can be cut to 24 weeks, from 48, in those patients without affecting the drug?s efficacy.<br /><br /><br />Johnson & Johnson, of New Brunswick, New Jersey, funded the study reported today. J&J agreed in 2006 to pay as much as $545 million to jointly develop the drug and sell it in Europe, South America, the Middle East, Africa and Australia. Vertex retained rights to North American sales. Mitsubishi Tanabe Pharma Corp. of Osaka, Japan, has rights for parts of Asia.<br /><br /><br />To contact the reporters on this story: Ellen Gibson in New York at egibson9@bloomberg.net; Elizabeth Lopatto in New York at elopatto@bloomberg.netScott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-32144140870902451082010-09-27T16:04:00.000-04:002010-09-27T16:05:06.502-04:0065% of People Whose Prior Treatment for Hepatitis C Was Unsuccessful Achieved SVR (Viral Cure) with Telaprevir-Based Therapy in Phase 3 REALIZE Study65% of People Whose Prior Treatment for Hepatitis C Was Unsuccessful Achieved SVR (Viral Cure) with Telaprevir-Based Therapy in Phase 3 REALIZE Study<br />-17% of people achieved SVR with pegylated-interferon and ribavirin alone in the control arm- <br /><br />press release<br /><br />Sept. 7, 2010, 4:01 p.m. EDT<br /><br /> CAMBRIDGE, Mass., Sep 07, 2010 (BUSINESS WIRE) -- ---Safety and tolerability results were consistent with prior Phase 3 studies-<br /><br />---Completion of rolling New Drug Application submission on track for the fourth quarter 2010-<br /><br />Vertex Pharmaceuticals Incorporated /quotes/comstock/15*!vrtx/quotes/nls/vrtx (VRTX 35.60, +0.59, +1.69%) today announced that 65% of people overall achieved a sustained viral response (SVR or viral cure) with a telaprevir-based regimen in the pivotal Phase 3 REALIZE study, as compared to 17% of people in the control arm who received pegylated-interferon and ribavirin alone. REALIZE enrolled three groups of patients with genotype 1 hepatitis C who had undergone at least one prior treatment course with pegylated-interferon and ribavirin but did not achieve SVR: (1) those who relapsed, (2) those who achieved a partial response and (3) those who had almost no response, known as a null response. REALIZE is the only Phase 3 hepatitis C study to date of an investigational direct-acting antiviral therapy that was designed to evaluate all major subgroups of people whose prior treatment was unsuccessful, including those who had a null response. The safety and tolerability results were consistent with results from the other two Phase 3 studies of telaprevir. The REALIZE study was conducted by Vertex's collaborator, Tibotec.<br /><br />"The REALIZE data represent a major milestone in the development of new treatments for hepatitis C, as patients who received telaprevir-based therapy had a viral cure rate almost four times greater than the cure rate in those treated with available medicines," said Stefan Zeuzem, M.D., Professor of Medicine and Chief of the Department of Medicine at the JW Goethe University Hospital, Frankfurt, Germany and Principal Investigator of the trial. "These results may provide hope to people who have not been cured and who are in need of new treatment options, including those with advanced liver disease."<br /><br />"Along with results from ADVANCE and ILLUMINATE, the REALIZE data provide us with a strong understanding of telaprevir's potential role in helping many people with hepatitis C achieve a cure, regardless of their treatment history," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "With these data, we look forward to completing our rolling New Drug Application submission for telaprevir later this year."<br /><br />Overview of SVR Results<br /><br />The primary endpoint of the study was SVR in each of the two telaprevir arms compared to the control arm, as well as across the three subgroups of people included in the study. One of the telaprevir treatment arms was designed to evaluate, for the first time, whether there was any further improvement in viral cure rates when delaying the start of telaprevir by four weeks, during which time patients received four weeks of pegylated-interferon and ribavirin alone, compared to a simultaneous start. The SVR rates between these two arms were similar and there was no clinical benefit to the telaprevir delayed start treatment arm in any of the subgroups of patients. The table below combines the two telaprevir arms compared to the control.<br /><br /> Relapsers Partial Responders Null Overall (ITT)<br /> (n=354) (n=124) Responders (n=662)<br /> (n=184)<br /> ----------- --------------------- ---------- -------------<br /> Telaprevir- 86%* 57%* 31%* 65%*<br /> based (n=245/286) (n=55/97) (n=46/147) (n=346/530)<br /> Treatment<br /> Arms+<br /> ----------- ---------------------<br /> Pooled Analysis: 78% (n=300/383)**<br /> ------------------------------------------<br /> Control 24% 15% 5% 17%<br /> Arm++ (n=16/68) (n=4/27) (n=2/37) (n=22/132)<br />----------- ----------- --------------------- ---------- -------------<br /> Pooled Analysis: 21% (n = 20/95)**<br /> --------------------------------<br />*Combined endpoint analysis: The SVR rates observed in<br />the overall combined telaprevir-based arms were statistically<br />significant when compared with the control arm (p<br />+Reflects SVR rates from the combined telaprevir-based<br />treatment groups. There were two telaprevir-based treatment groups:<br /> 1. 12 weeks of telaprevir (750 mg, q8h), pegylated-interferon<br /> (Peg-IFN) & ribavirin (RBV), followed by 36 weeks of Peg-IFN & RBV<br /> alone or<br /> 2. 4 weeks of Peg-IFN & RBV alone followed by 12 weeks of<br /> telaprevir (750 mg, q8h), Peg-IFN & RBV, followed by 32 weeks of<br /> Peg-IFN & RBV alone<br />++12 weeks of placebo, Peg-IFN & RBV, followed by 36<br />weeks of Peg-IFN and RBV alone<br />**Supplemental analysis<br />Null Responder: Defined as a<br />person who achieved a less than 2 log10 reduction in<br />HCV RNA at week 12 of a prior course of therapy.<br />---------------------------------------------------------------------------------------<br />Relapser: Defined as a<br />person whose hepatitis C virus was undetectable at the completion<br />of at least 42 weeks of a prior course of therapy but whose virus<br />became detectable during the follow-up period.<br />---------------------------------------------------------------------------------------<br />Partial Responder: Defined<br />as a person who achieved at least a 2 log10 reduction<br />at week 12, but whose hepatitis C virus never became undetectable<br />by week 24 of a prior course of therapy.<br />---------------------------------------------------------------------------------------<br />Backgrounders on hepatitis C treatment response and the REALIZE<br />http://investors.vrtx.com/press.cfm---------------------------------------------------------------------------------------<br /><br /><br /><br /><br />SVR rates for the telaprevir simultaneous start arm and the delayed start arm were 64% and 66%, respectively, overall, based on an intent-to-treat (ITT) analysis. For the primary analysis, the SVR rates for the telaprevir simultaneous start arm, delayed start arm and control arm, respectively, were 83%, 88% and 24% in relapsers (p<0.0001); 59%, 54% and 15% in partial responders, (p<0.0001); and 29%, 33% and 5% in null responders, (p<0.001).<br /><br />Safety & Tolerability Results<br /><br />The safety and tolerability results of the telaprevir-based regimens in the REALIZE study were consistent with results reported from the Phase 3 ADVANCE and ILLUMINATE studies. The most common adverse events, reported in any treatment arm during the telaprevir dosing periods and up to week 16 to account for the telaprevir delayed start arm in order of frequency, were fatigue, pruritis, headache, rash, flu-like symptoms, nausea and anemia, with the majority being mild to moderate. Of these, fatigue, pruritis, rash, flu-like symptoms, nausea and anemia were more common in the telaprevir-based treatment arms compared to control. Adverse events leading to discontinuation of all study drugs during the telaprevir dosing period and up to week 16 occurred in 4% of people in the combined telaprevir arms and 3% in the control arm during the same period. Discontinuation of all drugs due to anemia and rash during the telaprevir dosing period and up to week 16 occurred in 0.6% and 0.4% of patients, respectively, in the combined telaprevir arms, while discontinuation of all three drugs due to rash and anemia did not occur in the control arm during the same period. As in ADVANCE and ILLUMINATE, the use of erythropoiesis-stimulating agents (ESAs) was not allowed in this study.<br /><br />Telaprevir is an investigational, oral inhibitor of HCV protease, an enzyme essential for viral replication, and is being developed by Vertex Pharmaceuticals in collaboration with Tibotec Pharmaceuticals and Mitsubishi Tanabe Pharma. With results from the three Phase 3 studies of telaprevir - ADVANCE, ILLUMINATE and REALIZE - Vertex is on track to complete its rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2010.<br /><br />Patient Demographics<br /><br />REALIZE enrolled people with hepatitis C who did not achieve a viral cure after receiving at least one course of prior treatment with pegylated-interferon and ribavirin. Patients in the study were enrolled based on their response to prior treatment: 53% were prior relapsers, 19% were prior partial responders and 28% were prior null responders. In this study, 26% of patients overall had cirrhosis and 89% of patients overall had a high viral load (HCV RNA greater-than or equal to 800,000 IU/mL) when entering the study. Specifically in the null responder population, there were an even greater number of people with cirrhosis (33%) and high viral load (95%). Approximately 50% of patients were genotype 1a and 50% were genotype 1b.<br /><br />About the Study<br /><br />REALIZE was a pivotal Phase 3, randomized, double-blind, placebo-controlled study conducted in 662 people at more than 100 international clinical trial sites with the majority in Europe and North America. The study was designed to evaluate the efficacy, safety and tolerability of telaprevir-based regimens in people infected with genotype 1 chronic hepatitis C who did not achieve a viral cure after at least one prior treatment with interferon-based therapy. There were two telaprevir-based arms (simultaneous and delayed start) and one control arm. Patients were randomized 2:2:1 to the two telaprevir arms and the control arm, respectively.<br /><br />The primary endpoint of the REALIZE study was SVR, defined as the proportion of people who had undetectable HCV RNA (<25IU/mL undetectable by Roche COBAS Taqman HCV test) 24 weeks after the end of all treatment. REALIZE was designed to compare the SVR rates for each of the telaprevir-based regimens with the control arm, separately for the prior response subgroups of relapsers and non-responders (null and partial responders), and then for the two subgroups of non-responders. The secondary endpoint was to evaluate the safety and tolerability of telaprevir in combination with pegylated-interferon and ribavirin.<br /><br />As in all Phase 3 studies of telaprevir, patients received no more than 12 weeks of telaprevir given in combination with pegylated interferon and ribavirin. In REALIZE, the telaprevir arms included 12 weeks of telaprevir in combination with pegylated-interferon and ribavirin with 36 weeks of pegylated-interferon and ribavirin alone for a total of 48 weeks of treatment.<br /><br />About the Telaprevir Development Program<br /><br />To date, more than 2,500 people with hepatitis C have received telaprevir-based therapy as part of Phase 2 studies and the Phase 3 ADVANCE, ILLUMINATE and REALIZE studies. Together, these studies enrolled people with genotype 1 hepatitis C who had not been treated for their disease previously as well as people who had been treated before but did not achieve a viral cure.<br /><br />Vertex retains commercial rights to telaprevir in North America. Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.<br /><br />About Hepatitis C<br /><br />Hepatitis C is a liver disease caused by the hepatitis C virus, which is found in the blood of people with the disease.(2) According to a 2010 report from the Institute of Medicine, up to 3.9 million people in the United States have chronic hepatitis C and 75% of those infected are unaware of their infection.(3)Approximately 60 percent of genotype 1 patients who undergo an initial 48-week regimen with pegylated-interferon and ribavirin, the currently approved treatment regimen, do not achieve SVR, (4,5,6)or viral cure.(1)<br /><br />Hepatitis C is spread through direct contact with the blood of infected people.(2) Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.(2) Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.(2) If treatment is not successful and a person does not achieve a viral cure, they remain at risk for progressive liver disease.(7,8,9,10,11) In the United States, hepatitis C is the leading cause of liver transplantations and is reported to contribute to 4,600 to 12,000 deaths annually.(8) The majority of people with hepatitis C were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.(11) By 2029, total annual medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.(11)<br /><br />Additional resources for media, including a hepatitis C backgrounder and glossary of common terms, are available at: http://investors.vrtx.com/press.cfm<br /><br />About Vertex<br /><br />Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with major pharmaceutical companies. Vertex's product pipeline is focused on viral diseases, cystic fibrosis, inflammation, autoimmune diseases, epilepsy, cancer and pain.<br /><br />Vertex co-discovered the HIV protease inhibitor, Lexiva, with GlaxoSmithKline.<br /><br />Lexiva is a registered trademark of the GlaxoSmithKline group of companies.<br /><br />References:<br /><br />(1)Ghany, m.G., Strader, d.B., Thomas, d.L., Seeff, Leondard B. Diagnosis, Management and Treatment of Hepatitis C; An Update. 2009. Hepatology. 2009;49 (4):1-40. (2) Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed May 25, 2010. (3) Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Available at http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Accessed May 25, 2010. (4)Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. (5) Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. (6)McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593. (7) Morgan T.R, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115). (8)Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138: 513-521 (9) Volk, Michael I., Tocco, Rachel, Saini, Sameer, Lok, Anna S.F. Public Health Impact of Antiviral Therapy for Hepatitis C in the United States. Hepatology.2009;50(6):1750-1755. (10) Veldt, B.J., Heathcote, J., Wedmeyer, H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684. (11) Pyenson, B., Fitch, K., Iwasaki, K. Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease. Milliman, Inc. This report was commissioned by Vertex Pharmaceuticals, Inc. May, 2009.<br /><br />Special Note Regarding Forward-looking Statements<br /><br />This press release contains forward-looking statements, including statements regarding (i) the Company being on track to complete the NDA for telaprevir in the fourth quarter of 2010 and (ii) the REALIZE data providing the Company with a strong understanding of telaprevir's potential role in helping many people with hepatitis C achieve a cure, regardless of their treatment history. While the Company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the Company could experience unforeseen delays in submitting the NDA for telaprevir and/or obtaining approval to market telaprevir; that there may be varying interpretations of the data from the telaprevir clinical trials; that future outcomes from clinical trials of telaprevir may not be favorable; and that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir-based combination therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the Company's website at www.vrtx.com. The Company disclaims any obligation to update the information contained in this press release as new information becomes available.<br /><br />Investor Conference Call Today at 4:30 p.m. ET<br /><br />Vertex Pharmaceuticals will host a conference call and webcast today, September 7, at 4:30 p.m. ET. This call and webcast will be broadcast via the Internet at www.vrtx.com/finances. It is suggested that webcast participants go to the web site at least 10 minutes in advance of the call to ensure that they can access the slides. The link to the webcast is available on the Events & Presentations button. To listen to the call on the telephone, dial (888) 634-7543 (U.S. and Canada) or (719) 457-2573 (International) and use conference ID number ID 5433422. Vertex is also providing a podcast MP3 file available for download on the Vertex website at www.vrtx.com.<br /><br />The call will be available for replay via telephone commencing September 8, 2010 at 8:00 p.m. ET running through September 22, 2010 at 5:00 p.m. ET. To listen to the replay dial (888) 203-1112 (U.S. and Canada) or (719) 457-0820 (International) and use conference ID number 5433422. Following the live webcast, an archived version will be available on Vertex's website until 5:00 p.m. on September 15, 2010.<br /><br />New York City Investor and Analyst Webcast Tomorrow, September 8, at 8:00 a.m. ET<br /><br />Vertex Pharmaceuticals will also webcast its investor and analyst meeting from New York City on Wednesday, September 8, 2010 at 8:00 a.m. ET. This webcast will be broadcast via the Internet at www.vrtx.com/finances. The link to the webcast is available on the Events & Presentations button. The New York City webcast will not be available via telephone. It is suggested that webcast participants go to the web site at least 10 minutes in advance of the call to ensure that they can access the slides.<br /><br />(VRTX-GEN)<br /><br />Photos/Multimedia Gallery Available: http://www.businesswire.com/cgi-bin/mmg.cgi?eid=6419968&lang=en<br /><br />SOURCE: Vertex Pharmaceuticals IncorporatedScott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-16479609077633855402010-09-27T16:03:00.001-04:002010-09-27T16:03:50.791-04:00Proteome‐Wide Anti–Hepatitis C Virus (HCV) and Anti‐HIV Antibody Profiling for Predicting and Monitoring the Response to HCV Therapy in HIVProteome‐Wide Anti–Hepatitis C Virus (HCV) and Anti‐HIV Antibody Profiling for Predicting and Monitoring the Response to HCV Therapy in HIV‐Coinfected Patients<br /><br />JID Sept 15 2010<br /><br />"Declining anti‐HCV core and envelope‐specific antibody responses at the end of therapy were observed only in the SVR group, suggesting that these antibody responses could be used to discriminate between those who experience relapse and SVR at the end of therapy. The SVR group showed the largest and most consistent decrease in titers of antibodies against the core, E1, and NS4 proteins after 48 weeks of treatment. In contrast, the NR and relapse groups showed minimal decreases in antibody titers. Despite the less than detectable levels of HCV RNA at the end of HCV treatment in the relapse and SVR groups, significant decreases in anti‐HCV antibody titers do frequently occur among patients with SVRs. Given that HCV loads in the relapse and SVR groups were clinically indistinguishable and below the level of detection, it is possible that the decrease in levels of antibodies in the SVR group reflects a marked decline in antigen load in the liver rather than in the plasma. Regardless of the mechanism, the differential response in antibody titers between the SVR and relapse groups at the end of treatment offers a novel tool to predict who will experience relapse after treatment is stopped. This could lead to the development of novel therapeutic strategies, such as extended therapy for those with relapse. Studies addressing whether these antibodies and/or other biomarkers show robust differences at earlier time points may provide practical tools for monitoring therapy."<br /><br />"Titers of antibodies against the panel of HCV proteins were also evaluated before and after treatment for their value in monitoring HCV therapy. The Wilcoxon sign ranked test revealed that 4 of the 6 HCV proteins (core, E1, E2, and NS4) showed statistically significant (p<.05) decreases in antibody titer between the pre‐ and posttreatment samples (Figure 3). In contrast, antibody responses to the NS3 and NS5A antigens did not significantly change between before and after treatment (p>.44). Substratification by treatment outcome revealed that the SVR group showed the most consistent and largest decrease (p=.02) in titers of antibodies against the 3 most informative antigens (core, E1, and NS4) after treatment (Figure 3). In contrast, the NR and relapse groups had relatively stable titers of antibodies against these 3 antigens between before and after treatment (p=.70 and p=.43, respectively)"<br /><br /><br /> <br /><br />Peter D. Burbelo,1 <br /><br />Joseph A. Kovacs,2 <br /><br />Kathryn H. Ching,1 <br /><br />Alexandra T. Issa,1 <br /><br />Michael J. Iadarola,1 <br /><br />Alison A. Murphy,3 <br /><br />Joerg F. Schlaak,4 <br /><br />Henry Masur,2 <br /><br />Michael A. Polis,3 and <br /><br />Shyam Kottilil3<br /><br />1Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, 2Critical Care Medicine Department, National Institutes of Health Clinical Center, and 3Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; 4University Hospital of Essen, Essen, Germany<br /><br />We quantified antibody responses to the hepatitis C virus (HCV) proteome that are associated with sustained virologic response (SVR) in human immunodeficiency virus (HIV)/HCV–coinfected patients treated with pegylated interferon and ribavirin. Analysis of pre‐ and posttreatment samples revealed significant decreases in the combined anti‐core, anti‐E1, and anti‐NS4 HCV antibody titers in those with SVRs but not in those who experienced relapse or who did not respond. Furthermore, anti–HIV p24 antibody titers inversely correlated with treatment response. These results suggest that profiling anti‐HCV antibody is useful for monitoring HCV therapy, especially in discriminating between those who experience relapse and those who have SVRs at 48 weeks.<br /><br />Infection with hepatitis C virus (HCV) is seen in 15%–30% of all human immunodeficiency virus (HIV)–infected individuals in the United States, as a result of the shared routes of viral transmission [1, 2]. The introduction of antiretroviral therapy has improved clinical outcomes in patients infected with HIV. However, liver disease has become a leading cause of morbidity and mortality in this population [3, 4]. HIV/HCV coinfection is also associated with higher HCV levels in serum [5, 6], rapid progression of liver disease [7], and lower efficacy of treatment with pegylated interferon plus ribavirin [5, 8]. Development of biomarkers that can accurately predict therapeutic responses are needed to optimize HCV therapy in this coinfected population. Previously, HIV/HCV‐coinfected patients who were not responsive to HCV therapy with pegylated interferon plus ribavirin were found to have a gene‐activation signature present before treatment indicative of the activation of many immune‐related molecules, including interferon‐stimulated genes [9]. Quantitative and qualitative humoral responses over the course of HCV therapy among HIV/HCV‐coinfected subjects have never been studied, to our knowledge. The ability to clearly predict and monitor outcomes of HCV infection in a robust and simple serological test would have obvious clinical utility. Recently, luciferase immunoprecipitation system (LIPS) assays have been used to accurately quantify antibody responses to various viral pathogens [10]. In the present study, we used LIPS profiling of antibodies against the whole proteome of HCV and part of the proteome of HIV to evaluate its utility in predicting and monitoring the response to HCV therapy in HIV/HCV‐coinfected individuals.<br /><br />Methods. This was a prospective, open‐label trial performed at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, Maryland. All 29 patients provided written informed consent approved by the NIAID Institutional Review Board. HIV/HCV‐coinfected patients were treated with pegylated interferon alfa‐2b at 1.5 μg/kg subcutaneously every week (PegIntron; Schering‐Plough) and ribavirin daily (Rebetol; Schering‐Plough; 400 mg every morning and 600 mg every evening for those <75 kg or 600 mg twice per day for those >75 kg) for 48 weeks and followed up for 24 weeks after the end of treatment. All patients irrespective of virologic response were treated for 48 weeks. One patient discontinued ribavirin at week 24 because of refractory anemia but continued pegylated interferon until week 48.<br /><br /><br />Patients were eligible for the study if they were >18 years of age and had a CD4 T cell count of >100 cells/μL, an absolute neutrophil count of >1000 cells/μL, an HCV load of >2000 copies/mL, histologic evidence of chronic hepatitis C, and stable HIV disease with or without antiretroviral therapy. Patients with other causes of liver disease, advanced cirrhosis or severe liver decompensation, and several other conditions were excluded. These patients included 11 who experienced no response (NR group), 9 end‐of‐treatment responders who experienced relapse after 48 weeks of therapy (relapse group), and 9 who experienced sustained virologic responses (SVR group). All patients (except for 1 of the patients in the relapse group who was enrolled in the study and 1 of the previous patients in the NR group who was omitted because of lack of a serum sample) have been described elsewhere [9].<br /><br /><br />Renilla luciferase (Ruc) antigen fusions—including HCV core, HCV NS3, HCV NS5A, HIV p24 Gag, and HIV Tat—have been described elsewhere [10]. Four additional HCV proteins were generated as Ruc antigen fusions, including E1, E2, NS3, and NS4. One HCV protein, NS5B, was tested, but it was not found to be useful and was not used further. LIPS assays with these different HCV and other Ruc antigens were performed as described elsewhere [11]. All of the light unit (LU) data represent the average of 2 independent experiments and were corrected for background LU values.<br /><br /><br />Prism software (version 5; GraphPad) was used for statistical analyses. The Mann‐Whitney U test was used for comparison of antibody titers between groups, and the Wilcoxon signed rank test was used to evaluate statistical differences between values before and after HCV therapy.<br /><br />Results.<br />Antibody titers in serum samples from all patients and in 2 control samples were evaluated for 6 different recombinant HCV antigens, essentially derived from the whole proteome of HCV. A heat map, constructed with log10‐transformed antibody titers, was used to display the differing antibody responses to the 6 antigens in individual samples from these subgroups (Figure 1A). As shown by the heat map, LIPS profiling of responses to these 6 HCV antigens clearly distinguished the 29 HCV‐infected serum samples from the 2 uninfected control serum samples. The most useful antibody response was directed against the HCV core, for which all but 1 of the 29 HIV/HCV‐coinfected samples was positive. The second most useful antibody response was against NS3 (Figure 1A). The other 4 HCV proteins (E1, E2, NS4, and NS5) showed variable immunoreactivity with HIV/HCV‐coinfected serum samples (Figure 1A). Of interest, 1 patient in the NR group was completely negative for anti‐core, anti‐E1, and anti‐E2 antibodies but showed strong immunoreactivity to 3 other nonstructural HCV proteins (Figure 1A). Titers of antibodies against the 6 HCV antigens correlated poorly with each other (r8>0.60), suggesting marked heterogeneity in humoral responses (Table 1).<br /><br />Titers of antibodies against these HCV antigens in pretreatment serum samples showed no significant differences between the NR, relapse, and SVR groups (figure 2). For example, the mean anti‐core antibody titers in the NR, relapse, and SVR groups were 497,200 LUs (95% confidence interval [CI], 279,800–714,700 LUs), 483,400 LUs (95% CI, 292,500–674,200 LUs), and 545,600 LUs (95% CI, 299,400–791,900 LUs), respectively, and the Mann‐Whitney U test showed no statistically significant differences ( ). These results suggest that anti‐HCV antibody titers in the pretreatment HIV/HCV‐coinfected serum samples have no obvious predictive value for response to treatment.<br /><br />Because of the known effect that HIV/HCV coinfection has on HCV therapy, antibody responses to several HIV proteins were also evaluated in the 3 groups. As shown in Figure 1B, all 29 pretreatment serum samples were robustly seropositive for anti–HIV p24 Gag antibodies by previously determined cutoffs [10], whereas the 2 uninfected control samples were negative. The mean anti‐p24 antibody titers in the NR, relapse, and SVR groups were 2.77x10(6) , 2.17x10(6), and 1.71x10(6) LUs, respectively. The anti‐p24 antibody titer in the relapse group did not significantly differ from that in either the NR or SVR group (p>.47, Mann‐Whitney U test); the NR and SVR groups showed a statistically significant difference in anti‐p24 antibody titer (p=0.23). Anti‐p24 antibody titers did not correlate (p>.05) with HIV or HCV load, genotype, or CD4 T cell count (data not shown). However, anti‐p24 antibody titers paralleled the cumulative group scores for the interferon‐associated gene‐expression signature previously reported by Lempicki et al [9] for the same patients. Titers of antibodies against the Tat protein of HIV did not significantly differ between the NR, relapse, and SVR groups (p>.26) (data not shown). Because statistically higher anti‐p24 antibody titers were detected in the NR group versus the SVR group and correlated with failure of HCV therapy, a cutoff based on 2.2 million LUs was determined to optimally separate these 2 groups. By this approach, 9 of the 11 patients in the NR group were above the cutoff, compared with only 2 of the 9 patients in the SVR group (Figure 1B). On the basis of this analysis, anti‐p24 antibody titers provide 82% positive predictive value in identifying patients who will experience therapy failure. Although anti‐p24 antibody titers had value only in distinguishing NR from SVR (and none for relapse), there is little practical predictive value for this test in HIV/HCV‐coinfected individuals.<br /><br />Titers of antibodies against the panel of HCV proteins were also evaluated before and after treatment for their value in monitoring HCV therapy. The Wilcoxon sign ranked test revealed that 4 of the 6 HCV proteins (core, E1, E2, and NS4) showed statistically significant (p<.05) decreases in antibody titer between the pre‐ and posttreatment samples (Figure 3). In contrast, antibody responses to the NS3 and NS5A antigens did not significantly change between before and after treatment (p>.44). Substratification by treatment outcome revealed that the SVR group showed the most consistent and largest decrease (p=.02) in titers of antibodies against the 3 most informative antigens (core, E1, and NS4) after treatment (Figure 3). In contrast, the NR and relapse groups had relatively stable titers of antibodies against these 3 antigens between before and after treatment (p=.70 and p=.43, respectively) (Figure 3). Anti–HIV p24 and anti–BRLF2 Epstein‐Barr virus antibody titers also did not change with HCV therapy (data not shown). There was heterogeneity in response to the different HCV antigens in the SVR group, in which some patients showed the largest decrease in anti–HCV core antibody titers, whereas other patients showed more pronounced decreases in anti‐ENV1 and anti‐NS4 antibody titers. Because decreasing levels of antibodies against these 3 HCV antigens was a common feature of the SVR group versus the NR and relapse groups, the relative decrease in antibody titer between the pre‐ and posttreatment samples was the most useful approach for distinguishing SVR from NR and relapse. With an antibody titer decrease of >1.5‐fold between the pre‐ and posttreatment samples used as a marker of HCV therapy success, 6 of the 9 patients in the SVR group were positive, compared with only 1 of the 9 patients in the relapse group and none of the patients in the NR group. Overall, this LIPS assay measuring differences in titers of antibodies against these 3 HCV antigens between the pre and posttreatment samples showed an 86% positive predictive value in identifying a response to therapy.<br /><br />Figure 3. Informative antibody titers before and after hepatitis C virus (HCV) treatment in human immunodeficiency virus–coinfected patients in the no‐response (NR; n=11), relapse (n=9), and sustained virologic response (SVR) (n=9) groups. Shown are anti‐core, anti‐E1, and anti‐NS4 antibodies levels at baseline and after treatment in individual patients. The solid horizontal bars reflect the mean titer in each group for the pre‐ and posttreatment sample. Statistical differences between pre‐ and posttreatment values were calculated using the nonparametric Wilcoxon signed rank test. The P values derived from summation of the light unit (LU) antibody titers for the 3 antigens are shown at bottom.<br />Screen shot 2010-09-03 at 1.29.59 PM.png<br /><br />Discussion.<br /><br />Our study suggests that highly quantitative HCV proteome–wide antibody responses can be a valuable tool for monitoring and predicting HCV therapeutic responses among HIV‐coinfected patients. Few studies have examined the utility of anti‐pathogen antibodies for predicting and monitoring drug therapy. Our LIPS assay provided a clearer summary of the marked patient variability in humoral responses to the whole HCV proteome than has been previously reported. None of the baseline antibody responses to the 6 different HCV proteins predicted response to HCV therapy. This suggests that preexisting host humoral responses to HCV generally do not affect the response to HCV therapy. Previously, it has been shown that, among HCV‐monoinfected patients, those with SVRs had higher pretreatment anti‐NS4A and anti‐NS5a antibody titers (without normalization for HCV load) than did those with NRs [12]. It should be noted that our study differs from this published study in that our patient population was coinfected with HIV and HCV, and HCV loads were controlled for. Nevertheless, 1 patient in the NR group completely lacked anti‐core, anti‐E1, and anti‐E2 antibodies but had high levels of other HCV antibodies, possibly explaining the lack of responsiveness to HCV therapy. Given that this patient (infected with HCV genotype 1) had ample antibodies against HIV and nonstructural HCV proteins, it is likely that selective B cell exhaustion or deletion of certain populations of plasma B cells occurred [13, 14]. Intriguingly, anti–HIV p24 antibodies detected in the pretreatment samples inversely correlated with response to treatment. The highest anti‐p24 antibody titers were observed in the NR group, intermediate titers were observed in the relapse group, and the lowest titers were observed in the SVR group. The higher anti‐p24 antibody titers in the NR group compared with the SVR group suggests that some of the patients in the NR group who responded poorly to interferon treatment may have had an abnormal immune response to HIV.<br /><br /><br />Declining anti‐HCV core and envelope‐specific antibody responses at the end of therapy were observed only in the SVR group, suggesting that these antibody responses could be used to discriminate between those who experience relapse and SVR at the end of therapy. The SVR group showed the largest and most consistent decrease in titers of antibodies against the core, E1, and NS4 proteins after 48 weeks of treatment. In contrast, the NR and relapse groups showed minimal decreases in antibody titers. Despite the less than detectable levels of HCV RNA at the end of HCV treatment in the relapse and SVR groups, significant decreases in anti‐HCV antibody titers do frequently occur among patients with SVRs. Given that HCV loads in the relapse and SVR groups were clinically indistinguishable and below the level of detection, it is possible that the decrease in levels of antibodies in the SVR group reflects a marked decline in antigen load in the liver rather than in the plasma. Regardless of the mechanism, the differential response in antibody titers between the SVR and relapse groups at the end of treatment offers a novel tool to predict who will experience relapse after treatment is stopped. This could lead to the development of novel therapeutic strategies, such as extended therapy for those with relapse. Studies addressing whether these antibodies and/or other biomarkers show robust differences at earlier time points may provide practical tools for monitoring therapy.Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-39037555875340333102010-09-27T16:01:00.002-04:002010-09-27T16:02:42.096-04:00Is sexual contact a major mode of hepatitis C virus transmission?Is sexual contact a major mode of hepatitis C virus transmission? Review, early pub from CDC - pdf attached<br /><br /><br /><br />Hepatology Article first published online: 15 JUL 2010<br /><br />Rania A. Tohme1,2,*,‡, Scott D. Holmberg1<br /><br />1. Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Atlanta, GA<br /><br />2. Epidemic Intelligence Service, Office of Workforce and Career Development, Centers for Disease Control and Prevention, Atlanta, GA<br /><br />"This review focused on the risk of sexual transmission of hepatitis C infection and distinguished between heterosexual and homosexual contact. The real risk for sexual transmission appeared to be predominantly related to HIV infection: of all the practices considered in this review, the clearest and least equivocal risk behavior was unprotected sex between HIV-infected partners, particularly HIV-positive MSM. <br /><br />Since the last review of this topic in Hepatology, 80 the most notable trend has been a growing number of reports from European and American cities, indicating an increase in incidence and prevalence of HCV infection among HIV-infected MSM. <br /><br />This increase has mostly been reported after the introduction of highly active antiretroviral therapy treatment, which may contribute to risky sexual behavior due to the belief among these men that treatment will eliminate further risk of HIV infection. It has also been postulated that a greater proportion of HIV-infected MSM have been engaging in serosorting, 15, 16, 18, 74, 81-83 which is thought to be the source of a specific pan-national cluster of HCV infection in Europe. 68 In addition, the presence of several activities and conditions that disrupt anal mucosal integrity (traumatic sex, sex with visible blood, genital ulcerative diseases, use of sex toys) were frequently noted in these instances of putative sexual transmission......<br /><br />The use of condoms and refraining from high-risk sexual behavior is definitely indicated among persons who have HIV infection or another STI or who are not in a single-partner relationship. <br /><br />Initial testing for HCV is recommended for all individuals in the United States who are entering HIV care, 86 but annual or other regular testing should receive serious consideration. This review should form a basis for appropriate health messages to inform susceptible individuals of the real risks of HCV infection rather than distract them with highly unlikely sources of transmission.<br />"<br /><br /><br />"The presence of preexisting STIs has also been found to increase the risk of acquiring HCV by heterosexual contact. cross-sectional study in India showed that men infected with herpes simplex virus 2 were almost four times more likely to have HCV than men without herpes simplex virus 2 infection (aOR 3.85, 95% CI 1.18- 12.6). 47 Similarly, individuals with Trichomonas infection were much more likely to acquire HCV than individuals without an STI (aOR 3.3, 95% CI 1.7-6.3)......More unequivocal is the risk of heterosexual transmission to those who are infected with HIV. Two cross-sectional studies confirm a substantial increase in risk of acquiring HCV infection among heterosexual persons with preexisting HIV, particularly among those engaging in high-risk sexual behaviors and having unprotected sex with multiple sexual partners (Table 1). 48, 49 Notably, the large Women's Interagency HIV Study found that, controlling for IDU, HIV-infected women were still almost twice as likely as HIV-negative women to acquire HCV (aOR 1.9, 95% CI 1.2-2.9). 49 Likewise, a cross-sectional study among STD clinic attendees in Baltimore showed a four-fold increase in the risk of HCV infection among HIV-infected patients compared with those who were HIV-seronegative (aOR 4.4, 95% CI 1.9-10.3).......Incidence rates of HCV infection among HIV-uninfected men who have sex with men (MSM) have varied between zero cases per 100 person-years in Amsterdam 50 to 1.5 cases per 1,000 person-years in the United Kindgdom......The situation is entirely different for HIV-infected gay men, especially those who engage in high-risk and traumatic sex practices involving anal mucosal damage......Several longitudinal studies of HIV-infected MSM totaling more than 12,000 person-years of follow up have shown that these men are at much higher risk for sexually acquired HCV than HIV-uninfected MSM......Studies addressing the emerging public health problem of HCV in HIV-infected men are limited and are mainly from western Europe (Table 2), but they suggest that the incidence of HCV infection among HIV-positive MSM has been increasing......The French PRIMO cohort study also showed an increase in the incidence of HCV infection among HIV-infected individuals from 1.2 per 1,000 person-years before 2003 to 8.3 per 1,000 person-years after 2003.....The practice of “serosorting” among HIV-infected MSM – unprotected sex between two HIV-infected men who are aware of their own and their partners' HCV infection (but not necessarily HCV infection) –has been commonly reported in recent studies. (from Jules: I think this is a misprint, they meant to say they were aware of partner's HIV-infection but not HCV-infection status). Many common themes or risks have been observed in the majority of studies that have addressed HCV infection among HIV-infected MSM: engaging in unprotected sex with multiple partners, 14-16, 20, 53, 69-74 anal fisting, use of sex toys, and the presence of genital ulcerative disease."<br /><br />ABSTRACT<br /><br />Medical opinion varies considerably regarding the transmission of hepatitis C virus (HCV) through sexual contact. Based on the study design, representativeness of the study population, and the methods used for case ascertainment, we analyzed 80 qualifying reports regarding the evidence for or against sexual transmission. Regarding heterosexual transmission, the weight of evidence is that there is no increased risk of sexual transmission of HCV among heterosexual couples in regular relationships. This risk increases among persons with multiple sexual partners (adjusted odds ratio [aOR] 2.2-2.9), but this association may be confounded by increased likelihood of injection drug use with increased number of partners. There appears to be a real increased risk for women coinfected with human immunodeficiency virus (HIV) or other sexually transmitted infections (aOR 3.3-3.9) and especially for HIV-infected gay men who are having sex with one another compared with HIV-uninfected men (aOR 4.1-5.7). HIV-infected gay men increase their risk of such transmission in association with practices that lead to mucosal trauma (multiple sexual partners, fisting, use of sex toys) and the presence of genital ulcerative disease. Conclusion: This review should inform, and not distract from, recommendations to reduce the risk of HCV transmission. Health care providers need to pay special attention to sexual transmission of HCV among HIV-infected individuals. <br /><br /><br />Hepatitis C virus (HCV) infection is a blood-borne infection transmitted mainly through injection drug use (IDU), blood transfusions, organ transplantations, accidental needle sticks, 1, 2 and other parenteral exposures, including inappropriate use or reuse of needles and syringes in health care settings. 3, 4 Sexual transmission is a controversial mode of HCV transmission that has received considerable attention among health care providers and the lay public. For example, in 2009, the Centers for Disease Control and Prevention's Division of Viral Hepatitis received over 2,600 telephone and email inquiries about hepatitis C. When looking at available data that capture responses to inquiries, transmission modes of hepatitis C and the sexual transmission of hepatitis C infection were among the top used responses (Centers for Disease Control and Prevention, unpublished reports).<br /><br /><br />The possibility of sexual transmission of HCV infection is supported by the isolation of HCV RNA from semen and cervical smears in some studies 5-7 but not others. 8, 9 Furthermore, although the sexual transmission of the same hepatitis C virus strain, as determined by molecular analysis, has been documented in some case reports and case series, 10-20 the magnitude of the risk varies depending on the quality of the study design, the likelihood of unmeasured parenteral routes of transmission, and the level of risk behavior of the study participants.<br /><br /><br />Given the conflicting evidence and the ongoing inquiries, we conducted a review of the literature to summarize the best available data on the risk of HCV transmission through sexual activity.<br /><br />RESULTS<br /><br />Heterosexual Transmission.<br /><br /><br />Studies addressing heterosexual transmission of HCV distinguished among three types of sexual contacts: sexual contacts within regular partnerships; sexual contacts with multiple partners; and sexual contacts among persons with preexisting sexually transmitted infections (STIs) and/or human immunodeficiency virus (HIV). Table 1 summarizes major studies that assessed the risk of heterosexual transmission of HCV infection among these different groups.<br /><br />Several large prospective cohort studies did not show an increased risk for HCV transmission among heterosexual discordant couples (married or steady partners), even after 10 or more years of observation. 21-24 In these studies combined, there was no increased risk of sexual transmission of HCV, even after an estimated 750,000 vaginal and anal contacts between couples; accordingly, the probability of such transmission was less than 1 in 10 million sex contacts. Cross-sectional studies reported HCV prevalence rates among regular partners of infected persons varying between 2% and 10%. 21, 25, 26 However, no association was found between HCV infection and sexual transmission between partners in regular relationships after controlling for other risk factors. 25-32 Three studies documented the presence of the same virus in very few couples by molecular analysis and attributed this to sexual transmission of HCV, 33-35 but could not definitely exclude other common exposures.<br /><br /><br />A potentially confounding factor in the sexual transmission of HCV in heterosexual couples is the duration of the relationship, an index of the number of sexual exposures to HCV from an infected partner. Whereas a few studies found an increased risk of acquiring HCV infection with a longer relationship, 28, 35-37 other larger studies that controlled for age did not find a significant association between the duration of the relationship and HCV infection. 26, 27, 38, 39 The higher prevalence of HCV infection in older couples may represent a cohort effect (in which couples of the same age might be exposed to common sources of infection or common practices, such as the reuse of nondisposable but contaminated medical equipment), as was reported in Spain 40 and Taiwan. 41<br /><br /><br />Unlike couples in regular relationships, persons having multiple sexual partners have more than twice the likelihood of acquiring HCV infection (aOR 2.2-2.9). 42-45 Notably, a study conducted among pregnant women in Spain showed that women who had unprotected sexual relations with two to four partners were almost three times (aOR 2.8, 95% confidence interval [CI] 1.1-6.9) more likely to acquire HCV than women with only one steady partner. 42<br /><br /><br />Data regarding heterosexual transmission of hepatitis C should be interpreted with caution, however. Three large Italian cross-sectional studies showed that the risk of spousal transmission could also be explained by the common practice of sharing syringes. 25, 30, 36 Furthermore, a recent analysis of acute HCV infections in the United States has indicated that increased numbers of sexual partners correlates with increased likelihood of injection drug use (Monina Klevens, Centers for Disease Control and Prevention, unpublished data).<br /><br /><br />The presence of preexisting STIs has also been found to increase the risk of acquiring HCV by heterosexual contact. 46, 47 A cross-sectional study in India showed that men infected with herpes simplex virus 2 were almost four times more likely to have HCV than men without herpes simplex virus 2 infection (aOR 3.85, 95% CI 1.18- 12.6). 47 Similarly, individuals with Trichomonas infection were much more likely to acquire HCV than individuals without an STI (aOR 3.3, 95% CI 1.7-6.3). 46<br /><br /><br />More unequivocal is the risk of heterosexual transmission to those who are infected with HIV. Two cross-sectional studies confirm a substantial increase in risk of acquiring HCV infection among heterosexual persons with preexisting HIV, particularly among those engaging in high-risk sexual behaviors and having unprotected sex with multiple sexual partners (Table 1). 48, 49 Notably, the large Women's Interagency HIV Study found that, controlling for IDU, HIV-infected women were still almost twice as likely as HIV-negative women to acquire HCV (aOR 1.9, 95% CI 1.2-2.9). 49 Likewise, a cross-sectional study among STD clinic attendees in Baltimore showed a four-fold increase in the risk of HCV infection among HIV-infected patients compared with those who were HIV-seronegative (aOR 4.4, 95% CI 1.9-10.3). 46 In a study of hemophilic men and their partners 23 in which unacknowledged IDU was unlikely to be a confounding variable, 6% of hemophiliac men who were coinfected with HIV compared with only 2% of the men infected with HCV alone transmitted HCV to their spouses. In contrast, a smaller cohort study did not show evidence of sexual transmission of HCV from partners who were both HCV/HIV-coinfected. 22<br /><br />Homosexual Transmission.<br /><br /><br />Incidence rates of HCV infection among HIV-uninfected men who have sex with men (MSM) have varied between zero cases per 100 person-years in Amsterdam 50 to 1.5 cases per 1,000 person-years in the United Kindgdom. 51 The Omega Cohort Study, the only study that has included a large sample of MSM and controlled for all other HCV risk factors, did not find an increased risk for HCV infection among HIV-uninfected MSM, even among those engaging in risky sexual behaviors such as having multiple partners or unprotected anal sex 52; however, the observation time in this study was only 1 year, and few of the subjects engaged in such high-risk behavior. A prospective study from Australia showed lack of sexual transmission of HCV among HIV-negative MSM, 53 whereas another cohort study reported an HCV incidence of 0.11 per 100 person-years (95% CI 0.03-0.26) among HIV-negative MSM. 54 However, IDU was a common practice among these HCV-infected patients. Studies from Canada and Argentina also did not find an association between HCV infection and homosexual contact in HIV-uninfected men. 55, 56<br /><br /><br />The situation is entirely different for HIV-infected gay men, especially those who engage in high-risk and traumatic sex practices involving anal mucosal damage. Studies addressing the emerging public health problem of HCV in HIV-infected men are limited and are mainly from western Europe (Table 2), but they suggest that the incidence of HCV infection among HIV-positive MSM has been increasing. A cohort study in Amsterdam showed a significant increase in HCV incidence among HIV-infected MSM, from 0.08 cases per 100 person-years between 1984 and 1999 to 0.87 cases per 100 person-years between 2000 and 2003. 50 Similarly, it has been estimated that the incidence of acute HCV infections among HIV-infected MSM in the United Kingdom has increased by 20% every year since 2002. 57, 58 The French PRIMO cohort study also showed an increase in the incidence of HCV infection among HIV-infected individuals from 1.2 per 1,000 person-years before 2003 to 8.3 per 1,000 person-years after 2003. 59<br /><br />Several longitudinal studies of HIV-infected MSM totaling more than 12,000 person-years of follow up have shown that these men are at much higher risk for sexually acquired HCV than HIV-uninfected MSM (aOR, 4.1 to 5.7). 50, 51, 60 Likewise, a large cross-sectional study in Amsterdam reported that HIV-infected MSM were almost 43 times (95% CI 8.49-215.1) more likely to acquire HCV infection than HIV-uninfected MSM. 61 HIV-positive men were much more likely to be coinfected with HCV in a few Australian studies, 53, 62 but IDU was also known to be widely prevalent among MSM in Australia. 53, 54, 62 A smaller cross-sectional study from the United States showed that HCV-infected MSM with were more likely to be coinfected with HIV than those who were HCV-negative (70% versus 29%). 63 Similarly, sexual transmission was the sole identified route of HCV infection among HIV-infected MSM in France. 59 Only a few cross-sectional studies have not shown an increased risk of HCV infection among HIV-infected MSM or found an association between HCV and HIV coinfection. 64-67<br /><br /><br />The practice of “serosorting” among HIV-infected MSM – unprotected sex between two HIV-infected men who are aware of their own and their partners' HCV infection (but not necessarily HCV infection) –has been commonly reported in recent studies. 15, 16, 68, 69 Many common themes or risks have been observed in the majority of studies that have addressed HCV infection among HIV-infected MSM: engaging in unprotected sex with multiple partners, 14-16, 20, 53, 69-74 anal fisting, use of sex toys, and the presence of genital ulcerative disease. 15-20, 50, 54, 61, 63, 69, 70, 74-78 In the only well-designed case control study thus far, participation in group sex was more prevalent among HIV-coinfected HCV cases compared with controls (88% versus 52%). 69 Participation in group sex significantly increased the odds for HCV infection (aOR 9.16, 95% CI 3.51-23.9) if it involved at least two of the following four sexual practices: receptive and insertive anal intercourse and receptive and insertive fisting. 69 Fisting significantly increased the risk of HCV infection among HIV-infected MSM by more than five-fold (aOR 6.27-12.6), 61, 70 as did the use of sex toys (78% versus 43%). 69 Fisting was highly correlated with use of sex toys, group sex, and bleeding in a cross-sectional study from Amsterdam. 61 In addition, the use of psychoactive substances was common among HCV/HIV-coinfected MSM and might have acted as a disinhibitor for risky sexual practices, leading to traumatic sex and mucosal damage. 55, 74 Thus, some researchers have concluded that the real risk of sexual transmission in HIV-infected persons results from blood-to-blood contact during sex. 78<br /><br /><br />It is worth noting that phylogenetic analyses in cohort studies 50, 75 and in an international network of MSM 68 have also indicated concordance of gene sequences in recovered HCV strains. The difficult-to-treat genotypes 1a and 4d were usually recovered. 17, 18, 50, 59, 61, 68, 69, 74, 79<br /><br />DISCUSSION<br /><br />This review focused on the risk of sexual transmission of hepatitis C infection and distinguished between heterosexual and homosexual contact. The real risk for sexual transmission appeared to be predominantly related to HIV infection: of all the practices considered in this review, the clearest and least equivocal risk behavior was unprotected sex between HIV-infected partners, particularly HIV-positive MSM.<br /><br /><br />Since the last review of this topic in Hepatology, 80 the most notable trend has been a growing number of reports from European and American cities, indicating an increase in incidence and prevalence of HCV infection among HIV-infected MSM. 14, 18, 50, 54, 55, 57-59, 61, 69, 74, 75 This increase has mostly been reported after the introduction of highly active antiretroviral therapy treatment, which may contribute to risky sexual behavior due to the belief among these men that treatment will eliminate further risk of HIV infection. It has also been postulated that a greater proportion of HIV-infected MSM have been engaging in serosorting, 15, 16, 18, 74, 81-83 which is thought to be the source of a specific pan-national cluster of HCV infection in Europe. 68 In addition, the presence of several activities and conditions that disrupt anal mucosal integrity (traumatic sex, sex with visible blood, genital ulcerative diseases, use of sex toys) were frequently noted in these instances of putative sexual transmission.<br /><br /><br />The use of molecular sequencing in some case reports has led some researchers to conclude that HCV transmission between spouses was caused by sexual contact. However, this finding does not preclude that the virus might have been transmitted through unacknowledged needle (or other sharp object) sharing. 31, 84, 85 In fact, when the risk of spousal HCV transmission was analyzed in Italy, this resulted from the common practice of sharing syringes. 25, 30, 36 Although phylogenetic analysis is a useful laboratory technique to demonstrate genetic similarities or variations in recovered viruses, it does not obviate the role of careful epidemiological analysis.<br /><br /><br />The studies included in our review had several limitations. A major limitation common to all the studies was the unavoidable reliance on self reports for the ascertainment of IDU. Unacknowledged or unascertained IDU among men and women with multiple sex partners undoubtedly confounds all analyses of association of HCV infection with number of sex partners. Another limitation is that the risk from and exposure to other sharp objects as potential vehicles for transmission cannot be excluded. 63, 65, 66, 70 Furthermore, prospective cohort studies of heterosexual couples in a single-partner relationship may have preselected persons who would be unlikely to transmit the virus—that is, if transmission of HCV occurred in one of the first sexual encounters, choosing discordant couples for analysis (those who have not previously transmitted) may represent a selection bias.<br /><br /><br />Despite these limitations, studies could be categorized and evaluated as to their quality and credibility and conclusions drawn. The use of condoms and refraining from high-risk sexual behavior is definitely indicated among persons who have HIV infection or another STI or who are not in a single-partner relationship. Health care providers need to pay special attention to HIV-infected MSM. Initial testing for HCV is recommended for all individuals in the United States who are entering HIV care, 86 but annual or other regular testing should receive serious consideration. This review should form a basis for appropriate health messages to inform susceptible individuals of the real risks of HCV infection rather than distract them with highly unlikely sources of transmission.Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-54842673346325062622010-09-27T16:01:00.001-04:002010-09-27T16:01:28.008-04:00Prediction of Response to Pegylated Interferon plus Ribavirin by IL28B Gene Variation in Patients Coinfected with HIV and Hepatitis C VirusPrediction of Response to Pegylated Interferon plus Ribavirin by IL28B Gene Variation in Patients Coinfected with HIV and Hepatitis C Virus<br /><br />Juan A. Pineda,1 Antonio Caruz,3 Antonio Rivero,4 Karin Neukam,1 Irene Salas,3 Ángela Camacho,4 José C. Palomares,2 José A. Mira,1 Antonio Martínez,5 Carmen Roldán,1 Julián de la Torre,4 and Juan Macías1<br /><br />Units of 1Infectious Diseases and 2Microbiology, Hospital Universitario de Valme, Seville, 3Immunogenetics Unit, Faculty of Sciences, Universidad de Jaen, Jaen, and 4Unit of Infectious Diseases and 5Molecular Genetics Laboratory, Unit of Clinical Analysis, Hospital Universitario Reina Sofía, Cordoba, Spain<br /><br />"The results of this study show that the IL28B genotype is a strong predictor of SVR to pegylated interferon plus ribavirin in HIV/HCV‐coinfected patients with genotype 1 and non–genotype 1 HCV infection. Specifically, rs12979860 genotype CC is associated with a 2‐fold higher rate of SVR than TC/TT genotype. IL28B gene variation predicts SVR independently from other well‐defined factors that are associated with this outcome in HCV‐monoinfected and HIV/HCV‐coinfected patients, such as HCV genotype, baseline plasma HCV RNA burden, and sex [1, 11]. After viral genotype, IL28B is the strongest predictor of SVR, being even more potent than HCV RNA load. <br /><br />The effect of rs12979860 variation on SVR had been proven in HCV‐monoinfected patients with HCV genotype 1 [2] or in those harboring genotype 1 or 4 as a whole [5]. The present study shows that the impact of rs12979860 genotype is more potent in patients with HCV genotype 1 and in HCV genotype 4 carriers. However, the effect also appears to be exerted in patients with genotype 3.....<br /><br />The mechanisms whereby rs12979860 has an impact on the response to pegylated interferon plus ribavirin is not completely understood.....<br /><br />it is possible that changes in rs12979860 genotype are associated with abnormalities in the IFN‐λ3 signal transduction pathway, although functional data are lacking."<br /><br />"Determinations of the IL28B genotype should be incorporated into daily clinical care soon. In fact, the rs12979860 genotype allows us to select a subpopulation with a high likelihood to respond to therapy, and more importantly, used along with other predictors of SVR, it identifies patients with a very low probability of SVR. Thus, just 10% of patients with HCV genotype 1 or 4, a baseline plasma HCV RNA load >600,000 IU/mL, and rs12979860 TC/TT achieved SVR in the population included herein. According to these findings, therapy with pegylated interferon plus ribavirin in patients with the former profile could be deferred until new options are available, at least in patients without advanced fibrosis. This is important because a course of therapy with a low likelihood of success could be spared in almost one‐quarter of all patients, because 25% of the participants in this study carried HCV genotype 1 or 4, an HCV RNA load >600,000 IU/mL, and rs12979860 genotype TC/TT. Moreover, the IL28B genotype, along with other baseline predictors of response or the viral kinetics in the early stages of treatment, might allow us to design models to accurately predict SVR or lack thereof, at least in some of the candidates treated with pegylated interferon plus ribavirin."<br /><br /><br />"Beside HCV genotype 2–3 and rs12979860 genotype CC, female sex, baseline HCV RNA level <600,000 IU/mL, an exposure to the planned dosage of HCV therapy >80%, lack of concomitant antiretroviral treatment, and lack of treatment with abacavir were associated with SVR in the univariate analysis (Table 3). The median baseline level of plasma LDL‐C was 90 mg/dL (interquartile range, 74–117 mg/dL) in patients who achieved SVR and 73 mg/dL (interquartile range, 61–97 mg/dL) in those who did not (p=.033). In the multivariate analysis, HCV genotype 2–3, rs12979860 genotype CC, plasma HCV level <600,000 IU/mL, and female sex independently predicted SVR (Table 3)."<br /><br />"In the intention‐to‐treat analysis, 77 patients (46%) attained SVR. Specifically, 33 (30%) of 111 patients with genotypes 1–4 and 44 (76%) of 58 patients with genotypes 2–3 (p<.001) achieved SVR.....rs12979860 genotypes were TT in 20 patients (13%), TC in 66 patients (43%), and CC in the remaining 68 patients (44%)......34 patients (41%) with HCV genotype 1, 1 (100%) with genotype 2, 28 (56%) with genotype 3, and 5 (24%) with genotype 4 harbored rs12979860 CC (p=.049).......HCV viral load among patients with rs12979860 CC was 6.11 log10 IU/mL versus 6.09 log10 IU/mL among those with genotype TC/TT (p=.467).....The frequency of the allele C was significantly higher among patients with SVR (75% vs 56%; p<.005). The rates of SVR according to the rs12979860 genotype were 50% in TT carriers, 29% in TC carriers, and 71% in CC carriers (p<.001). SVR was significantly more common among patients with genotype CC than among those with genotypes TC/TT, considered as a whole (71% vs 34%; odds ratio [OR], 4.7; 95% confidence interval [CI], 2.4–9.4; p<.001). Differences between patients with rs12979860 CC and those with TC/TT regarding SVR were mainly seen in patients with HCV genotype 1 or 4 (Figure 1). The rates of SVR in patients with HCV genotype 1–4 were 54% in CC carriers and 19% in TC/TT carriers (p<.001). The corresponding rates in patients with HCV genotype 2 or 3 were 93% for genotype CC and 77% for TC/TT (p=.104).....<br /><br />Nine nonresponders (18%) had the CC genotype, and 41 (82%) had the TC/TT genotype ( ). No statistically significant difference was found in terms of viral breakthroughs or relapses in relation to rs12979860 (Table 2). The rates of response at each time point of the follow‐up with respect to the IL28B genotype are given in Table 2."<br /><br />Figure1. Rate of sustained virologic response (SVR) according to rs12979860 genotype in patients with hepatitis C virus (HCV) genotype 1, 3, and 4.<br />Screen shot 2010-09-02 at 9.32.29 AM.png<br /><br />ABSTRACT<br /><br /><br />Background. Variation in the IL28B gene is associated with sustained virologic response (SVR) to pegylated interferon plus ribavirin in hepatitis C virus (HCV)–monoinfected patients with genotype 1. Data on other genotypes and on patients coinfected with human immunodeficiency virus (HIV) and HCV are more limited. We aimed to assess the predictive ability of variations in the single‐nucleotide polymorphism rs12979860 for SVR in HIV/HCV‐coinfected patients, regardless of HCV genotype.<br /><br /><br />Methods. The rs12979860 genotype was determined by polymerase chain reaction in 154 patients who had received therapy against HCV with pegylated interferon plus ribavirin.<br /><br /><br />Results. rs12979860 genotype was TT in 20 patients (13%), TC in 66 patients (43%), and CC in 68 patients (44%). Rates of SVR in patients with genotype CC and in those with genotype TC or TT, according to HCV genotype, were, respectively, 50% and 17% (p<.001) in patients with genotype 1, 80% and 25% (p=.027) in patients with genotype 4, and 93% and 77% (p=.115) in patients with genotype 3. The median (interquartile range) low‐density lipoprotein cholesterol level in patients with rs12979860 CC was 89 mg/dL (73–120 mg/dL) versus 75 mg/dL (55–91 mg/dL) (p=.001) in those with TC or TT. Independent predictors of SVR were HCV genotype 2–3 (odds ratio [OR], 13.98; 95% confidence interval [CI], 4.87–40.1; p<.001), rs12979860 CC (OR, 5.05; 95% CI, 2.04–12.5; p<.001), baseline plasma HCV RNA load of 600,000 IU/mL (OR, 1.99; 95% CI, 1.18–3.34; p=.009), and female sex (OR, 4.28; 95% CI, 1.08–16.96;p=.039 ).<br /><br /><br />Conclusions. IL28B gene variations independently predict SVR in HIV/HCV‐coinfected patients with HCV genotype 1 and non–genotype 1 HCV infection. The association between rs12979860 and plasma low‐density lipoprotein cholesterol suggests that the system low‐density lipoprotein ligand/receptor might be involved in the effect of this genotype.<br /><br />The likelihood of attaining a sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infection depends on viral‐, disease‐, and host‐related factors [1]. Among host‐related factors, genetic factors may play a critical role. Thus, it has been proven that polymorphisms near the IL28B gene on chromosome 19, which encodes the type III interferon (IFN‐λ3), predict SVR in HCV‐monoinfected patients bearing genotype 1 who are treated with pegylated interferon plus ribavirin [2–5]. Specifically, the single‐nucleotide polymorphism (SNP) rs12979860, located 3 kilobases upstream of the IL28B gene, is associated with more than a 2‐fold difference in the rate of SVR [2]. Likewise, this polymorphism confers a 3‐fold higher ability to spontaneously clear HCV [6]. The use of these genetic markers may help us to select patients who are more or less prone to respond to pegylated interferon plus ribavirin. The information on the predictive value of variations in the IL28B gene in patients harboring HCV genotypes other than 1 is more limited, but recent studies have shown that they are also associated with response to pegylated interferon plus ribavirin in genotype 1 or 4 carriers, considered as a whole, but not in those bearing genotype 2 or 3 [5, 7].<br /><br /><br />Patients who are coinfected with human immunodeficiency virus (HIV) and HCV have singularities regarding predictors of SVR. Thus, the overall rate of response in HIV/HCV‐coinfected patients is lower than that in HCV‐monoinfected patients [8]. Moreover, certain conditions that may have a negative impact on SVR are more common among or exclusive to HIV‐infected patients, such as antiretroviral drugs interfering with hepatitis C therapy, CD4+ cell depletion, insulin resistance, steatosis, or advanced fibrosis [8]. A recent study has suggested that the rs12979860 genotype also predicts SVR in HIV/HCV‐coinfected patients with genotypes 1–4 considered together [7], but additional studies are required to confirm this point, to know the role of the IL28B genotype in patients with specific HCV genotypes, and to analyze the associations of the IL28B genotype with other factors that may influence SVR in HIV/HCV‐coinfected patients.<br /><br /><br />In this study, we aimed to assess whether the polymorphism rs12979860 in the IL28B region independently predicts SVR in a cohort of HIV‐infected patients with chronic hepatitis C who were treated with pegylated interferon plus ribavirin without HCV genotype restriction.<br /><br /><br />Discussion<br /><br /><br />The results of this study show that the IL28B genotype is a strong predictor of SVR to pegylated interferon plus ribavirin in HIV/HCV‐coinfected patients with genotype 1 and non–genotype 1 HCV infection. Specifically, rs12979860 genotype CC is associated with a 2‐fold higher rate of SVR than TC/TT genotype. IL28B gene variation predicts SVR independently from other well‐defined factors that are associated with this outcome in HCV‐monoinfected and HIV/HCV‐coinfected patients, such as HCV genotype, baseline plasma HCV RNA burden, and sex [1, 11]. After viral genotype, IL28B is the strongest predictor of SVR, being even more potent than HCV RNA load.<br /><br /><br />The effect of rs12979860 variation on SVR had been proven in HCV‐monoinfected patients with HCV genotype 1 [2] or in those harboring genotype 1 or 4 as a whole [5]. The present study shows that the impact of rs12979860 genotype is more potent in patients with HCV genotype 1 and in HCV genotype 4 carriers. However, the effect also appears to be exerted in patients with genotype 3. Statistically significant differences were not reached in terms of SVR between patients with HCV genotype 3 who bore rs12979860 CC and those who did not in this study, although there was a difference of 16% in the rate of SVR. Recently, an association has also been reported between rs12979860 CC in HIV/HCV‐coinfected patients with HCV genotype 1–4 but not in those with genotype 3 [7]. However, both in this case and in our study, this finding might be merely a matter of statistical power.<br /><br /><br />The distribution of rs12979860 genotypes according to the HCV genotypes that the patients harbored was notable. Indeed, rs12979860 genotype CC was significantly more common in patients with genotype 3 than in patients with HCV genotype 1 or 4, similar to what has been reported in HCV‐monoinfected patients [12]. The underlying mechanism for this finding is not clear. Whether genotype CC leads the individual to be more prone to infection with HCV genotype 3 or whether infection with HCV genotype 3 becomes chronic more often than does infection caused by other genotypes in patients with rs12979860 CC are topics to be investigated.<br /><br /><br />The mechanisms whereby rs12979860 has an impact on the response to pegylated interferon plus ribavirin is not completely understood. In previous studies involving HCV‐monoinfected patients, allele C was unexpectedly associated with a higher baseline plasma HCV RNA level [2]. This finding has not been confirmed in this study. In any case, rs12979860 CC does not seem to negatively influence the replication of HCV, at least in untreated patients. This SNP has a strong linkage disequilibrium with a nonsynonymous coding variant in the IL28B gene (213A>G, K70R; rs81031142) [2]. Thus, it is possible that changes in rs12979860 genotype are associated with abnormalities in the IFN‐λ3 signal transduction pathway, although functional data are lacking. IFN‐λ1, another type III interferon, inhibits HCV replication, increases the levels of interferon‐stimulated genes, and enhances the antiviral effect of interferon alfa [13]. It is conceivable that IFN‐λ3, a closely related cytokine with activity against other viruses comparable to that of IFN‐λ1 [14], works in a similar way against HCV [6]. However, the lack of association between rs12979860 genotype CC and lower baseline plasma HCV RNA burden argues against this hypothesis.<br /><br /><br />The association between rs12979860 genotype and plasma levels of LDL‐C is striking [15]. In vitro studies have shown that LDL may competitively inhibit the binding of HCV to the LDL receptor, which functions as one of the cellular receptors for HCV [16, 17]. This competitive blockade would hamper the infection of hepatocytes with HCV [18]. Accordingly, higher levels of plasma LDL‐C have been shown to be an independent predictor of SVR, both in HCV‐monoinfected [19, 20] and in HIV/HCV‐coinfected patients [21], in studies specifically designed to appraise this issue. Likewise, SNP in LDL receptor, similar to rs12979860 variations, are associated with both response to treatment and spontaneous clearance of HCV [22]. How variations in rs12979860 could determine the levels of LDL‐C is unclear. Certain soluble LDL receptor isoforms are induced in response to interferon stimulation [23]. We could speculate that an rs12979860 genotype other than CC could induce soluble isoforms of the LDL receptor, which join to plasma LDL, decreasing LDL levels and allowing an easier entrance of HCV into the hepatic cell. Studies aimed to search for a genetic interaction between the IL28B locus and the LDL receptor or the LDL ligands and LDL receptor system are warranted. In the meantime, an effect on this system should be regarded as one of the putative underlying mechanisms that explain the impact of IL28B gene variations on the spontaneous and drug‐induced clearance of hepatitis C virus.<br /><br /><br />This study has several limitations. A pretherapy liver biopsy and a determination of baseline LDL‐C level were not available in all patients. Concerning preexisting advanced liver fibrosis, an assessment of this parameter could be performed in most participants using either biopsy or transient elastography. In any case, the potential impact of LDL‐C level and advanced liver fibrosis on the probability of SVR was much lower than that of rs12979860 genotype. In addition, insulin resistance, a factor that has been reported to be associated with a lower rate of SVR [24], was not measured here. However, the role of insulin resistance in response to HCV therapy in HIV‐coinfected patients is controversial [25, 26]. Because of all these reasons and the results of previous studies, it is extremely unlikely that the association between the IL28B genotype and SVR found in this study is the result of confounding factors. On the other hand, these results provide data on the predictive value of IL28B gene variations coming from daily clinical practice, outside randomized clinical trials. Moreover, we provide specific data on this factor in HCV genotype 3 and 4 infections. These are strengths of this study.<br /><br /><br />Determinations of the IL28B genotype should be incorporated into daily clinical care soon. In fact, the rs12979860 genotype allows us to select a subpopulation with a high likelihood to respond to therapy, and more importantly, used along with other predictors of SVR, it identifies patients with a very low probability of SVR. Thus, just 10% of patients with HCV genotype 1 or 4, a baseline plasma HCV RNA load >600,000 IU/mL, and rs12979860 TC/TT achieved SVR in the population included herein. According to these findings, therapy with pegylated interferon plus ribavirin in patients with the former profile could be deferred until new options are available, at least in patients without advanced fibrosis. This is important because a course of therapy with a low likelihood of success could be spared in almost one‐quarter of all patients, because 25% of the participants in this study carried HCV genotype 1 or 4, an HCV RNA load >600,000 IU/mL, and rs12979860 genotype TC/TT. Moreover, the IL28B genotype, along with other baseline predictors of response or the viral kinetics in the early stages of treatment, might allow us to design models to accurately predict SVR or lack thereof, at least in some of the candidates treated with pegylated interferon plus ribavirin.<br /><br /><br />In summary, variation in the IL28B locus is a more potent predictor of response in HIV/HCV‐coinfected patients than others currently used, such as plasma HCV RNA load. Its effect is evident not only in patients with HCV genotype 1 but also in those with HCV genotype 4 and, probably, in genotype 3 carriers. The SNP rs12979860 correlates with plasma LDL‐C level, which might play a role in the mechanism of action of this polymorphism. The use of this genotype in routine clinical practice may select patients with very high or very low likelihood of therapy success.<br /><br />Results<br /><br /><br />Features of the study population.<br />All patients were of European ancestry. Nine (5%) of 169 patients who started therapy discontinued it because of adverse events, and 6 (4%) voluntarily dropped out. Consequently, 154 patients constituted the on‐treatment population. The main baseline characteristics of this group are given in Table 1. Baseline plasma HCV RNA load was <600,000 IU/mL in 62 patients (40%). CD4+ cell counts were <250 cells/mm3 in 17 patients (11%).<br /><br />Response to HCV therapy.<br />In the intention‐to‐treat analysis, 77 patients (46%) attained SVR. Specifically, 33 (30%) of 111 patients with genotypes 1–4 and 44 (76%) of 58 patients with genotypes 2–3 (p<.001) achieved SVR. The corresponding figures in the on‐treatment analysis were 50% for the overall population, 32% for genotype 1–4 carriers, and 86% for those harboring genotype 2–3 (p<.001).<br /><br /><br />IL28B genotype.<br />rs12979860 genotypes were TT in 20 patients (13%), TC in 66 patients (43%), and CC in the remaining 68 patients (44%). These genotypes were in the Hardy‐Weinberg equilibrium (p=.97). The frequency of the allele C was significantly higher among patients with SVR (75% vs 56%; p=.005). The rates of SVR according to the rs12979860 genotype were 50% in TT carriers, 29% in TC carriers, and 71% in CC carriers (p<.001). SVR was significantly more common among patients with genotype CC than among those with genotypes TC/TT, considered as a whole (71% vs 34%; odds ratio [OR], 4.7; 95% confidence interval [CI], 2.4–9.4; p<.001) (Figure 1). Differences between patients with rs12979860 CC and those with TC/TT regarding SVR were mainly seen in patients with HCV genotype 1 or 4 (Figure 1). The rates of SVR in patients with HCV genotype 1–4 were 54% in CC carriers and 19% in TC/TT carriers (p<.001). The corresponding rates in patients with HCV genotype 2 or 3 were 93% for genotype CC and 77% for TC/TT (p=.104).<br /><br />Nine nonresponders (18%) had the CC genotype, and 41 (82%) had the TC/TT genotype (p<.001). No statistically significant difference was found in terms of viral breakthroughs or relapses in relation to rs12979860 (Table 2). The rates of response at each time point of the follow‐up with respect to the IL28B genotype are given in Table 2.<br /><br />The distribution of rs12979860 genotypes in carriers of different HCV genotypes was not uniform. Thus, 34 patients (41%) with HCV genotype 1, 1 (100%) with genotype 2, 28 (56%) with genotype 3, and 5 (24%) with genotype 4 harbored rs12979860 CC (p=.049). Median (interquartile range) baseline HCV viral load among patients with rs12979860 CC was 6.11 log10 IU/mL versus 6.09 log10 IU/mL among those with genotype TC/TT (p=.467). There was a strong relationship between rs12979860 genotype and the baseline level of plasma low‐density lipoprotein cholesterol (LDL‐C) level (Figure 2). Thus, the median (interquartile range) LDL‐C level in patients with rs12979860 CC was 89 mg/dL (73–120 mg/dL) versus 75 mg/dL (55–91 mg/dL) (p=.001) in those with genotype TC/TT.<br /><br />Predictors of SVR.<br />Beside HCV genotype 2–3 and rs12979860 genotype CC, female sex, baseline HCV RNA level <600,000 IU/mL, an exposure to the planned dosage of HCV therapy >80%, lack of concomitant antiretroviral treatment, and lack of treatment with abacavir were associated with SVR in the univariate analysis (Table 3). The median baseline level of plasma LDL‐C was 90 mg/dL (interquartile range, 74–117 mg/dL) in patients who achieved SVR and 73 mg/dL (interquartile range, 61–97 mg/dL) in those who did not (p=.033). In the multivariate analysis, HCV genotype 2–3, rs12979860 genotype CC, plasma HCV level <600,000 IU/mL, and female sex independently predicted SVR (Table 3).<br /><br />Thirty‐nine patients (25%) carried HCV genotype 1–4, rs12979860 TC/TT, and a plasma HCV load 600,000 IU/mL. Only 4 (10%) of these individuals attained SVR.<br /><br />Table 3. Predictors of Sustained Virologic Response in the Univariate and Multivariate Analyses<br />Screen shot 2010-09-02 at 9.42.49 AM.png<br />Screen shot 2010-09-02 at 9.43.09 AM.png<br /><br /><br />Methods<br /><br /><br />Study cohort.<br />From October 2001 through June 2008, a cohort of 169 HIV/HCV‐coinfected patients, previously naive for pegylated interferon and ribavirin, consecutively started therapy for chronic HCV infection in 2 tertiary care centers in southern Spain. Patients were prospectively followed up. Visits were scheduled at least every 4 weeks during the first 24 weeks of treatment and every 8–12 weeks thereafter. In addition, all patients were assessed 24 weeks after stopping therapy. At each visit, clinical, biochemical, and hematologic assessments were performed. A whole blood sample was collected from all patients and cryopreserved at −70°C for genetic determinations.<br /><br /><br />Drug therapy.<br />All patients were given pegylated interferon alfa‐2a at a dosage of 180 μg once per week or pegylated interferon alfa‐2b at a dosage of 1.5 μg/kg once per week, both in combination with ribavirin at a daily dose of 800–1200 mg. Patients harboring HCV genotype 2 or 3 received HCV therapy for 24 weeks if they had an undetectable plasma HCV RNA load at week 4. The length of therapy was 48 weeks in the remaining patients. At weeks 12 and 24, HCV therapy was prematurely discontinued in nonresponders.<br /><br /><br />Definition of viral response.<br />The outcome variable in this study was SVR, defined as undetectable HCV RNA in serum 24 weeks after the completion of HCV therapy. A decrease in plasma HCV RNA level >2 log10 or below the detection threshold at week 12 was considered to be an early virologic response. An end‐of‐treatment response was defined as undetectable plasma HCV RNA at the completion of therapy. Patients without early virologic response, as well as those with detectable plasma HCV RNA at week 24, were considered to be nonresponders. Virologic breakthrough was defined as detectable plasma HCV RNA after week 24 of therapy in patients with a previous undetectable HCV load. Relapse was defined as a lack of SVR after having reached end‐of‐treatment response.<br /><br /><br />The plasma HCV RNA load was measured using a quantitative polymerase chain reaction assay according to the available technique (Cobas Amplicor HCV Monitor [Roche Diagnostic Systems], with a detection limit of 600 IU/mL; Cobas AmpliPrep‐Cobas TaqMan [Roche Diagnostic Systems], with a detection limit of 50 IU/mL; and Cobas TaqMan [Roche Diagnostic Systems], with a detection limit of 10 IU/mL).<br /><br /><br />Determination of the IL28B genotype. DNA was extracted using the automated MagNA Pure DNA extraction method (Roche Diagnostics). The rs129679860 SNP was genotyped using a custom TAQMAN genotyping assay (Applied Biosystems) on DNA isolated from whole blood samples. The DNA was genotyped according to the manufacturer’s instructions on a MX3005 thermocycler using MXpro software (Stratagene). The researchers responsible for genotyping procedures were unaware of other data from the patients.<br /><br /><br />Data analysis. Hardy‐Weinberg equilibrium was calculated using Haploview software (http://www.broadinstitute.org/haploview/haploview) [9]. The association between SVR and rs12979860 genotype was analyzed. A dominant model (TT=TC<CC) was used. Likewise, we assessed the relationship between SVR rate and parameters that might have an impact on the response to HCV therapy. For this analysis, advanced fibrosis was defined as a stage of fibrosis of F3 or higher, according to Scheuer’s scoring system [10], in patients who had undergone a pretreatment liver biopsy, or as a baseline liver stiffness of 11 kPa, as determined by transient elastography (FibroScan; Echosens), in those who had not undergone a pretherapy liver biopsy. Two sensitivity analyses were performed for estimating SVR. On the one hand, we conducted an intention‐to‐treat approach, considering all noncompleters or missing patients as having experienced treatment failure. On the other hand, an on‐treatment analysis, excluding patients who dropped out or discontinued therapy because of adverse events, was performed. The associations between SVR and these variables were appraised on an on‐treatment basis.<br /><br /><br />The frequencies were compared using the χ2 test or Fisher’s exact test. The Student’s t test was used for comparisons among continuous variables in the 2 groups if a normal distribution was followed, and the Mann‐Whitney U test was used if a normal distribution was not followed. For comparing continuous variables in >2 groups, the Kruskal‐Wallis test was used. The median was used as the cutoff value when continuous variables were categorized, unless otherwise specified. Variables associated with SVR in the univariate analysis with p<.20 were entered in logistic regression models, where SVR was the dependent variable. The analysis was performed using the SPSS statistical software package, version 15.0 (SPSS), and the Stata/SE 9 package (Stata).<br /><br /><br />Ethical aspects. The study was designed and performed according to the Helsinki Declaration and was approved by the ethics committees of both participating hospitals. All patients provided written informed consent to participate in this study.Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-85681735219146000542010-09-27T16:00:00.001-04:002010-09-27T16:00:48.171-04:00Abbott Receives FDA Approval for First Automated Molecular Test for Assessing Hepatitis B TreatmentAbbott Receives FDA Approval for First Automated Molecular Test for Assessing Hepatitis B Treatment<br /><br /> <br /><br /><br />DES PLAINES, Ill., Sept. 1 /PRNewswire-FirstCall/ -- Abbott (NYSE: ABT) announced today it has received approval from the U.S. Food and Drug Administration (FDA) to market the Abbott RealTime HBV assay for measuring viral load or the amount of hepatitis B virus (HBV) in a patient's blood. It is the first and only approved test capable of automating HBV viral load testing from sample extraction to final results.<br /><br /><br />The Abbott RealTime HBV assay, based on real-time PCR (polymerase chain reaction) technology, is now available for laboratories that use the Abbott m2000 automated instrument system for molecular diagnostic testing. The test offers sensitive measurement (quantitation) of HBV in human plasma or serum from individuals chronically infected with HBV.<br /><br /><br />The assay is intended for use as an aid in the management of patients with chronic HBV infection undergoing anti-viral therapy. The assay can be used to measure HBV DNA levels at baseline and during treatment to aid in assessing response to treatment. Assay results must be interpreted within the context of all relevant clinical and lab findings. Use of the assay to determine the clinical stage of HBV infection has not been established. Clinical performance characteristics have been established for individuals treated with adefovir dipivoxil. The assay is not intended as a screening test for HBV or as a diagnostic test for confirming the presence of HBV infection. <br /><br /><br />"The Abbott RealTime HBV assay, which is the first and only automated HBV viral load test approved by the FDA, is an important tool for helping physicians make and adjust treatment decisions for newly diagnosed patients and those taking anti-viral medications," said Stafford O'Kelly, head of Abbott's molecular diagnostics business. "The test will also help improve laboratory productivity by automating the most labor intensive steps of HBV testing."<br /><br /><br />Abbott's molecular HBV assay detects and measures all known HBV genotypes (A-H) by targeting an essential, highly conserved segment of the HBV genome. The capability for detecting HBV genotypes is important for both monitoring the disease and guiding treatment decisions. For example, genotype C is prevalent in Asia and is associated with more severe liver disease and development of hepatocellular carcinoma. In contrast, genotype B (also prevalent in Asia) has a better prognosis, is rarely associated with progression to liver cancer, and patients seem to respond better to certain antiviral therapies. Immigration and international travel have increased the incidence of HBV strains predominantly found outside the United States.<br /><br /><br />In addition, the Abbott RealTime HBV assay offers a broad dynamic range, capable of quantitating both very low levels of the virus (10 IU/mL) and very high levels of the virus (1 billion IU/mL) in a patient's blood. This broad dynamic range is an important factor in helping physicians accurately assess a patient's response to therapy.<br /><br /><br />The Abbott RealTime HBV assay, initially introduced in Europe and other markets in 2007, was developed for use on the Abbott m2000 system, an automated instrument for DNA and RNA testing. The m2000 is designed to efficiently detect viruses and bacteria in patient samples in less than six hours. The Abbott m2000 instrument is available in most major markets throughout the world. Outside the United States, an extensive menu for infectious disease testing is available that includes HIV-1 viral load, HBV viral load, chlamydia, chlamydia/gonorrhea (CT/NG) combination, hepatitis C (HCV) viral load, HCV genotyping, cytomegalovirus (CMV), Epstein Barr virus (EBV) and human papillomavirus (HPV). In December 2009, Abbott Molecular introduced the first oncology assay on its m2000 system outside the United States — the Abbott RealTime mS9 Colorectal Cancer — that detects the methylated form of Septin 9, a gene linked to colorectal cancer, in blood specimens. In the United States, the following tests are currently available on the m2000 platform: RealTime HIV-1, CT/NG, and now HBV. <br /><br /><br />About Hepatitis B<br /><br /><br />According to the World Health Organization, hepatitis B is a serious global public health problem, but preventable with safe and effective vaccines that have been available since 1982. Of the two billion people who have been infected with the hepatitis B virus, more than 350 million have chronic (lifelong) infections. These chronically infected persons are at high risk of death from cirrhosis of the liver and liver cancer, diseases that kill about one million people each year. Although the vaccine will not cure chronic hepatitis, it is 95 percent effective in preventing chronic infections from developing. <br /><br /><br />The prevalence of HBV infection and the method of transmission vary greatly around the world. In countries with a high prevalence of chronic HBV infection, the most common route of infection is from mother to child at birth or from child to child during early childhood. In areas of low prevalence, the infection is usually acquired during adulthood through intravenous drug use or high-risk sexual activity.<br /><br /><br />About Abbott Molecular<br /><br /><br />Abbott Molecular, abbottmolecular.com, is an emerging leader in molecular diagnostics - the analysis of DNA, RNA, and proteins at the molecular level. Some of Abbott Molecular's tests are designed to detect subtle but key changes in human genes and chromosomes. The results of these tests may aid in the earlier detection or diagnosis of disease, may influence the selection of appropriate therapies, or may improve monitoring of disease recurrence. <br /><br /><br />About Abbott<br /><br /><br />Abbott is a global, broad-based health care company devoted to the discovery, development, manufacture and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. The company employs approximately 83,000 people and markets its products in more than 130 countries.<br /><br /><br />Abbott's news releases and other information are available on the company's Web site at www.abbott.com.<br /><br /><br />SOURCE Abbott<br /><br />Back to top<br /><br /><br />RELATED LINKS<br /><br />http://www.abbott.comScott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com1tag:blogger.com,1999:blog-3205772196563366012.post-41217978019151721492010-09-27T15:59:00.002-04:002010-09-27T16:00:09.363-04:00Cirrhosis Outcomes Better When Tx Guidelines FollowedCirrhosis Outcomes Better When Tx Guidelines Followed - below is full text Editorial and full text article, attached is pdf of published study<br /><br />MedPage Today<br /><br />Published: August 31, 2010<br /><br /><br />Action Points <br /><br /><br /> * Explain that current guidelines recommend screening liver cirrhosis patients for esophageal varices and beta-blocker treatment or variceal ligation -- for those patients found to be at risk for bleeding -- along with periodic follow-up endoscopy.<br /><br /><br /><br /> * Explain to interested patients that following screening and treatment guidelines led to lower-than-expected rates of variceal hemorrhage.<br /><br /><br />Routinely screening liver cirrhosis patients for esophageal varices and treating them according to published guidelines led to lower-than-expected rates of subsequent variceal hemorrhage, researchers found.<br /><br /><br />A review of patient charts in a center that showed strong compliance with cirrhosis management guidelines found that the actuarial two-year likelihood of variceal bleeding was 13% -- compared with a predicted rate of 27% calculated on the basis of liver dysfunction severity, variceal size, and so-called "red wale markings" seen on endoscopy (P<0.05), according to Jayavani Moodley, MD, of the Cleveland Clinic, and colleagues.<br /><br /><br />"In our population, management according to principles endorsed by a recently published practice guideline was associated with a lower bleeding rate than that expected in untreated patients," Moodley and co-authors wrote in the August issue of Clinical Gastroenterology and Hepatology.<br /><br /><br />Guidelines issued in 2007 jointly by the American Gastroenterological Association and the American Association for the Study of Liver Disease call for screening cirrhosis patients for esophageal varices and beta-blocker treatment or variceal ligation for patients found to be at risk for bleeding, along with periodic follow-up endoscopy.<br /><br /><br />Moodley's team reviewed charts from 179 patients evaluated for cirrhosis at the Cleveland Clinic from 2003 to 2006 and found that 80% had endoscopic screens for esophageal varices within six months of their initial visit, and a total of 94% had such screens at some point during treatment at the clinic.<br /><br /><br />A chart review of endoscopy results revealed that 83 patients had varices -- including 35 with medium to large lesions.<br /><br /><br />The review also indicated that treatments conforming to the AGA/AASLD guidelines were given to 91% of patients with medium or large varices. On the other hand, compliance with the guidelines was lower (60%) among patients with small varices.<br /><br /><br />Of those patients without bleeding episodes during follow-up, 82% had their screening endoscopy within six months of their initial visit -- whereas only 50% of the patients suffering hemorrhages received such prompt screening (P=0.016).<br /><br /><br />Hemorrhage from esophageal varices occurred in nine patients with varices at screening of 12 total bleeding episodes that occurred during the follow-up period.<br /><br /><br />Moodley and colleagues had calculated a two-year actuarial probability of 13% that patients with varices would have hemorrhages. In comparison -- under the standard North Italian Endoscopy Club model for predicting variceal hemorrhage rates -- 27% of the Cleveland Clinic patients with varices would have been expected to develop hemorrhages in two years. This model takes into account the severity of liver dysfunction, the size of varices, and whether red wale markings are present.<br /><br /><br />Moodley and colleagues noted that 80% of the clinic's patients with medium to large varices underwent ligation procedures as opposed to beta-blocker therapy.<br /><br /><br />In their report, they wrote that the clinic's institutional preference was "influenced by two meta-analyses which indicate superiority of esophageal variceal ligation in preventing initial bleeding." But they also noted that a study published last year found better outcomes for beta-blockers.<br /><br /><br />"This finding, if verified, will likely alter our treatment strategy in the future," Moodley and colleagues commented.<br /><br /><br />In an accompanying editorial, two physicians at Boston's Beth Israel Deaconess Medical Center noted an odd paradox in the study's findings.<br /><br /><br />Although the rate of variceal hemorrhage was low in patients receiving guideline-compliant recommendations (8%), wrote Michelle Lai, MD, MPH, and Nezam Afdhal, MD, it was even lower (6%) among 54 patients who were screened but did not receive the recommended treatment.<br /><br /><br />Lai and Afdhal also suggested that findings at a tertiary care center such as the Cleveland Clinic may not apply to community gastroenterology practices. As a result, they indicated, "the findings, therefore, need to be confirmed ... in future studies."<br /><br />Primary source: Clinical Gastroenterology and Hepatology<br />Source reference:<br />Moodley J, et al "Compliance with practice guidelines and risk of a first esophageal variceal hemorrhage in patients with cirrhosis" Clin Gastrenterol Hepatol 2010; 8: 703-708. <br /><br />Additional source: Clinical Gastroenterology and Hepatology<br />Source reference:<br />Lai M, et al "Health care quality measurement in the care of patients with cirrhosis" Clin Gastrenterol Hepatol 2010; 8: 650-651.<br />-------------------------------<br /><br />EDITORIAL<br /><br />Health Care Quality Measurement in the Care of Patients With Cirrhosis<br /><br /><br /> * Michelle Lai, MD, MPH<br /><br /> * Nezam H. Afdhal, MD<br /><br /><br />published online 17 May 2010.<br /><br />In recent years, there has been increasing emphasis by the US government on health care quality assessment and improvement. Increased funding for the Agency for Healthcare Research and Quality has led to new initiatives by the agency to achieve its mission of improving the quality, safety, efficiency, and effectiveness of health care for Americans. After expanding its support of health information technology initiatives in 2004, the agency established the Effective Health Care Program in 2005 to conduct comparative effectiveness reviews and provide understandable and actionable information for patients, clinicians, and policy makers. The Patient Safety and Quality Improvement Act of 2005 established a system of patient safety organizations and a national patient safety database. More recently, the American Recovery and Reinvestment Act of 2009, known as the “Stimulus Package,” created the Federal Coordinating Council for Comparative Effectiveness and Research and allocated $1.1 billion for “comparative effectiveness research” to provide patients, clinicians, and others with evidence-based information to make informed decisions about health care.<br /><br /><br />Third-party payors have followed the governmental agencies in their emphasis on quality assessment and improvement as shown by a move toward an outcomes and quality-based reimbursement model. This pay-for-performance model of payment links quality of care with the level of payment for health care services. California leads the way with the California Pay for Performance Program, now the largest pay-for-performance program in the country. Medicare also launched various pay-for-performance initiatives in physician offices, clinics, and hospitals. More than 100 private and federal pilot pay-for-performance programs are under way.<br /><br /><br />According to criteria defined by the Institute of Medicine, cirrhosis (and its complications) is recognized as a chronic disease that requires quality of care measurement to reduce practice variation and improve clinical outcomes.1 Although clinical guidelines put forth by a panel of experts who have reviewed all the evidence (ie, comparative effectiveness review) is an important first step in evidence-based health care quality assessment and improvement, they are not, in themselves, assessment of health care quality. Currently, there are limited data on how to define and measure quality of care for patients with cirrhosis. Recent data show that, despite the existence of evidence-based practice guidelines, there is poor adherence (54%) to the clinical guidelines of the use of β-blockers for primary and secondary prevention of esophageal variceal hemorrhage (EVH).2, 3, 4, 5, 6, 7 It also remains to be seen whether compliance with the guidelines leads to improved patient outcomes. It is important to go one step further and translate these guidelines into a quality-assessment tool. Two articles in this current issue of Clinical Gastroenterology and Hepatology address quality assessment in the care of patients with cirrhosis. Moodley et al8 examines the association of compliance with guidelines to patient outcome whereas Kanwal et al9 identify quality indicators in the care of patients with cirrhosis.<br /><br /><br />Although there have been studies examining the compliance rate with clinical guidelines on the management of varices,7, 10 Moodley et al report on whether compliance leads to improved patient outcome. They examined the compliance with practice guidelines for screening of esophageal varices (EV) in patients with cirrhosis and intervention to prevent EVH as well as the impact of compliance on the rate of first EVH. The authors reviewed the charts of a random sample of 179 adult patients newly evaluated for cirrhosis at a tertiary liver unit, excluding patients with a previous history of EV, EVH, or treatment with β-blockers. They looked at the association of compliance with practice guidelines to subsequent esophageal variceal hemorrhage rates. Moodley et al found a high rate of compliance with screening guidelines (94%; and 80% in the first 6 months) at this tertiary liver unit. Compliance with intervention guidelines (ie, β-blockers, esophageal variceal ligation, or follow-up esophagogastroduodenoscopy [EGD]) was 68% in all screened patients and higher (91%) in patients with large varices. Twelve of the 179 patients had an EVH. Of the 12 subjects who had an EVH, only 50% had a screening EGD within 6 months of evaluation compared with 82% of those without an EVH who had an EGD within 6 months. The authors concluded that this showed the effectiveness of early variceal screening. However, it appears that in the group of patient who were not screened (9%), there were no cases of EVH. All subjects who bled had undergone a screening EGD at some point and 75% also had practice guideline compliant management after the screening. In addition, patients screened but not compliant with practice guideline management had a lower rate of EVH (3 of 54; 5.6%) than subjects who were compliant with practice guideline management (9 of 114; 7.9%). These results are somewhat contradictory and suggest that more data are needed before concluding that early screening led to lower rates of first EVH. The high compliance rate found in this study likely is owing to the practice setting of a tertiary care center. The findings, therefore, need to be confirmed in community gastroenterology practices in future studies.<br /><br /><br />The second article by Kanwal et al is an ambitious study to identify a set of evidence-based quality indicators (QI) for cirrhosis in clinical practice. By using the RAND/UCLA Appropriateness method, a panel of 11 experts came up with a list of the 8 most important QIs in 3 domains: ascites, variceal bleeding, and hepatocellular carcinoma. A list of candidate QIs that were linked to clinically important outcomes was generated using existing clinical guidelines. A comprehensive literature review of data linking candidate QIs to outcomes then was performed and presented to the panel of experts. Through an iterative, evidence-based process, the panel of experts chose the final 8 QIs. There were 3 QIs in the ascites domain, which were timely antibiotic treatment for spontaneous bacterial peritonitis, management of ascites with diuretics and salt restriction, and diagnostic paracentesis for hospitalized patients with ascites. The 4 QIs in the domain of variceal bleeding were timely endoscopies for patients with cirrhosis and upper gastrointestinal bleeding, appropriate treatment of EVH, as well as both primary and secondary prevention of an esophageal variceal bleed. The quality indicator in the domain of hepatocellular carcinoma was adherence to the hepatocellular carcinoma screening guideline of imaging every 6 to 12 months. These quality indicators are constructed as “if–then” statements, where “if” characterizes the eligible patient population and “then” describes the care that should be given. This format allows them to be translated easily into a practical checklist to be used as a tool for practices to assess quality and improve quality. However, before the use of this list of QIs is implemented into quality-assessment processes, studies need to be performed to evaluate whether adherence to this list of QIs in clinical practice leads to improved patient outcome.<br /><br /><br />We have seen the current focus by both government agencies and payors of quality assessment and quality improvement. In light of this increasing emphasis on quality assessment and quality-based reimbursement models, it is important that researchers and professional societies identify the optimal tools for assessing health care quality and also tools for implementing guidelines. These 2 articles represent a good start toward identifying tools for assessing health care quality in the care of patients with cirrhosis.<br />-------------------------------------<br /><br />Compliance With Practice Guidelines and Risk of a First Esophageal Variceal Hemorrhage in Patients With Cirrhosis<br /><br /><br /> Jayavani Moodley, Cleveland Clinic Foundation, Department of Gastroenterology and Hepatology, 9500 Euclid Avenue, Cleveland, Ohio 44195. fax: (216) 445-5477, Rocio Lopez , William Carey<br /><br /><br />published online 12 March 2010.<br /><br />Background & Aims<br /><br /><br />Esophageal variceal hemorrhage (EVH) is a serious complication of cirrhosis, with 20% mortality per episode. The 2007 American Association for the Study of Liver Disease and American College of Gastroenterology practice guidelines regarding esophageal varices in patients with cirrhosis recommend screening and intervention to prevent EVH. We assessed practice guideline compliance and its impact on the rate of first EVH.<br /><br />Methods<br /><br /><br />An institutional review board-approved retrospective chart review was conducted on a random sample of adult patients newly evaluated for cirrhosis at the Cleveland Clinic from 2003 to 2006 (n = 179). Exclusion criteria were a previous diagnosis of esophageal varices or EVH and/or treatment with β-adrenergic antagonists. Patients were followed for 23 months (range, 9–38 months). Conformity with practice guidelines and subsequent bleeding rates were determined. Observed bleeding rates were compared to the North Italian Endoscopy Club (NIEC) model.<br /><br />Results<br /><br /><br />Of the patients, 94% had a screening endoscopy, 80% within 6 months of the initial visit. Varices were present in 50% of the patients; 68% of all patients screened and 91% with large varices received a practice guideline-recommended treatment. Twelve patients (7%) had an episode of EVH; 82% of subjects without bleeding had their screening endoscopy within 6 months versus 50% of those with bleeding (P = .016). Actuarial likelihood of bleeding at 2 years was 13% versus 27% predicted by the NIEC model (P < .05).<br /><br />Conclusion<br /><br /><br />Compliance with practice guideline recommendations is associated with reduction in first EVH in the first 2 years.<br /><br /><br />The risk of developing gastroesophageal varices in patients with cirrhosis is between 50% and 66%1 and 30%–40% of patients with varices suffer a variceal hemorrhage.2 Although the mortality rate associated with an episode of esophageal variceal hemorrhage (EVH) has decreased almost 3-fold in the past 2 decades owing to the combined use of endoscopic and pharmacological interventions, it is still high at 15%–20%.3, 4 If untreated, variceal hemorrhage portends a 70% risk of death within 1 year2; this high mortality rate makes primary prevention of bleeding the best approach to improving outcomes for these patients. The American Association for the Study of Liver Disease (AASLD) jointly with the American College of Gastroenterology (ACG) recently published practice guidelines (PG) (Supplementary Appendix A) that recommend screening and intervention for high risk EV.5 In 1988 the North Italian Endoscopy Club (NIEC) defined high risk varices as a composite measure of 3 variables: the severity of liver disease as determined by the Child–Pugh Score (CPS); the size of varices, with large varices being the most ominous; and the presence and severity of red wale markings or red signs (longitudinal dilated venules on the varix, similar to whip marks)6 (Supplementary Appendix B). In 2004 Zaman et al documented that self-reported PG compliance among gastroenterologists improved from 18% to 54% following the publication of the 1997 American College of Gastroenterology guidelines for the management of varices.7 Four years later the compliance rate in the same population still sits at 54%.8 There have been, however, no studies evaluating the impact improved compliance has on clinical outcomes such as rates of variceal hemorrhage or mortality among patients with cirrhosis. We undertook this study to assess actual compliance rates of gastroenterologists at a large tertiary institution with the current AASLD/ACG practice guidelines concerning EV screening and management. We also aimed to elucidate whether compliance resulted in improved patient outcomes, namely decreased risk of first variceal hemorrhage.<br /><br />Methods <br /><br /><br />An institutional review board-approved retrospective chart review was conducted on 179 adult patients (age >18 years), selected by computerized randomization from 468 eligible patients, newly evaluated for cirrhosis at the Cleveland Clinic from 2003–2006. Exclusion criteria were a previous diagnosis of EV or EVH and/or treatment with β-adrenergic antagonists. The diagnosis of cirrhosis was based on historical, clinical, and pathological data.<br /><br /><br />The electronic database EPIC was used to retrieve relevant information spanning hepatology outpatient visits, hospital admissions, endoscopic procedures, and laboratory and other pathology-related data. Our analysis aimed to determine whether or not patients underwent timely screening for varices after initial evaluation by a hepatologist, follow-up surveillance endoscopies, and if found, were varices appropriately managed. Patients were followed for an average of 23.0 months (range, 9.2–37.8 months). Our endpoint was first EVH or last EPIC encounter. Information about bleeding episodes that occurred at the Cleveland Clinic was obtained directly from endoscopy reports, laboratory data, or hospital discharge summaries. If an episode of EVH occurred at another institution the data were documented by the hepatologist in the patient's outpatient record. The NIEC index was calculated for the patients who bled from EV, and the observed bleeding rates were compared with the NIEC predicted rates at 1 and 2 years.<br /><br /><br />For the purpose of appropriate data collection the following variables were defined.<br /><br />Practice Guideline Recommended Management <br /><br /><br />In compliance with the 2007 AASLD/ACG PG (Supplementary Appendix A), effective screening required that patients have their screening endoscopy within 6 months of their initial visit to a hepatologist; patients should be placed on a noncardio-selective beta blocker (BB) or have esophageal variceal ligations (EVL) when needed; follow-up upper intestinal endoscopy (EGD) should be performed at appropriate intervals post esophageal variceal ligation (EVL); and for routine surveillance, BB should be titrated to the maximum tolerated dose.<br /><br />Clinically Significant Bleeding (Baveno IV Criteria)9 <br /><br /><br />Transfusion requirement ≥2 units of blood within 24 hours of time zero, and systolic blood pressure <100 mm Hg or postural systolic change >20 mm Hg, and/or heart rate >100 beats/minute.<br /><br />Endoscopic Findings and Description of Varices <br /><br /><br />The presence or absence of esophageal varices was noted. Varices were classified as small, medium, or large. A 5 mm diameter was used as the cutoff for designating small from medium and large varices. The presence or absence of gastric varices and red wale markings was also documented. Unlike in the NIEC study, red wale markings were not graded in the endoscopy records reviewed. For the purpose of calculating the NIEC index in patients who bled we assigned those with red wale markings to the mild category (Supplementary Appendix C). As such, patients with red wale markings may have been placed in a lower risk NIEC category.<br /><br />Length of Follow-Up <br /><br /><br />Patients were followed until their first bleeding episode from EV or their last encounter in EPIC, with the average length of follow-up being 23.0 months (range, 9.2–37.8 months).<br /><br />Statistical Analysis <br /><br /><br />Descriptive statistics were computed for all variables. These include median and percentiles for age and frequencies for categorical variables. Pearson's χ2 tests were used to assess association between compliance to practice guidelines and factors such as presence of varices and CPS. The same was done to study factors associated with the presence and size of varices. Kaplan–Meier estimates were used to study bleeding rates in patients with EV, and a log-rank test was used to compare NIEC groups. Time of follow-up was defined as months between EV diagnosis and either bleeding or last follow-up visit if no bleeding was observed. A P < .05 was considered statistically significant. SAS version 9.2 software (The SAS Institute, Cary, NC) and R version 2.4.1 (The R Foundation for Statistical Computing, Vienna, Austria) were used for all analyses.<br /><br />Results <br /><br /><br />Records of 562 cirrhotic patients presenting for the first time to a tertiary care liver clinic were screened. Ninety-four were excluded because of a previous diagnosis of EV, having suffered an EVH, or being recently (within the previous 12 months) or currently treated with beta blockers. Of the remaining eligible 468 patients, 179 were randomly selected for detailed analysis.<br /><br />Compliance With Practice Guidelines <br /><br /><br />Screening for varices was accomplished in 169 cases (94%), although only 143 (80%) were screened within 6 months of their first encounter with the hepatologist (Figure 1). Ten (6%) were never screened. Two thirds (68%) received PG recommended management after their screening endoscopy, 47 (28%) did not, and 7(4%) were lost to follow-up. PG compliance was found in 73.8% of patients with varices and 67.9% with no varices (P = .41). Ninety-one percent of patients with medium and large varices received a PG recommended treatment compared with 60% with small varices (P = .002). When stratified according to CPS, 75% of CPS A, 57% of CPS B, and 80% of CPS C received PG-recommended treatment (A vs B, P = .048; C vs B, P = .28). Failure of compliance to practice guidelines was noted in 57 patients. Reasons for fallout were due to physician-related factors in 47 patients (82%). Of these, 20 did not receive a follow-up surveillance endoscopy, 14 were not given BB (for CPS B/C with small varices), 10 did not have a screening EGD, and 3 did not receive either BB or EVL once diagnosed with varices. Eighteen percent (10 patients) had their subsequent EGD beyond the recommended interval due to nonphysician or indeterminate factors.<br /><br />Findings at Screening Endoscopy <br /><br /><br />One hundred and sixty-nine patients had a screening EGD (Table 2). One was excluded because of incomplete records; there was no description of the size or appearance of varices in the endoscopy report. Eighty-four (50%) of the remaining 168 patients had varices. Seventy (58%) of CPS A had no varices while 6 (60%) of CPS C had medium/large varices. CPS A patients were more likely to have small varices than CPS B (P = .002) and CPS C (P = .003). The presence of red wale markings on varices was noted in 3 (2.5%) of CPS A patients and 2 (20%) of CPS C.<br /><br />Bleeding <br /><br /><br />Twelve patients (7%) of the study population had an episode of clinically significant bleeding during the follow-up period. Nearly all (11/12) had either esophageal or gastric varices at the time of initial screening endoscopy. Thirteen percent (11/84) of those with varices at initial screening subsequently bled. Of the 9 patients with EV, 2 (17%) had small and 7 (58%) had medium or large varices. Eight subjects bled within 1 year, 3 in the second year, and 1 subject 2 years after their screening EGD. At screening, 6 (50%) patients with subsequent EVH were CPS A, 4 (33%) CPS B, and 2 (17%) CPS C. Six (50%) of the patients who bled had received a screening endoscopy within 6 months of initial diagnosis. Eighty-two percent (137/167) of subjects without bleeding had their screening EGD within 6 months of initial visit compared with 50% (6/12) of those with bleeding (P = .016). Seventy-five percent (9/12) of patients with EVH did receive a PG-recommended treatment after their screening EGD. There were 52 patients with a NIEC score ≤26 and 32 with a NIEC >26 (Table 3). Three patients (5.8%) in the lower NIEC category bled compared with 6 (18.8%) in the group with a NIEC >26 (P = .032), in conformity with previous predictions of increased bleeding risk with higher NIEC scores (Figure 2).6<br /><br />Eleven percent (9/84) of subjects with EV had EVH compared with 26.5% in the NIEC study (P = .002). The cumulative actuarial likelihood of bleeding was 9.2% and 13.0% at 1 and 2 years respectively, significantly lower than predicted by the NIEC model namely 16% and 27% (P < .05). As the NIEC index was developed for patients with EV, only the 9 patients with EV were used in comparison studies with the original NIEC.<br /><br /><br />We observed no bleeding episodes attributable to band ligation. Eighteen percent of those with small varices were given beta blockers; eighty percent of those with medium/large varices were treated with EVL, indicating a preference in this facility for this management tool. Observed bleeding rates were not different between treatment groups.<br /><br />Discussion <br /><br /><br />Our study confirms the high prevalence of esophageal varices (50%) in cirrhotic patients with no history of bleeding. Sixty-three percent of those with varices had features putting them at high risk for bleeding. These results are similar to findings in other screening programs.6 We further demonstrated that high compliance (80%–94%) with screening for esophageal varices among cirrhotic patients seen at a large tertiary care facility appears to translate into better patient outcomes. We are unaware of other published reports demonstrating actual compliance with esophageal varices screening practice guidelines. Two studies evaluating practice guideline compliance regionally and nationally among gastroenterologists found a low rate of reported adherence (54%).7, 8 These reports surveyed gastroenterologists (not hepatologists) from a variety of practice settings. Our study examined behavior of hepatologists in an academic center. Nearly all (94%) of newly diagnosed cirrhotic patients had a screening endoscopy, 80% within 6 months of being evaluated by a hepatologist. Endoscopic screening remains the gold standard for the diagnosis of varices.5 The ACG/AASLD PG recommend a screening EGD to assess the presence of EV when the diagnosis of cirrhosis is made. Subsequent management depends on the nature of the varices, that being their size and appearance, and the patient's CPS.<br /><br /><br />Both beta-blockers and EVL are advocated in the primary prophylaxis of first EVH, and use of these measures significantly reduces the risk of bleeding.10, 11, 12 Of the 168 patients who received a screening endoscopy (regardless of when) 114 (68%) received PG-recommended management including either beta-blockers, EVL and/or timely follow-up. Significantly, 91% of patients with medium or large varices compared with 60% with small varices were treated in compliance with PG (P = .002). This may reflect that practitioners consider small varices less threatening than larger ones and thus are less likely to treat them. However it is known that 4%–10% of small varices progress to large varices per year, and therefore appropriate and timely management is warranted.2<br /><br /><br />Our center prefers EVL to beta blocker therapy, a choice influenced by 2 meta-analyses which indicate superiority of EVL in preventing initial bleeding.12, 13 Of our patients with medium or large varices, 80% were treated with EVL and only 11% by beta-blocker therapy. Concern about major hemorrhage caused by EVL was not realized in this study population. There was no significant difference in early bleeding (within 3 months of initiation of treatment) in those who received EVL and BB (10% and 3.7%, respectively, P = .34) (Supplementary Table 4). We are aware of the recently published report of BB superiority compared with EVL in primary bleeding prophylaxis.14 This finding, if verified, will likely alter our treatment strategy in the future.<br /><br /><br />The most common reason for divergence from PG recommendations is lack of timely follow-up endoscopy for surveillance in patients with no or small esophageal varices, explained, in part, by the referral nature of this practice (Figure 3). Eighteen patients with Child–Pugh B or C had small varices, a group for whom intervention with beta blocker therapy (with dose titration) is recommended. In this group only 22% were given beta blockers. Reasons for noncompliance have not been systematically determined, but may relate to many factors including the complexity of the management algorithm, or unfamiliarity or disagreement with individual PG recommendations. More emphasis may be needed in the specific care of this subset of patients. Bringing to light these areas of noncompliance can help physicians identify those patients who fall into potential gray areas where management may be unclear.<br /><br />The NIEC provides a rich and detailed prospective assessment of bleeding risk in cirrhotic patients with newly discovered varices.6 Based on this, a scoring system of bleeding risk has been constructed and validated.6, 15 Recently suggestions have been made that the original NIEC assigns too much weight to the CPS limiting its prognostic efficiency and accuracy.15, 16 Zoli et al16 propose that more leverage be assigned to the size and appearance of the varices instead and have proposed a revised NIEC index. The differences in predicted bleeding risk between the original and revised scoring systems seem small. Pending further studies, the original NIEC index remains the most widely used system and was selected for our analysis.<br /><br /><br />This study suggests that the significant reduction in observed bleeding rates may be related to adherence to PG-recommended care. Patients who did not bleed were more likely to have received their screening EGD within the 6 month window as compared with those who bled (82% vs 50%, P = .016), demonstrating the effectiveness of early variceal screening. Seventy-five percent of patients who bled (9/12) did actually receive PG-compliant management after their screening EGD. This finding underscores the fact that no currently available strategy will eliminate the risk of variceal hemorrhage. It is noteworthy that both patients found to have isolated gastric varices (IGV) suffered clinically significant bleeding from these culprit vessels. One patient was found to have bleeding from IGV at the time of initial EGD and subsequently underwent placement of a transjugular intrahepatic portosystemic shunt (Supplementary Table 4). Gastric varices are found in about 20% of patients with cirrhosis either alone as IGV or as gastroesophageal varices in direct continuity with their esophageal counterparts. IGV are less prevalent than gastroesophageal varices (10% versus 90%), but they have a greater propensity to bleed; bleeding is difficult to control and is associated with a high mortality rate.2, 17 Currently there is no consensus on optimum treatment of gastric varices, and therefore more studies are necessary to provide data for guidelines on appropriate prophylaxis.9, 17 In patients with IGV it is prudent to rule out the presence of splenic vein thrombosis.<br /><br /><br />Our data need to be confirmed and validated. Of note, our endoscopists most often describe red wale markings as either present or absent (rather than following the NIEC protocol of mild-moderate-severe), making use of the NIEC scoring system difficult and subject to possible interpretive errors (Supplementary Appendix B). We also note a discrepancy between the higher rates of red signs in the NIEC data, namely 41% in Child's A and 39% in Child's C patients compared with 2.5% and 20%, respectively, in our study. This may represent the possibility of underreporting of red signs by our endoscopists and pose a potential limitation of our study.<br /><br /><br />Retrospective studies sometimes lack “granularity,” ie, the ability to capture nuances such as reasons for clinical decision-making. Compliance depends on factors other than physician recommendations and includes patient understanding, motivation, family support, and logistical issues such as financial means. From our data set it is difficult to attribute definitively the cause of failure to the physician or patient. Nevertheless, the cumulative effect of physician recommendation plus patient factors has been shown in this population to be highly effective in achieving the goals of practice guideline compliance. A future study is planned to attempt to better understand the relative roles of patient, environment, and physician factors associated with noncompliance.<br /><br /><br />In conclusion, this study confirms the high prevalence of esophageal varices in patients with cirrhosis and also finds high compliance rates with practice guidelines among hepatologists at a large tertiary institution regarding the prevention and management of EV. In our population, management according to principles endorsed by a recently published practice guideline was associated with a lower bleeding rate than that expected in untreated patients. It is recommended that efforts to promote increased awareness of and compliance to PG for the screening and management of EV are warranted.Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-91581495192961674922010-09-27T15:59:00.001-04:002010-09-27T15:59:26.120-04:00Inhibitex Successfully Completes Phase 1a Trial of INX-189Inhibitex Successfully Completes Phase 1a Trial of INX-189<br /><br />Proof-of-Concept Trial in Patients with Chronic Hepatitis C Planned for Q4 2010<br /><br />press release<br /><br /><br />Sept. 1, 2010<br /><br /><br /><br />ATLANTA, Sep 01, 2010 (BUSINESS WIRE) -- Inhibitex, Inc. /quotes/comstock/15*!inhx (INHX 1.42, -0.01, -0.70%) , announced today that it has successfully completed a Phase1a, first-in-man, single ascending dose trial of INX-189, its nucleotide polymerase inhibitor in development for the treatment of chronic hepatitis C (HCV) infections. In this trial, 42 healthy volunteers received either a single oral dose of INX-189, ranging from 3 mg to 100 mg, or placebo. The Company plans to present detailed results from this trial during a future scientific meeting. Preliminary data from the trial are as follows:<br /><br /><br />-- INX-189 was generally well tolerated at all dose levels;<br /><br /><br />-- No drug-related serious adverse events;<br /><br /><br />-- No dose-related trends in frequency or type of adverse events; adverse events occurring in more than one subject were headache and nasal congestion;<br /><br /><br />-- No grade II or higher laboratory abnormality adverse events or clinically significant changes in ECGs; and<br /><br /><br />-- Pharmacokinetic data supports INX-189's potential for once daily (QD) dosing.<br /><br /><br />"We are encouraged with the initial safety and pharmacokinetic profile of INX-189 in this first-in-man trial," stated Dr. Joseph Patti, Senior Vice President and Chief Scientific Officer of Inhibitex, Inc. "Based upon the pharmacokinetics observed in this study, we continue to believe that INX-189 has the potential to demonstrate antiviral activity with a low once-daily dose, and we look forward to assessing its ability to reduce HCV RNA viral loads in patients with chronic hepatitis C in a Phase 1b multiple ascending dose trial we plan to start in the fourth quarter."<br /><br /><br />About Inhibitex<br /><br /><br />Inhibitex, Inc., headquartered in Alpharetta, Georgia, is a biopharmaceutical company focused on developing products to prevent and treat serious infectious diseases. The Company's pipeline includes FV-100, which is in Phase II clinical development for the treatment of shingles, and INX-189, a nucleotide polymerase inhibitor in development for the treatment of chronic hepatitis C infections. The Company also has additional HCV nucleotide polymerase inhibitors in preclinical development and has licensed the use of its proprietary MSCRAMM(R) protein platform to Pfizer for the development of staphylococcal vaccines. For additional information about the Company, please visit www.inhibitex.com.<br /><br /><br />Safe Harbor Statement<br /><br /><br />This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than historical facts included in this press release, including statements regarding the Company's plans to present detailed results from the Phase 1a trial during a future medical meeting and its intention to initiate a Phase 1b multiple ascending dose trial in the fourth quarter of 2010 are forward looking statements. These intentions, expectations, or results may not be achieved in the future and various important factors could cause actual results or events to differ materially from the forward-looking statements that the Company makes, including the risk of: either the Company, the FDA, a data and safety monitoring board, or an investigational review board delaying, suspending or terminating the clinical de velopment of INX-189 for a lack of safety or antiviral activity, manufacturing-related issues, questions or issues regarding the design of the planned Phase 1b clinical study of INX-189, or any other reasons; the Company obtaining, maintaining and protecting the intellectual property incorporated into and supporting the commercial viability of INX-189; and other cautionary statements contained elsewhere herein and in its Annual Report on Form 10-K for the year ended December 31, 2009, as filed with the Securities and Exchange Commission, or SEC, on March 26, 2010, and its Quarterly Report on Form 10-Q for the quarter ended June 30, 2010, as filed with the SEC on August 12, 2010. Given these uncertainties, you should not place undue reliance on these forward-looking statements, which apply only as of the date of this press release.<br /><br /><br />There may be events in the future that the Company is unable to predict accurately, or over which it has no control. The Company's business, financial condition, results of operations and prospects may change. The Company may not update these forward-looking statements, even though its situation may change in the future, unless it has obligations under the Federal securities laws to update and disclose material developments related to previously disclosed information. The Company qualifies all of the information contained in this press release, and particularly its forward-looking statements, by these cautionary statements.<br /><br /><br />Inhibitex(R) and MSCRAMM(R) are registered trademarks of Inhibitex, Inc.<br /><br /><br />SOURCE: Inhibitex, Inc.<br /><br /><br />Inhibitex, Inc. <br /><br />Russell H. Plumb <br /><br />Chief Executive Officer <br /><br />678-746-1136 <br /><br />rplumb@inhibitex.com <br /><br />or <br /><br />Lee M. Stern, CFA <br /><br />The Trout Group <br /><br />646-378-2922 <br /><br />lstern@troutgroup.comScott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-26840054748081815112010-09-27T15:57:00.000-04:002010-09-27T15:58:10.175-04:00Roche Receives FDA Approval for Second-Generation Hepatitis B Viral Load TestRoche Receives FDA Approval for Second-Generation Hepatitis B Viral Load Test <br /><br />Roche Molecular Diagnostics announced today that the U.S. Food & Drug Administration (FDA) has approved the COBAS® AmpliPrep / COBAS® TaqMan® HBV Test v2.0 for use in the United States. The new Roche test provides a fully automated solution for the quantitative detection of hepatitis B virus (HBV) DNA in human plasma or serum for patients on HBV antiviral therapy. <br /><br />"This new test enables clinicians to follow best practices in patient care with standardized viral load measurements, a broad range of detection, and high sensitivity," said Paul Brown, Ph.D., President and CEO of Roche Molecular Diagnostics. "The system is also carefully designed to protect the integrity of each patient result, so clinicians can make key medical decisions about therapy with confidence."<br /><br />According to the Centers for Disease Control, an estimated 1.2 million people in the United States are living with chronic hepatitis B. Clinical practice guidelines for chronic HBV highlight the importance of monitoring the levels of circulating hepatitis B viral DNA as an indicator of when hepatitis B therapies should be started, and to measure response to treatment, including suppression of HBV replication.<br /><br />"Viral load testing remains the gold-standard for the management of HBV antiviral therapy," said Teresa Wright, MD, Chief Medical Officer of Roche Molecular Diagnostics. "Roche's new HBV test provides accurate and reproducible results at the key medical decision points, allowing the clinician to optimize patient outcomes."<br /><br />About the COBAS® AmpliPrep/COBAS® TaqMan® HBV Test v2.0<br /><br />The Roche COBAS® AmpliPrep / COBAS® TaqMan® HBV Test v2.0 has been validated to quantify diverse samples from genotypes A-H and pre-core mutants across a broad linear dynamic range of 20 IU/mL to 1.7E+08 IU/mL. The new assay uses a reduced sample input volume of 650 uL of either serum or plasma specimens and is standardized against the World Health Organization (WHO) Standard for hepatitis B.<br /><br />This test is designed for use on Roche's fully automated COBAS® AmpliPrep/COBAS® TaqMan® System that is used in more than 250 clinical laboratories across the U.S.<br /><br />The platform combines the COBAS® AmpliPrep Instrument for automated sample preparation and the COBAS® TaqMan® Analyzer or the smaller COBAS® TaqMan® 48 Analyzer for automated real-time PCR amplification and detection.<br /><br />"Sample in/results out" testing eliminates manual intervention between steps and configuration options allow for customizable solutions for throughput needs. For a flexible throughput solution, the test offers 72 tests per kit in self sealing, ready-to-use reagent cassettes. Roche's proprietary AmpErase enzymes are also included in each test and are designed to prevent cross-contamination of samples and labs.<br /><br />About Hepatitis B<br /><br />Approximately 4,500 cases of acute hepatitis B in the United States are reported to CDC each year and each year an estimated 43,000 persons are newly infected with HBV.(1) However, because many HBV infections are either asymptomatic or never reported, the actual number of new infections is estimated to be approximately tenfold higher. <br /><br />The hepatitis B virus is spread through having unprotected sex, by sharing needles, or from an infected mother to her baby during child birth. Symptoms occur in about 70 percent of patients and include jaundice, fatigue, abdominal pain, loss of appetite, nausea and vomiting. <br /><br />About Roche<br /><br />Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche's personalized healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2009, Roche had over 80,000 employees worldwide and invested almost 10 billion Swiss francs in R&D. The Group posted sales of 49.1 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com1tag:blogger.com,1999:blog-3205772196563366012.post-32418980511154485432010-09-27T15:56:00.002-04:002010-09-27T15:57:03.074-04:00The Next Step for Taribavirin - CommentaryThe Next Step for Taribavirin - Commentary<br /> <br /> <br /> Hepatology Sept 24 2010<br /> <br />Paul Y Kwo and Rakesh Vinayek<br /> <br />Excerpts:<br /> <br />In this issue of Hepatology, Poordad and colleagues report the SVR rates of weight-based TBV compared to weight-based RBV in naïve genotype I HCV-infected patients. In this US Phase 2b randomized open-label controlled parallel group study, 278 naïve genotype I subjects were randomized to TBV 20, 25, or 30 mg/kg/day or RBV 800-1400 mg, pegIFN alfa-2b for 48 weeks. An early virologic response (EVR) defined as undetectable HCV RNA (< 39 I.U. at Week 12) or a 2 log reduction in baseline HCV RNA, the primary endpoint of the study, was comparable across all treatment arms. The SVR rate was also preserved across all treatment arms, ranging between 27 and 28%. The overall response rates in this trial were low though the high percentage of African Americans (20%) and those with advanced fibrosis may explain the lower SVR rates. It would be interesting to know the IL-28 composition of the treatment population as there may have been a high prevalence of unfavorable Il-28 CT or TT genotype patients present which could also explain in part the low SVR rates.<br /> <br />While SVR rates were not different between treatment arms, a lower relapse rate was seen with an incremental increase in the dose of TBV, similar to that observed with RBV. In addition, the per protocol SVR rates were substantially higher again demonstrating the importance of adherence to therapy to provide optimal SVR rates in the genotype I population. Lower anemia rates (defined as hemoglobin < 10 grams/dL) were seen in the TBV arms throughout the entire 48 weeks, with cumulative anemia rates being significantly lower across the two lower TBV arms (20 mg and 25 mg/kg) compared to weight-based RBV. However, as the dose of TBV was increased to 30 mg/kg, the anemia rate was numerically lower than with RBV but was not significant, other than at week 4, suggesting that higher doses TBV may lead to similar rates of anemia and other side effects observed with RBV. The pharmacokinetic analysis showed that this effect correlated with RBV plasma exposure. Furthermore, within the first 12 weeks of treatment when maintaining the dose of RBV has been shown to be most critical, significantly lower rates of anemia were observed with TBV compared with RBV (7-15% vs 24%, respectively) within the first 12 weeks of treatment although this translated clinically into comparable, not superior SVR rates in the TBV arms. Even though, fewer patients treated with TBV required dose reduction (13-28%) compared to 32% patients treated with RBV, it should also be noted that dropout rates for anemia were not different amongst the TBV arms compared to the RBV arms in this study, though this may be due to relatively small sample size. There does appear to be an increased rate of diarrhea in the TBV arms compared to RBV. This may be significant as some DAA agents are also associated with increased GI side effects and, as we enter an era where DAA agents and other drugs are combined, side effects could limit the efficacy of multi-drug combinations. Finally, while not statistically significant, insomnia was numerically higher in the TBV arms and should be a side effect of some concern in future trials. Thus, as significantly fewer dose reductions were noted only in the TBV 20 mg/kg arm as compared to the higher doses of TBV and RBV with similar SVR rates, the dose of 20 mg/kg may also require study in the future with DAA agents<br /> <br />So what does the future hold for taribavirin? Phase 2 and ongoing Phase 3 trials strongly suggest that DAA agents will be added to pegIFN and RBV to obtain higher SVR rates, albeit at the expense of higher rates of anemia and other side effects. Currently, the role of ESAs in the treatment of HCV with DAA agents is not yet precisely defined, though we await the results of ongoing trials. The inclusion of TBV into the HCV armamentarium may serve as an opportunity to combine with pegIFN and DAA agents to reduce the rates of anemia and avoid RBV dose reduction or introduction of ESAs. As RBV reduction or removal of RBV is associated with increased rates of breakthrough and development of resistance to DAA agents, TBV may have a role in populations particularly sensitive to ribavirin-related anemia , including those with advanced liver disease, older patients, patients who have undergone liver transplantation, HIV/HCV coinfected individuals, patients with hemoglobulinopathies and chronic renal failure 20. However, with the commencement of several trials comprising of multiple combinations of DAA agents with and without pegIFN/RBV, and the development of newer protease inhibitors with potentially lower rates of anemia, the role of TBV remains less precisely defined and could potentially have a finite life cycle. Studies with combinations of DAA agents with PEGIFN/RBV have been initiated and these studies will multiply. Whether or not RBV (and TBV) can be eliminated altogether remains to be determined.<br /> <br />Particularly in those patients with unfavorable treatment characteristics, RBV may remain a part of our therapeutic armamentarium for years to come; and, if so, TBV could be an option which has the potential to limit toxicity and potentially reduce costs. The ideal study may be to combine TBV with a DAA agent and pegIFN and compare it to RBV, to see if SVR rates can be preserved or improved by minimizing dose reductions and reducing the emergence of resistance. Given the long wait between the approval of pegIFN and RBV and yet unapproved DAA agents, one should not discount the potential contribution of TBV. Many promising agents have already been stopped in development due to lack of efficacy or toxicity 21-22. Thus, if TBV can be shown to preserve or improve efficacy rates in combination with DAAs and Peg IFN, with lower rates of anemia, the use of TBV in these clinical settings would be a welcome addition to the HCV armamentarium as we begin to expand the HCV populations that we treat.Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0tag:blogger.com,1999:blog-3205772196563366012.post-91283623723812096502010-09-27T15:56:00.001-04:002010-09-27T15:56:31.248-04:00Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis CVirologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C - pdf attached<br /> <br /> <br /> Download the PDF here<br /> <br />Hepatology Sept 24 2010<br /> <br />Fred Poordad1,*,, Eric Lawitz2, Mitchell L. Shiffman3, Tarek Hassanein4, Andrew J. Muir5, Bruce R. Bacon6, Jamie Heise7, Deanine Halliman7, Eric Chun7, Janet Hammond7<br /> <br />"In conclusion, TBV administered in a weight-based fashion demonstrated similar rates of efficacy to RBV via SVR with significantly less anemia and lower rates of dose modification. The recommended dose of TBV for future development in patients with chronic hepatitis C genotype 1 is 25 mg/kg. These data suggest TBV may be an effective agent to substitute for RBV in the future and could be incorporated in upcoming trials using emerging small molecules for HCV treatment......However, diarrhea and insomnia were more common (>10% different) in the groups that received TBV, whereas anemia was more common (>10% different) in the RBV group (Table 3). The mean insomnia rate of the TBV arms was 35% compared to 24% for the RBV arm and was not considered clinically relevant. The mean TBV diarrhea rate was 39% versus 23% in the RBV group."<br /> <br />ABSTRACT<br /> <br />Ribavirin-induced hemolytic anemia can prompt dose reductions and lower sustained virologic response (SVR) rates in the treatment of patients with chronic hepatitis C. The study aimed to determine if weight-based dosing of taribavirin (TBV), an oral prodrug of ribavirin (RBV), demonstrated efficacy comparable to RBV while maintaining its previously demonstrated anemia advantage with fixed dose administration. A U.S. phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naive patients infected with genotype 1 who were stratified by body weight and baseline viral load. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800-1400 mg/day) with pegylated interferon alfa-2b for 48 weeks. The SVR rates in this difficult-to-cure patient demographics (mean age, 49 years; 61% male; 30% African American or Latino; high viral load; advanced fibrosis; and mean weight, 82 kg) were 28.4%, 24.3%, 20.6%, and 21.4% in the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. There were no statistical differences in the efficacy analyses. Anemia rates were significantly lower (P < 0.05) in the 20 and 25 mg/kg/day TBV treatment groups (13.4% and 15.7%, respectively) compared to RBV (32.9%). The most common adverse events in all groups were fatigue, diarrhea, and insomnia. Diarrhea, reported in 38% of TBV patients versus 21% of RBV patients, was generally mild and not dose-limiting.<br /> <br />Conclusion: All TBV doses demonstrated efficacy and tolerability comparable to that of RBV; however, the 25 mg/kg dose demonstrated the optimal balance of safety and efficacy. Anemia rates were significantly lower for TBV given at 20-25 mg/kg than RBV. These data suggest weight-based dosing with TBV provides a safe and effective treatment alternative to RBV for chronic hepatitis C.<br /> <br /><br />Adverse Events Requiring Dose Modification or Discontinuation.<br /> <br />The percentages of patients with AEs leading to dose reduction or discontinuations are shown in Table 5. Dose modifications of TBV or RBV were most common in the TBV 30 mg/kg/day and RBV groups. Dose reductions were less frequent in the 20 and 25 mg/kg TBV groups compared to RBV by 21% and 12.9%, respectively. The proportion of patients withdrawn from the study as a result of adverse events were 12%, 25%, 19%, and 26% for the 20, 25, 30 mg/kg TBV groups and RBV group, respectively. The proportion of patients withdrawn for anemia adverse events was 1%, 4%, 4%, and 6%, for the 20, 25, and 30 mg/kg groups and the RBV group, respectively. The corresponding number of patients withdrawn for diarrhea AEs was 1%, 1%, 3%, and 0%. Dose reductions due to anemia were 7.5%, 12.9%, 20.6%, and 30% for the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. Stepwise reductions in peg-IFN, RBV, and TBV dosages were used primarily to manage anemia AEs.<br /> <br /><br />Ribavirin (RBV) is essential for the treatment of chronic hepatitis C virus (HCV) infection. When used in combination with peginterferon alfa (peg-IFN alfa), it significantly enhances on-treatment virologic response and reduces relapse.1-3 RBV has been demonstrated to be essential in achieving high rates of sustained virologic response (SVR) when used in combination with direct-acting antiviral agents.4-6 One of the most significant toxicities of RBV is hemolytic anemia.5, 7 When used as monotherapy, RBV-induced hemolytic anemia is marginal because of a compensatory reticulocytosis.8, 9 However, peg-IFN alfa suppresses the bone marrow and significantly reduces reticulocytosis. Therefore, anemia associated with the combination of IFN and RBV therapy is much greater. Approximately 25%-30% of patients receiving peg-IFN and RBV develop a decline of 4 g or greater in hemoglobin (Hb).1, 2, 10 This significantly impairs quality of life and leads to dose reduction and premature discontinuation of treatment in 15%-30% of patients.1, 3, 11, 12 Decreasing the dose of RBV to below 10.6 mg/kg body weight/day during the first 12 weeks of treatment has been shown to increase relapse rates and reduce SVR in both treatment-naive patients and during retreatment.11, 13, 14<br /> <br />Taribavirin (TBV), formerly known as Viramidine, is a nucleoside analogue and oral prodrug of RBV that is converted from TBV to RBV by adenosine deaminase. Its structural difference from RBV, a positively charged carboxamidine group at position 3, significantly reduces the ability of this agent to enter red cells. Because accumulation of RBV within red blood cells is the primary mechanism causing hemolytic anemia, TBV should therefore be associated with significantly less anemia.<br /> <br />Two previous phase 3 clinical trials, ViSER 1 and ViSER 2 (Viramidine's Safety and Efficacy versus Ribavirin), compared a fixed dose of TBV 600 mg twice a day to weight-based dosing (WBD) of RBV 1000 mg/1200 mg (²75 kg/>75 kg body weight), in combination with either peg-IFN alfa-2b or peg-IFN alfa-2a, respectively.15, 16 Both ViSER studies met the primary safety endpoint defined as Hb < 10 g/dL or at least a 2.5 g/dL decrease from baseline at any time point during therapy. Statistically less anemia was observed in patients treated with TBV compared to RBV. However, the primary efficacy endpoint of these studies-a noninferior SVR between the TBV and RBV groups-was not achieved. Detailed subgroup analyses of the data suggested the reasons for the lower SVR in TBV-treated patients were: fixed dose as opposed to WBD and the selection of an inadequate dose. The present study explored several higher WBD regimens of TBV to determine a dosage regimen that was able to deliver comparable responses to RBV with less anemia.<br /> <br />RESULTS<br /> <br />Study Patients.<br /> <br />A total of 278 patients were randomized at 51 U.S. centers between March 2007 and October 2008. A total of 86 (41%) of patients in the TBV arms and 25 (36%) in the RBV arm completed treatment and follow-up. Overall, 122 (59%) patients withdrew prematurely in the TBV arms compared to 45 (64%) in the RBV group. The most commonly cited reasons for premature withdrawal were lack of response (29%) and adverse events (20%). Figure 1 shows the disposition of patients during treatment.<br /> <br />Baseline characteristics across the four treatment groups were similar (Table 1). The majority of patients were male (61%) with a mean weight of 82.1 kg and mean age of 49 years. African American or Latino patients accounted for 30% of the study population and 81% had high viral load defined as >400,000 IU/mL at baseline.<br /> <br />Efficacy.<br /> <br />The proportions of patients in the ITT population with an EVR, the primary endpoint of this study, were comparable between all groups with no statistical difference versus RBV. EVR was achieved in 64.2% (43 of 67) in the 20 mg/kg group, 57.1% (40 of 70) in the 25 mg/kg group, 54.4% (37 of 68) of the 30 mg/kg group and 51.4% (36 of 70) in the RBV group. Virologic response for TW4, 12, 24, and 48 as well as SVR are shown in Table 2. The proportion of patients with undetectable HCV RNA at every time point was similar between the TBV and RBV groups. Although responder rates were numerically lower at TW12 in the TBV 30 mg/kg group and somewhat higher at TW24 and TW48 in the TBV 20 mg/kg group, they were not significantly different for any of the TBV doses compared with RBV.<br /> <br />The relapse rates for the TBV groups (35%, 20 mg/kg; 21%, 25 mg/kg; 14%, 30 mg/kg) were inversely proportional to the TBV dose and are most likely indicative of the recognized effects of RBV dosing (Fig. 2). The lowest TBV dose resulted in the lowest RBV exposure and subsequently, the greatest relapse rate (35%).<br /> <br />The SVR rates observed in the per-protocol population were 60%, 64%, 62%, and 62% for the 20, 25, and 30 mg/kg/day TBV groups and the RBV group, respectively, and there were no statistically significant differences between the groups. These results were more than double the ITT SVR demonstrating maximal response as RBV or TBV exposure increases with adherence to therapy.<br /> <br />Safety.<br /> <br />The most common AEs were typical of those previously reported for chronic hepatitis C therapy with peg-IFN and RBV. However, diarrhea and insomnia were more common (>10% different) in the groups that received TBV, whereas anemia was more common (>10% different) in the RBV group (Table 3). The mean insomnia rate of the TBV arms was 35% compared to 24% for the RBV arm and was not considered clinically relevant. The mean TBV diarrhea rate was 39% versus 23% in the RBV group.<br /> <br />Diarrhea, which was previously noted to occur more frequently in the ViSER studies, was also reported more frequently in the current study. It occurred predominantly during the first 12 weeks of therapy and was generally mild, not dose-limiting and of short duration. Through FW24, cumulative diarrhea rates occurred in 40.3%, 37.1%, and 36.8% of patients on 20, 25, and 30 mg/kg/day TBV respectively. This indicates no apparent TBV dose relationship. In the majority of cases diarrhea classification was "mild" or "moderate." Serious diarrhea AEs (grade 3) were reported in two patients and were determined by their physician assessment as un-related to study medication and due to concomitant disease. There were no grade 4 diarrhea events reported. During the 24-week follow up period, the incidence of diarrhea returned to baseline at a frequency similar to that of RBV.<br /> <br />The cumulative incidence of anemia throughout the trial is shown in Table 4. The 20 and 25 mg/kg groups were statistically significantly lower than the RBV group (P < 0.05) at all time points. The anemia rate of TBV 30 mg/kg was lower than that observed with RBV but did not achieve statistical significance, other than at week 4. The pharmacokinetic analysis showed this effect correlated with RBV plasma exposure in the TBV group. Exposure of RBV associated with TBV dosing was consistently lower compared to RBV exposure due to RBV dosing by pharmacokinetic measures (data not shown) until after TW18. At that time, TBV 30 mg/kg/day generated RBV plasma trough levels that exceeded the levels observed due to RBV oral administration. In addition, the exposure of TBV and RBV due to TBV were dose linear over the dosage range 20-30 mg/kg/day evaluated.<br /> <br />Adverse Events Requiring Dose Modification or Discontinuation.<br /> <br />The percentages of patients with AEs leading to dose reduction or discontinuations are shown in Table 5. Dose modifications of TBV or RBV were most common in the TBV 30 mg/kg/day and RBV groups. Dose reductions were less frequent in the 20 and 25 mg/kg TBV groups compared to RBV by 21% and 12.9%, respectively. The proportion of patients withdrawn from the study as a result of adverse events were 12%, 25%, 19%, and 26% for the 20, 25, 30 mg/kg TBV groups and RBV group, respectively. The proportion of patients withdrawn for anemia adverse events was 1%, 4%, 4%, and 6%, for the 20, 25, and 30 mg/kg groups and the RBV group, respectively. The corresponding number of patients withdrawn for diarrhea AEs was 1%, 1%, 3%, and 0%. Dose reductions due to anemia were 7.5%, 12.9%, 20.6%, and 30% for the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. Stepwise reductions in peg-IFN, RBV, and TBV dosages were used primarily to manage anemia AEs.<br /> <br />DISCUSSION<br /> <br />The present study demonstrated that WBD TBV achieved comparable efficacy to RBV as demonstrated by SVR. This was observed in all three TBV WBD treatment groups, which met the study's primary endpoint. Notably, patients treated with TBV had less than half the anemia and a 13%-21% lower dose modification rate compared to RBV treated patients treated. These results suggest WBD of TBV can significantly improve the tolerability of HCV treatment while maintaining efficacy. Specifically, the 25 mg/kg dose offered the optimal balance of efficacy and safety in this patient population.<br /> <br />The relapse rates for the TBV groups were inversely proportional to the TBV dose and are most likely indicative of the recognized effects of RBV dosing. The similar SVR and higher relapse rates observed in the 20 mg/kg group are a reflection of higher end of treatment response rates. The high on-treatment response can be explained by the greater percentage of women and Caucasians randomized to this group. The higher relapse rate observed in the 20 mg/kg group is likely due to the lower TBV/RBV exposure.<br /> <br />The overall response rates observed in this trial appeared lower than expected for a Caucasian based genotype 1 trial. However, the demographics of this patient population were quite different than in many other controlled clinical trials reported to date. Approximately 20% of enrolled patients were African American, which was more than double many previous controlled clinical trials.1, 3 African Americans with genotype 1 HCV, have lower response rates to peg-IFN/RBV than Caucasians.17 Recent studies also demonstrated that African Americans have a much lower population frequency of a gene associated with SVR.18 A genetic predisposition for nonresponse in these patients is not likely to be overcome by a more favorable treatment, though the addition of direct acting antiviral agents should improve SVR rates in these populations. In addition to a high percentage of African and Latino races, other poor response characteristics present in the study population were: 81% of patients had high viral load; a higher age than reported in previous registration trials and up to 40% of patients had bridging fibrosis.1-3 The drop out rate in this trial was approximately 10% higher than other U.S.-based trials and this difference is likely related to the poor response characteristics described above.<br /> <br />Similar to dosing experiences with RBV, we found WBD with TBV provides optimal RBV exposure. The pharmacokinetics of TBV administered at doses of 20, 25, and 30 mg/kg/day demonstrated steady state by TW4 for both prodrug and parent drug. This is equivalent to what is seen of RBV exposure from a RBV weight adjusted dosage of 800-1400 mg/day. TBV pharmacokinetics were dose linear, predictable and consistently generated RBV plasma levels that were lower than seen by RBV administration, without an impact on efficacy. The lower RBV concentrations positively affected the critical safety concern for RBV-anemia. The TBV 25 mg/kg/day dose had similar efficacy results as WBD RBV with significantly lower anemia rates.<br /> <br />As was reported in previous TBV clinical trials, an increase in the frequency of diarrhea was observed in all TBV cohorts when compared to RBV. Diarrhea was considered an adverse event of special interest in this study, therefore a more rigorous medical history specific to diarrhea was collected prospectively and this likely accounted for increased reporting frequency. The majority of cases across all treatment groups were classified as common toxicity criteria grade 1, occurred early in therapy and were single episode. The exact mechanism of action leading to diarrhea in patients receiving TBV remains unknown. After the end of treatment, the incidence of diarrhea returned to baseline, suggesting it is treatment related, and reversible.<br /> <br />Anemia is considered to be significant when the Hb falls below 10 g/dL. Patients treated with TBV had lower rates of anemia throughout the entire 48 weeks of treatment. Within the first 12 weeks of treatment, when maintaining the dose of RBV has been shown to be most critical, significant anemia was observed in only 7%-15% of patients treated with TBV compared to 24% of patients treated with RBV. As a result, fewer patients treated with TBV required dose reductions (13%-28%) compared to 32% of patients treated with RBV. Less frequent dose modification in patients treated with TBV may alleviate the need to use ESAs. Several studies have now demonstrated the use of ESAs can significantly decrease the need to dose reduce RBV and leads to an improvement in the quality of life during HCV treatment,19-21 but fail to improve the SVR.22 However, the use of ESAs adds significant cost to HCV treatment and is associated with significant adverse events including thrombosis and red cell aplasia.19, 23 Thus, limiting anemia during HCV treatment is clearly desirable.<br /> <br />The future of HCV treatment will incorporate potent antiviral agents such as protease and polymerase inhibitors, with peg-IFN and RBV. Despite its toxicity, RBV remains critical to optimizing SVR rates of hepatitis C and is unlikely to be replaced by the first generation direct acting antiviral agents.4-6 Data from the new small molecule trials have demonstrated that anemia is a common consequence of treatment of protease inhibitors and when used with RBV there appears to be a significant need to either dose modify RBV or use ESAs to limit anemia.4-6 Therefore, TBV should be considered as a RBV substitution to future clinical trials with peg-IFN and protease inhibitors as it may yield a significant treatment advantage over RBV.<br /> <br />Other potential TBV opportunities that need to be explored in clinical trials would be in patients susceptible to anemia and where RBV is contraindicated (including chronic renal failure and hemoglobinopathies). Patients who are slow to respond and may require 72 weeks of treatment may also benefit from using TBV as opposed to RBV. The lower anemia rates associated with TBV may allow these patients to remain on a prolonged course to achieve SVR. Finally, TBV may be particularly useful in liver transplant recipients with recurrent HCV and in patients coinfected with HCV and human immunodeficiency virus. Many of these patients have preexisting anemia and this worsens considerably during treatment with peg-IFN and RBV. The low SVRs in these populations are at least in part secondary to anemia and the inability to optimize RBV dosage.<br /> <br />In conclusion, TBV administered in a weight-based fashion demonstrated similar rates of efficacy to RBV via SVR with significantly less anemia and lower rates of dose modification. The recommended dose of TBV for future development in patients with chronic hepatitis C genotype 1 is 25 mg/kg. These data suggest TBV may be an effective agent to substitute for RBV in the future and could be incorporated in upcoming trials using emerging small molecules for HCV treatment.<br /> <br />METHODS & PATIENTS<br /> <br />Study Patients.<br /> <br />Approximately 260 patients were planned for enrollment in the study, with approximately 65 patients in each of the four treatment groups. Eligible patients were treatment-naive, at least 18 years of age, diagnosed with chronic HCV genotype 1 infection (>2000 copies/mL or >780 IU/mL), and showed histologic changes consistent with chronic HCV as demonstrated on liver biopsy within 3 years of screening. Patients were excluded from the study if they had histologic evidence of cirrhosis (F4), low Hb concentrations (men, <13 g/dL; women, <12 g/dL), neutropenia (absolute neutrophil count <1200 x 103/µL), thrombocytopenia (<90 x 103 platelets/µL) or serum creatinine levels ³1.5 mg/dL. Additional exclusion criteria included chronic hepatic disease other than HCV, human immunodeficiency virus, or hepatitis B coinfection; severe psychiatric disorders; alcoholism or drug addiction within 1 year of screening; use of erythropoiesis-stimulating agents (ESAs); and presence of comorbid conditions considered significant by the investigator.<br /> <br />Study Design.<br /> <br />This was a phase 2b, multicenter, randomized, open-label, active-control, and parallel-group trial. Although the study was open-label, the sponsor was blinded to treatment allocation and viral load results until treatment week 12. Patients were enrolled at 51 centers in the United States. Patients were stratified by serum HCV RNA titers (²780,000 IU/mL or >780,000 IU/mL) and baseline weight (²75 or >75 kg). An interactive voice response system was used to randomize patients in a 1:1:1:1 ratio to receive weight-based TBV 20 mg/kg/day, 25 mg/kg/day, or 30 mg/kg/day (Valeant Pharmaceuticals North America, Aliso Viejo, CA) or weight-based RBV at 800, 1000, 1200, or 1400 mg/day (Copegus; Hoffmann-La Roche, Nutley, NJ) in combination with peg-IFN alfa 2b (PegIntron; Schering Corp., Kenilworth, NJ). All patients received doses twice daily with their morning and evening meals.<br /> <br />Patients were treated for 48 weeks, but treatment was discontinued for evidence of nonresponse defined as <2-log decline at week 12 or a positive viral load at week 24. Study treatment was initiated on day 1 and clinic visits occurred at treatment weeks (TWs) 1, 2, 3, 4, 8, 12, 18, 24, 30, 36, and 48, as well as posttreatment follow-up weeks (FWs) 4, 12, 20, and 24. All patients who completed treatment with study drug or discontinued treatment prematurely (except nonresponders) immediately entered a 24-week follow-up period.<br /> <br />The study protocol was approved by the institutional review boards of participating institutions and was conducted in accordance with the Declaration of Helsinki and provisions of Good Clinical Practices. All patients provided written informed consent.<br /> <br />Study Objective.<br /> <br />The objective of this study was to select an optimal dose of TBV by comparing the efficacy and safety of three TBV dose levels versus RBV based on body weight, both administered with peg-IFN alfa-2b to therapy-naive compensated patients with genotype 1 chronic hepatitis C.<br /> <br />Efficacy Assessments.<br /> <br />The primary efficacy endpoint was early virologic response (EVR) defined as the proportion of patients with at least a 2-log decrease from baseline in serum HCV RNA levels at TW12. Additional efficacy endpoints assessed in the trial included SVR; undetectable HCV RNA at TW4, TW24, and TW48; and viral relapse for those who were responders at the end of treatment. Subgroup analyses were carried out to determine the impact of various baseline demographic factors such as sex, age, race, weight, baseline HCV RNA, and fibrosis score on response.<br /> <br />Lack of efficacy was defined as less than a 2-log decrease of HCV RNA (IU/mL) at TW12 or detectable HCV RNA at TW24. Relapse rates were calculated by measuring the proportion of responding patients whose plasma HCV levels changed from undetectable at end of treatment to detectable at FW24.<br /> <br />Safety Assessments.<br /> <br />The primary safety endpoint was the proportion of patients with Hb < 10 g/dL at any time during the treatment period. Subgroup analyses were carried out to determine the impact of various baseline demographic factors such as sex, age, race, weight, baseline HCV RNA, and fibrosis score on safety. Safety assessments included laboratory values, vital signs, and monitoring of adverse events (AEs) at each study visit. Patients who discontinued therapy prematurely due to an AE were followed to study completion. Stepwise reductions in peg-IFN, RBV, and TBV dosages were allowed to manage AEs or laboratory abnormalities that had reached predetermined thresholds of severity. If a dose modification of TBV or RBV was required for nonhematologic AEs, the dose was decreased in a stepwise manner, starting with a reduction of approximately 20% of the assigned dose. Hematologic AEs, except anemia, initially required a dose reduction of 50%. Anemia AEs were managed according to presence or absence of cardiac disease. Upon AE resolution, increases of peg-IFN, RBV, or TBV dose in a reverse stepwise manner could be attempted at the investigator's discretion. Use of ESAs was prohibited.<br /> <br />Because diarrhea was identified as an AE of special interest in previous clinical trials, a more extensive diarrhea history was obtained at baseline, and a diarrhea-specific AE report form was developed and employed in this trial. Diarrhea was classified on the form by common toxicity criteria grades of 1 to 4 (mild to severe). A diarrhea management plan was developed and employed. An independent data monitoring committee convened at various time points during the study treatment period to assess safety but also to determine the risk-benefit ratio considering the higher dosages studied.<br /> <br />Pharmacokinetic Analyses.<br /> <br />Serial plasma samples for the determination of TBV and RBV concentrations were collected across the first dosing interval (0-12 hours) of the twice daily dosing regimen at TW4 and TW12 in a representative subset of the patients at select sites for noncompartmental pharmacokinetic analysis and assessment of dose linearity. In addition, predose plasma samples for determination of TBV and RBV concentrations were obtained at each treatment week with an assessment of steady state at TW4.<br /> <br />Statistical Analyses.<br /> <br />There were 275 patients enrolled in the study, with approximately 70 patients in each of the four treatment groups. The projected study power was 70% to detect a linear trend in proportions as well as to detect noninferiority of TBV versus RBV using a margin of 12%.<br /> <br />Analysis of the primary efficacy and safety variables used data from the intent-to-treat (ITT) population, defined as patients who were randomized and received at least one dose of study drug.<br /> <br />The per-protocol population, defined as ITT patients with no major protocol deviations, no use of prohibited concomitant medications, and who completed treatment with >80% compliance, was used for the sensitivity analysis at TW12, TW24, and TW48 and FW4, FW12, and FW24.<br /> <br />Unless otherwise noted, all tests of hypotheses were two-sided at the overall 5% level of significance. The trend test determined the dose response relationship of the three TBV treatment groups, and the Fisher's exact test was performed for the various treatment group comparisons. For each of these three comparisons, the difference in responder rate and associated 95% confidence interval was determined. Once the optimum TBV dose was identified, a test of noninferior efficacy was performed by comparing the proportions of responders at TW12 in the optimal TBV and RBV treatment arms. Chi-squared or the Fisher's exact test compared anemia rates between the TBV and RBV groups with a 95% confidence interval.<br /> <br />Secondary efficacy measures included the SVR defined as HCV RNA <100 copies/mL (39 IU/mL) and/or at least a 2-log decrease from baseline at TW4, TW24, TW48 and FW4 and FW12 and relapse rates at FW4, FW12, and FW24. Secondary safety measures included the comparison of incidence of treatment-emergent adverse events.<br /> <br />Subgroup analysis by HCV RNA levels at baseline, body weight, age, sex, race, and baseline fibrosis were performed using the trend test and the Fisher's exact test for the primary endpoint. In addition, the Cochran-Mantel-Haenszel procedure, with the Breslow-Day test was used to examine the homogeneity of treatment effect across strata.<br /> <br />The investigators and the sponsor managed the data for this study. The sponsor completed the statistical analysis. The authors had access to the clinical study report and have either written or provided intellectual input to the manuscript.Scott Weinsteinhttp://www.blogger.com/profile/07897590491601740429noreply@blogger.com0