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New HCV Nucleotide
PSI-7851
from Pharmasset Sept 25 2009
PSI-7851 is a pro-drug of a nucleotide analog and is currently in development for the treatment of chronic HCV infection. PSI-7851 has demonstrated in vitro anti-HCV activity with EC50 values of approximately 90 +/- 60 nM, which is approximately 15- to 20- fold more potent than the active metabolite of our first generation nucleoside polymerase inhibitor, PSI-6130. The half-life of the triphosphate (the biologically active form of the molecule) in primary human hepatocytes is approximately 38 hours, which suggests the possibility for once-daily dosing. Like RG7128, PSI-7851 has demonstrated in vitro activity against HCV genotypes 1, 2, 3 and 4.
During March 2009, we initiated a Phase 1 study for PSI-7851. As part of the Phase 1 study, we completed a single ascending dose study that assessed the safety, tolerability and pharmacokinetics of PSI-7851 in healthy subjects at doses ranging from 25mg to 800mg. Preliminary results from this study indicated there were:
* No serious adverse events or discontinuations;
* No dose-related adverse events;
* No grade III/ IV lab abnormalities; and
* No clinically significant changes in vital signs or ECGs.
During June 2009, we initiated a Phase 1 multiple ascending dose study in HCV-infected patients. Subjects were enrolled at two U.S. centers and randomized to PSI-7851 (8 per cohort) or placebo (2 per cohort). The primary objective of this study was to assess the safety, tolerability, and pharmacokinetics of PSI-7851 after once-daily dosing for three days. The secondary objective of this study was to assess antiviral activity by measuring the change in HCV RNA. Three dose cohorts of PSI-7851 (50mg QD, 100mg QD, and 200mg QD) were evaluated. Preliminary results from this study indicated:
* PSI-7851 was generally safe and well tolerated across all cohorts with no discontinuations, no serious adverse events, and no dose-related trends in adverse events or laboratory abnormalities.
* PSI-7851 demonstrated potent antiviral activity with a mean HCV RNA decrease of -0.49 log IU/mL, -0.61 log IU/mL, and -1.01 log IU/mL in patients receiving 50mg QD, 100mg QD, and 200mg QD, respectively.
Sunday, September 27, 2009
HIV Vaccine Reduces Infection Risk
HIV Vaccine Reduces Infection Risk
By Michael Smith, North American Correspondent, MedPage Today
Published: September 24, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine. Click here to rate this report
For the first time, an investigational HIV vaccine has shown it can protect people from the virus -- a giant step forward in a field that has been humbled by repeated failure, experts said.
Scientists involved in the so-called RV-144 study, a large proof-of-concept trial conducted in Thailand, released some details early today.
The key finding: In a large population of everyday people at relatively low risk for HIV, the vaccine reduced the chances of infection by 31.2% compared with placebo, according to Col. Jerome Kim, MD, deputy director of science for the U.S. Military HIV Research Program.
"This is the first evidence that a safe and effective HIV vaccine is possible," Kim said.
Although the effect was repeatedly described as "modest," the finding was also called a major scientific achievement that paves the way for better vaccines.
"We now know that this is a doable objective," said Alan Bernstein, PhD, executive director of the New York-based Global HIV Vaccine Enterprise, which was not involved in the study.
Bernstein said there were many who, after repeated failures, considered an HIV vaccine impossible. Most recently, a closely watched vaccine candidate failed dramatically, and even seemed to increase the risk of getting HIV. (See CROI: HIV Vaccine's Mysterious Failure Leads to Call for New Directions)
Given previous failures, the latest finding is "incredibly important," said Harriet Robinson, PhD, of Atlanta-based GeoVax, which is developing its own HIV vaccine candidates.
"This is a ground-breaking demonstration that an HIV/AIDS vaccine can prevent infection, something that the scientific community had begun to doubt," she said.
But Bernstein and others cautioned that the result is only proof that a vaccine can be made to work. It is likely to take years of additional research to get a drug on the market, they said.
"I'm incredibly optimistic about it -- it made me smile this morning," said Jill Gilmour, PhD, of the New York-based International AIDS Vaccine Initiative, which did not have a role in the research.
The trial results will "re-energize the field," she said.
But Gilmour said she and other researchers will now want to drill down into the data collected in the study to see how a more effective vaccine can be developed.
"We're out of the blocks," she said. "Now can we get to the finish line?"
The researchers involved in the trial, too, said they need more time to digest all the data.
For one thing, despite the success in preventing infection, Kim said, there was no effect on the other main goal of the trial -- to see if the vaccine could lower the amount of virus in the bloodstream of infected people. When volunteers were tested between three and six months after their infection, levels among those in the placebo and vaccine arms were the same.
Side effects were the same in both arms of the trial and more information is expected in October, at a Paris conference sponsored by the vaccine initiative.
The Army was one of the partners in the $105-million trial, along with the Thai Ministry of Public Health, the National Institute of Allergy and Infectious Diseases (NIAID), Sanofi Pasteur, and Global Solutions for Infectious Diseases.
A host of questions remains to be answered, according to Anthony Fauci, MD, director of the NIAID.
The key one, he said, is what caused the result.
"We have a positive signal," Fauci told reporters. But "what immunological parameters gave us this result" remains a mystery.
Fauci and other experts have, in a sense, been working blind for years because they didn't know what a positive immune response to HIV would look like on a biological level.
Now, with a vaccine that has demonstrated at least some protection, they hope to be able to tease out the so-called "correlates of immunity" -- biological changes that signal an immune response.
"There's nothing like a positive result to help us focus on some critical questions," he said.
Fauci said a central scientific question is why there was a discordant effect on the two study endpoints -- some protection against infection but no apparent effect on viral load.
The finding "strongly suggests" that the immune mechanisms that block infection and those that control the virus after infection are different, he said.
Among the other questions that need answers, Fauci said:
* How long does the benefit of the vaccine last?
* Will booster shots be needed?
* Can the efficacy be boosted above the 30% level?
* How well will the approach work in high-risk groups, such as men who have sex with men, or injection drug users?
* Will the approach work against all subtypes of HIV?
"We have a great deal of work ahead of us," Fauci said.
"But today I have a renewed sense of optimism -- cautious optimism -- at the possibility of improving on these encouraging results," he said, "and ultimately developing a highly effective vaccine to protect against HIV infection."
It's unlikely, however, that this vaccine candidate will go to the FDA for licensing, if only because the trial itself was not set up to provide the kind of data the agency requires, according to Col. Nelson Michael, MD, PhD, director of the U.S. Military HIV Research Program.
Also -- even in places where the incidence of HIV is high -- a 31% benefit is not enough to justify using a vaccine, Bernstein said.
The trial randomized 16,395 community volunteers from the central Thai provinces of Chon Buri and Rayong, rather than high-risk groups, as many other vaccine studies have done.
In the final analysis, there were 74 infections in the placebo arm, compared with 51 in the vaccine arm, a difference that was significant at P=0.039 with a 95% confidence interval from 1.1% to 52.1%.
The trial tested a so-called "prime-boost strategy" using two different medications.
The first, dubbed ALVAC-HIV, was a canarypox virus, engineered so it could not cause disease, and modified to carry synthetic versions of three HIV genes, known as gag, env, and pro.
Volunteers were given four injections of ALVAC-HIV over six months or a matching placebo.
At the last two injections, they were also given a shot of AIDSVAX B/E (or placebo) -- a vaccine candidate that had been tested on its own and found to be safe, but without benefit. After the six-month vaccination phase, the volunteers were followed for three years, with HIV testing every six months.
The AIDSVAX B/E contains an HIV protein known as gp120.
The idea was to prime the immune system with the first vaccine and then boost it with the second. Researchers hoped to elicit both antibodies to HIV and killer T cells that would destroy the virus.
Both medications contained HIV fragments from subtype B -- common in Europe and North America -- and subtype E, found in Thailand and Southeast Asia.
It does not contain elements of the so-called clade C HIV strain, which is the main subtype found in Africa, where an estimated 22 million people are living with HIV -- 67% of the global total.
The trial was controversial when it started, largely because of the previous failure of the AIDSVAX component.
"There were many prominent scientists who thought this trial should not go forward," Bernstein said, and even supporters could not have predicted the outcome, especially the discordant results of the two endpoints.
"Like all good experiments, (the trial) raises more questions than it answers," he said.
This article was developed in collaboration with ABC News.
By Michael Smith, North American Correspondent, MedPage Today
Published: September 24, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine. Click here to rate this report
For the first time, an investigational HIV vaccine has shown it can protect people from the virus -- a giant step forward in a field that has been humbled by repeated failure, experts said.
Scientists involved in the so-called RV-144 study, a large proof-of-concept trial conducted in Thailand, released some details early today.
The key finding: In a large population of everyday people at relatively low risk for HIV, the vaccine reduced the chances of infection by 31.2% compared with placebo, according to Col. Jerome Kim, MD, deputy director of science for the U.S. Military HIV Research Program.
"This is the first evidence that a safe and effective HIV vaccine is possible," Kim said.
Although the effect was repeatedly described as "modest," the finding was also called a major scientific achievement that paves the way for better vaccines.
"We now know that this is a doable objective," said Alan Bernstein, PhD, executive director of the New York-based Global HIV Vaccine Enterprise, which was not involved in the study.
Bernstein said there were many who, after repeated failures, considered an HIV vaccine impossible. Most recently, a closely watched vaccine candidate failed dramatically, and even seemed to increase the risk of getting HIV. (See CROI: HIV Vaccine's Mysterious Failure Leads to Call for New Directions)
Given previous failures, the latest finding is "incredibly important," said Harriet Robinson, PhD, of Atlanta-based GeoVax, which is developing its own HIV vaccine candidates.
"This is a ground-breaking demonstration that an HIV/AIDS vaccine can prevent infection, something that the scientific community had begun to doubt," she said.
But Bernstein and others cautioned that the result is only proof that a vaccine can be made to work. It is likely to take years of additional research to get a drug on the market, they said.
"I'm incredibly optimistic about it -- it made me smile this morning," said Jill Gilmour, PhD, of the New York-based International AIDS Vaccine Initiative, which did not have a role in the research.
The trial results will "re-energize the field," she said.
But Gilmour said she and other researchers will now want to drill down into the data collected in the study to see how a more effective vaccine can be developed.
"We're out of the blocks," she said. "Now can we get to the finish line?"
The researchers involved in the trial, too, said they need more time to digest all the data.
For one thing, despite the success in preventing infection, Kim said, there was no effect on the other main goal of the trial -- to see if the vaccine could lower the amount of virus in the bloodstream of infected people. When volunteers were tested between three and six months after their infection, levels among those in the placebo and vaccine arms were the same.
Side effects were the same in both arms of the trial and more information is expected in October, at a Paris conference sponsored by the vaccine initiative.
The Army was one of the partners in the $105-million trial, along with the Thai Ministry of Public Health, the National Institute of Allergy and Infectious Diseases (NIAID), Sanofi Pasteur, and Global Solutions for Infectious Diseases.
A host of questions remains to be answered, according to Anthony Fauci, MD, director of the NIAID.
The key one, he said, is what caused the result.
"We have a positive signal," Fauci told reporters. But "what immunological parameters gave us this result" remains a mystery.
Fauci and other experts have, in a sense, been working blind for years because they didn't know what a positive immune response to HIV would look like on a biological level.
Now, with a vaccine that has demonstrated at least some protection, they hope to be able to tease out the so-called "correlates of immunity" -- biological changes that signal an immune response.
"There's nothing like a positive result to help us focus on some critical questions," he said.
Fauci said a central scientific question is why there was a discordant effect on the two study endpoints -- some protection against infection but no apparent effect on viral load.
The finding "strongly suggests" that the immune mechanisms that block infection and those that control the virus after infection are different, he said.
Among the other questions that need answers, Fauci said:
* How long does the benefit of the vaccine last?
* Will booster shots be needed?
* Can the efficacy be boosted above the 30% level?
* How well will the approach work in high-risk groups, such as men who have sex with men, or injection drug users?
* Will the approach work against all subtypes of HIV?
"We have a great deal of work ahead of us," Fauci said.
"But today I have a renewed sense of optimism -- cautious optimism -- at the possibility of improving on these encouraging results," he said, "and ultimately developing a highly effective vaccine to protect against HIV infection."
It's unlikely, however, that this vaccine candidate will go to the FDA for licensing, if only because the trial itself was not set up to provide the kind of data the agency requires, according to Col. Nelson Michael, MD, PhD, director of the U.S. Military HIV Research Program.
Also -- even in places where the incidence of HIV is high -- a 31% benefit is not enough to justify using a vaccine, Bernstein said.
The trial randomized 16,395 community volunteers from the central Thai provinces of Chon Buri and Rayong, rather than high-risk groups, as many other vaccine studies have done.
In the final analysis, there were 74 infections in the placebo arm, compared with 51 in the vaccine arm, a difference that was significant at P=0.039 with a 95% confidence interval from 1.1% to 52.1%.
The trial tested a so-called "prime-boost strategy" using two different medications.
The first, dubbed ALVAC-HIV, was a canarypox virus, engineered so it could not cause disease, and modified to carry synthetic versions of three HIV genes, known as gag, env, and pro.
Volunteers were given four injections of ALVAC-HIV over six months or a matching placebo.
At the last two injections, they were also given a shot of AIDSVAX B/E (or placebo) -- a vaccine candidate that had been tested on its own and found to be safe, but without benefit. After the six-month vaccination phase, the volunteers were followed for three years, with HIV testing every six months.
The AIDSVAX B/E contains an HIV protein known as gp120.
The idea was to prime the immune system with the first vaccine and then boost it with the second. Researchers hoped to elicit both antibodies to HIV and killer T cells that would destroy the virus.
Both medications contained HIV fragments from subtype B -- common in Europe and North America -- and subtype E, found in Thailand and Southeast Asia.
It does not contain elements of the so-called clade C HIV strain, which is the main subtype found in Africa, where an estimated 22 million people are living with HIV -- 67% of the global total.
The trial was controversial when it started, largely because of the previous failure of the AIDSVAX component.
"There were many prominent scientists who thought this trial should not go forward," Bernstein said, and even supporters could not have predicted the outcome, especially the discordant results of the two endpoints.
"Like all good experiments, (the trial) raises more questions than it answers," he said.
This article was developed in collaboration with ABC News.
HEPDART
December 6-10, 2009
Fairmont Orchid
Kohala Coast (Big Island), Hawaii, USA
www.hepdart.com
ABSTRACT SUBMISSION AND EARLY REGISTRATION DEADLINE: FRIDAY, OCTOBER 2, 2009
This year's meeting will be held at the Fairmont Orchid on the Big Island of Hawaii from December 6-10, 2009, celebrating 20 years of HCV Research. Registration to this meeting is limited to 400 persons, with priority given to those submitting an accepted abstract (deadline for abstract submission is October 2, 2009).
ABSTRACT SUBMISSION
Abstract submission is via an online process. For abstract guidelines and to submit an abstract, please click below:
www.hepdart.com
ABSTRACT CATEGORIES
Advances in HCV and HBV Cell-based Assays & Animal Models
Clinical Development of HBV/HCV Inhibitors
Co-infection with HIV and Other Viruses
Hepatocellular Carcinoma and Fibrosis
Immunology & Vaccine Development
Next Generation of HBV and HCV Inhibitors
New Therapeutic Approaches, Combinations, Pharmacology, and Emerging Targets
Optimizing Outcome of Therapeutics for HBV/HCV
Pathogenesis, Therapeutics, Viral Dynamics and Emerging Viruses
Resistance to Antiviral Agents, Replication Fitness and Vaccine Escape Mutants
Diagnostic Approaches and Non-invasive Markers
ONLINE REGISTRATION
Please take advantage of the discounted registration fee for early registration and register on or before October 2, 2009.
For more information regarding the HEP DART 2009 meeting, please find below a link to the brochure. Simply click on the picture below and it will open the entire brochure in your web browser window.
I appreciate your forwarding this email to anyone who might be interested in attending this meeting. If you have any questions, please contact the Conference Secretariat at: hepdart2009@informedhorizons.com. We look forward to seeing you in Hawaii in December.
On behalf of the Organizing Committee
Raymond F. Schinazi, Emory University/VA Medical Center, USA
Robert Murphy, Northwestern University, USA
Charles Rice, The Rockefeller University, USA
Eugene Schiff, University of Miami, USA
Fairmont Orchid
Kohala Coast (Big Island), Hawaii, USA
www.hepdart.com
ABSTRACT SUBMISSION AND EARLY REGISTRATION DEADLINE: FRIDAY, OCTOBER 2, 2009
This year's meeting will be held at the Fairmont Orchid on the Big Island of Hawaii from December 6-10, 2009, celebrating 20 years of HCV Research. Registration to this meeting is limited to 400 persons, with priority given to those submitting an accepted abstract (deadline for abstract submission is October 2, 2009).
ABSTRACT SUBMISSION
Abstract submission is via an online process. For abstract guidelines and to submit an abstract, please click below:
www.hepdart.com
ABSTRACT CATEGORIES
Advances in HCV and HBV Cell-based Assays & Animal Models
Clinical Development of HBV/HCV Inhibitors
Co-infection with HIV and Other Viruses
Hepatocellular Carcinoma and Fibrosis
Immunology & Vaccine Development
Next Generation of HBV and HCV Inhibitors
New Therapeutic Approaches, Combinations, Pharmacology, and Emerging Targets
Optimizing Outcome of Therapeutics for HBV/HCV
Pathogenesis, Therapeutics, Viral Dynamics and Emerging Viruses
Resistance to Antiviral Agents, Replication Fitness and Vaccine Escape Mutants
Diagnostic Approaches and Non-invasive Markers
ONLINE REGISTRATION
Please take advantage of the discounted registration fee for early registration and register on or before October 2, 2009.
For more information regarding the HEP DART 2009 meeting, please find below a link to the brochure. Simply click on the picture below and it will open the entire brochure in your web browser window.
I appreciate your forwarding this email to anyone who might be interested in attending this meeting. If you have any questions, please contact the Conference Secretariat at: hepdart2009@informedhorizons.com. We look forward to seeing you in Hawaii in December.
On behalf of the Organizing Committee
Raymond F. Schinazi, Emory University/VA Medical Center, USA
Robert Murphy, Northwestern University, USA
Charles Rice, The Rockefeller University, USA
Eugene Schiff, University of Miami, USA
Rockefeller virologists and MIT tissue engineers receive $5.8 million NIH grant to study hepatitis
Rockefeller virologists and MIT tissue engineers receive $5.8 million NIH grant to study hepatitis
Scientists studying hepatitis at Rockefeller University and the Massachusetts Institute of Technology will receive a $5.8 million grant to study hepatitis infection under the National Institutes of Health?s inaugural Transformative R01 grant program, a groundbreaking initiative designed to encourage high-risk research. The grant, which will run for five years beginning in 2009, will fund efforts to elucidate the notoriously complex mechanisms underlying disease progression in hepatitis B and C virus infection.
Chronic infections with hepatitis B and C viruses, which take root in the liver, affect an estimated 500 million people worldwide, leading to diseases including hepatitis, cirrhosis, liver failure and cancer, and causing more than 1.5 million deaths each year. Though a vaccine and several drugs that target the hepatitis B virus exist, there are no vaccines for hepatitis C, and numerous obstacles stand in the way of developing treatments. Both viruses, for example, employ robust replication systems that are difficult to permanently disrupt. The hepatitis C virus, furthermore, has already exhibited resistance to antiviral drugs currently available to help fight it. Coinfection with both viral strains is relatively common, compounding their individual impacts. And scientists do not currently have in vitro or in vivo models that accurately imitate human liver biology and pathogenesis, which would help facilitate research.
In collaboration with Sangeeta N. Bhatia, professor in the Harvard-MIT Division of Health Sciences and Technology, researchers in Rockefeller?s Laboratory of Virology and Infectious Disease, headed byCharles M. Rice, Maurice R. and Corinne P. Greenberg Professor, first aim to address this last issue by refining cell culture techniques recently developed by Bhatia and Salman Khetani, a former postdoctoral associate in Bhatia?s laboratory who is now director of research at Hepregen. Recent investigations with such cultures by Alexander Ploss, a research associate in the Rice lab, have already revealed important insights about the disease progression of the two viruses. The team is also developing three-dimensional human liver organoids for use in mice reconstituted with a human immune system. With these tools, Rice, Bhatia, Ploss and their colleagues propose to characterize hepatitis B and C infections, to clarify how they influence each other on both the cellular and systemic levels and, ultimately, to inform the development of novel preventive and therapeutic remedies.
The Transformative R01 (TR01) program was launched this year under the NIH Roadmap for Medical Research, an umbrella program established in 2004 to identify and address traditional roadblocks to innovative research. TR01 grants support exceptionally innovative, high-risk, original and/or unconventional research projects that have the potential to create or overturn fundamental paradigms. These projects tend to be inherently risky, but if successful can profoundly impact a broad area of biomedical research.
Before joining Rockefeller University in 2000, Rice completed his Ph.D. in biochemistry and postdoctoral studies at the California Institute of Technology and served on the faculty of the Washington University School of Medicine for 14 years. Rice is the executive and scientific director of the Center for the Study of Hepatitis C, an interdisciplinary center established jointly by Rockefeller, NewYork-Presbyterian Hospital and Weill Cornell Medical College. Rice is a member of the National Academy of Sciences.
Scientists studying hepatitis at Rockefeller University and the Massachusetts Institute of Technology will receive a $5.8 million grant to study hepatitis infection under the National Institutes of Health?s inaugural Transformative R01 grant program, a groundbreaking initiative designed to encourage high-risk research. The grant, which will run for five years beginning in 2009, will fund efforts to elucidate the notoriously complex mechanisms underlying disease progression in hepatitis B and C virus infection.
Chronic infections with hepatitis B and C viruses, which take root in the liver, affect an estimated 500 million people worldwide, leading to diseases including hepatitis, cirrhosis, liver failure and cancer, and causing more than 1.5 million deaths each year. Though a vaccine and several drugs that target the hepatitis B virus exist, there are no vaccines for hepatitis C, and numerous obstacles stand in the way of developing treatments. Both viruses, for example, employ robust replication systems that are difficult to permanently disrupt. The hepatitis C virus, furthermore, has already exhibited resistance to antiviral drugs currently available to help fight it. Coinfection with both viral strains is relatively common, compounding their individual impacts. And scientists do not currently have in vitro or in vivo models that accurately imitate human liver biology and pathogenesis, which would help facilitate research.
In collaboration with Sangeeta N. Bhatia, professor in the Harvard-MIT Division of Health Sciences and Technology, researchers in Rockefeller?s Laboratory of Virology and Infectious Disease, headed byCharles M. Rice, Maurice R. and Corinne P. Greenberg Professor, first aim to address this last issue by refining cell culture techniques recently developed by Bhatia and Salman Khetani, a former postdoctoral associate in Bhatia?s laboratory who is now director of research at Hepregen. Recent investigations with such cultures by Alexander Ploss, a research associate in the Rice lab, have already revealed important insights about the disease progression of the two viruses. The team is also developing three-dimensional human liver organoids for use in mice reconstituted with a human immune system. With these tools, Rice, Bhatia, Ploss and their colleagues propose to characterize hepatitis B and C infections, to clarify how they influence each other on both the cellular and systemic levels and, ultimately, to inform the development of novel preventive and therapeutic remedies.
The Transformative R01 (TR01) program was launched this year under the NIH Roadmap for Medical Research, an umbrella program established in 2004 to identify and address traditional roadblocks to innovative research. TR01 grants support exceptionally innovative, high-risk, original and/or unconventional research projects that have the potential to create or overturn fundamental paradigms. These projects tend to be inherently risky, but if successful can profoundly impact a broad area of biomedical research.
Before joining Rockefeller University in 2000, Rice completed his Ph.D. in biochemistry and postdoctoral studies at the California Institute of Technology and served on the faculty of the Washington University School of Medicine for 14 years. Rice is the executive and scientific director of the Center for the Study of Hepatitis C, an interdisciplinary center established jointly by Rockefeller, NewYork-Presbyterian Hospital and Weill Cornell Medical College. Rice is a member of the National Academy of Sciences.
CDC Revises Guidance on Hib and Hepatitis A Vaccination
CDC Revises Guidance on Hib and Hepatitis A Vaccination
Download Complimentary Source PDF
By Todd Neale, Staff Writer, MedPage Today
Published: September 18, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
for reading medical news
Action Points
Supplies of Haemophilus influenzae type b (Hib) conjugate vaccine are now sufficient for clinicians to recall children who deferred their booster dose, according to the CDC's Advisory Committee on Immunization Practices (ACIP).
If a recall isn't feasible or office vaccine supplies aren't adequate, clinicians should continue following the guidance issued in June and give booster doses during routine visits, ACIP said.
The new recommendations were published in the Sept. 18 issue of Morbidity and Mortality Weekly Report.
There was a shortage of Hib vaccine following the recall of some lots of Merck's PedvaxHIB and Comvax in December 2007.
This led ACIP to recommend deferring the booster dose -- administered at 12 to 15 months -- until supplies were replenished.
Since then, two new Hib vaccine products have been approved: Pentacel for either the primary series in infancy or the booster dose and Hiberix, which is only approved for the booster dose up to age 4.
ActHib was already on the market but production was increased earlier this summer to help address the shortage.
The recommendations released in June said the supply was sufficient to reinstitute the booster but not to recall children who had deferred getting it.
The vaccine supply is now sufficient for a recall, ACIP said in the current recommendations, and all children should get the booster as soon as possible.
In the same issue of MMWR, CDC reported new recommendations for hepatitis A vaccination for close contacts of newly arriving international adoptees from countries with high or intermediate hepatitis A endemicity.
All unvaccinated household members and other close personal contacts, such as babysitters, who come into contact with international adoptees should be vaccinated within 60 days of the adoptee's arrival, according to the recommendations.
The first dose of the two-dose series should be administered as soon as adoption is planned and ideally, at least two weeks before the arrival of the child, they stated.
The new guidance adds to previous recommendations for hepatitis A vaccination for travelers to countries with high or intermediate endemicity, as well as postexposure prophylaxis for travelers who have come into close contact with people infected with the virus.
ACIP made the current recommendations based on the likelihood that an international adoptee coming to the U.S. might be actively infected at the time of adoption.
The risk of contracting hepatitis A among close personal contacts of new international adoptees is estimated at 106 per 100,000 household contacts, the agency said.
That compares with just 1 per 100,000 contacts for the general U.S. population in 2007.
From 1998 to 2008, about 18,000 children a year were adopted from foreign countries, and of those, 99.8% came from countries where hepatitis A is of high or intermediate endemicity.
The predominant country of origin for these children has changed over time. In the early 1990s, it was South Korea. In the late '90s, most of the adoptions came from Russia and China. Currently, most come from Guatemala, China, Russia, and Ethiopia.
In these countries, according to the CDC, hepatitis A infection is highest in children younger than 5, who make up about 85% of international adoptees. In children this young, infection is likely to be asymptomatic.
The CDC has also identified cases of close contacts becoming infected by newly adopted children.
A study conducted at three adoption clinics in the U.S. found that about 1% to 6% of international adoptees are infected with hepatitis A, according to the CDC.
The ACIP members did not make any financial disclosures.
Primary source: Morbidity and Mortality Weekly Report
Source reference:
CDC "Updated recommendations from the Advisory Committee on Immunization Practices (ACIP) for use of hepatitis A vaccine in close contacts of newly arriving international adoptees" MMWR 2009; 58: 1006-07.
Additional source: Morbidity and Mortality Weekly Report
Source reference:
CDC "Licensure of a Haemophilus influenzae type b (Hib) vaccine (Hiberix) and updated recommendations for use of Hib vaccine" MMWR 2009; 58: 1008-1009.
Download Complimentary Source PDF
By Todd Neale, Staff Writer, MedPage Today
Published: September 18, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
for reading medical news
Action Points
Supplies of Haemophilus influenzae type b (Hib) conjugate vaccine are now sufficient for clinicians to recall children who deferred their booster dose, according to the CDC's Advisory Committee on Immunization Practices (ACIP).
If a recall isn't feasible or office vaccine supplies aren't adequate, clinicians should continue following the guidance issued in June and give booster doses during routine visits, ACIP said.
The new recommendations were published in the Sept. 18 issue of Morbidity and Mortality Weekly Report.
There was a shortage of Hib vaccine following the recall of some lots of Merck's PedvaxHIB and Comvax in December 2007.
This led ACIP to recommend deferring the booster dose -- administered at 12 to 15 months -- until supplies were replenished.
Since then, two new Hib vaccine products have been approved: Pentacel for either the primary series in infancy or the booster dose and Hiberix, which is only approved for the booster dose up to age 4.
ActHib was already on the market but production was increased earlier this summer to help address the shortage.
The recommendations released in June said the supply was sufficient to reinstitute the booster but not to recall children who had deferred getting it.
The vaccine supply is now sufficient for a recall, ACIP said in the current recommendations, and all children should get the booster as soon as possible.
In the same issue of MMWR, CDC reported new recommendations for hepatitis A vaccination for close contacts of newly arriving international adoptees from countries with high or intermediate hepatitis A endemicity.
All unvaccinated household members and other close personal contacts, such as babysitters, who come into contact with international adoptees should be vaccinated within 60 days of the adoptee's arrival, according to the recommendations.
The first dose of the two-dose series should be administered as soon as adoption is planned and ideally, at least two weeks before the arrival of the child, they stated.
The new guidance adds to previous recommendations for hepatitis A vaccination for travelers to countries with high or intermediate endemicity, as well as postexposure prophylaxis for travelers who have come into close contact with people infected with the virus.
ACIP made the current recommendations based on the likelihood that an international adoptee coming to the U.S. might be actively infected at the time of adoption.
The risk of contracting hepatitis A among close personal contacts of new international adoptees is estimated at 106 per 100,000 household contacts, the agency said.
That compares with just 1 per 100,000 contacts for the general U.S. population in 2007.
From 1998 to 2008, about 18,000 children a year were adopted from foreign countries, and of those, 99.8% came from countries where hepatitis A is of high or intermediate endemicity.
The predominant country of origin for these children has changed over time. In the early 1990s, it was South Korea. In the late '90s, most of the adoptions came from Russia and China. Currently, most come from Guatemala, China, Russia, and Ethiopia.
In these countries, according to the CDC, hepatitis A infection is highest in children younger than 5, who make up about 85% of international adoptees. In children this young, infection is likely to be asymptomatic.
The CDC has also identified cases of close contacts becoming infected by newly adopted children.
A study conducted at three adoption clinics in the U.S. found that about 1% to 6% of international adoptees are infected with hepatitis A, according to the CDC.
The ACIP members did not make any financial disclosures.
Primary source: Morbidity and Mortality Weekly Report
Source reference:
CDC "Updated recommendations from the Advisory Committee on Immunization Practices (ACIP) for use of hepatitis A vaccine in close contacts of newly arriving international adoptees" MMWR 2009; 58: 1006-07.
Additional source: Morbidity and Mortality Weekly Report
Source reference:
CDC "Licensure of a Haemophilus influenzae type b (Hib) vaccine (Hiberix) and updated recommendations for use of Hib vaccine" MMWR 2009; 58: 1008-1009.
Gilead GS-9350 Protease Inhibitor Booster
Gilead GS-9350 Protease Inhibitor Booster
49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 12-15, 2009, San Francisco
Mark Mascolini
from Jules: GS-9350 could be considered for boosting HCV protease inhibitors.
GS-9350, the "pharmacoenhancer" from Gilead Sciences, boosted the protease inhibitor (PI) atazanavir as well as ritonavir in a crossover study involving 42 healthy volunteers [1]. Gilead has already bundled GS-9350 with tenofovir/emtricitabine and its integrase inhibitor, elvitegravir, which until now relied on ritonavir for a pharmacokinetic kick [2]. The 4-in-1 pill, QUAD, is smaller than the 3-in-1 combo of efavirenz, tenofovir, and emtricitabine. QUAD is in a phase 2 trial.
Like ritonavir, GS-9350 strongly inhibits CYP3A. Gilead's booster appears not to threaten lipid metabolism and has properties that could make coformulation with other drugs simpler [2]. Gilead investigators tested that last proposition in a prelude to the ongoing phase 2 trial comparing atazanavir plus 150 mg of GS-9350 with atazanavir plus 100 mg of ritonavir--both with tenofovir and emtricitabine--in previously untreated people.
All healthy volunteers took once-daily atazanavir for 10 days with 100 mg of ritonavir, for 10 days with 100 mg of GS-9350, and for 10 days with 150 mg of GS-9350 in one of seven sequences [1]. Researchers measured atazanavir levels at the end of each 10-day stint, then the volunteers took 4 days off and returned for the next 10-day interval. Everyone took their drugs with a meal of about 400 kcal containing 13 grams of fat. The group included 28 men and 14 women, 28 whites, 10 blacks, 3 Asians, and 1 native American. Their ages averaged 28 years and ranged from 18 to 45.
Thirty-three people (79%) completed the study. Five dropped out because of adverse events, 2 withdrew consent, and 2 stopped at the investigator's discretion. The clinical problems that caused dropouts were all grade 2 in severity: anemia with atazanavir/ritonavir, paresthesia with atazanavir/ritonavir, and 3 rashes with atazanavir/GS-9350 (2 at 100 mg and 1 and 150 mg). All rashes resolved when the drugs stopped.
Total bilirubin rose by an average 3.1 mg/dL with 100 mg of GS-9350, 4.1 mg/dL with 150 mg of GS-9350, and 4.2 mg/dL with 100 mg of ritonavir. There were no changes in alanine aminotransferase, aspartate aminotransferase, or gamma glutamyl transferase. ECG showed no differences between GS-9350 and ritonavir in PR interval changes (3 people had grade 1 PR interval prolongations with all three treatments). There were no clinically relevant changes in GTcF or QRS intervals.
Atazanavir area under the concentration-time curve (AUC), maximum concentration, trough concentration, elimination half-life, and time to maximum concentration were nearly identical with 150 mg of GS-9350 and 100 mg of ritonavir. Atazanavir trough was lower with 100 mg of GS-9350 than with ritonavir (837 versus 1340 ng/mL), as were maximum concentration (4420 versus 5270 ng/mL) and AUC (45,100 versus 55,200 ng/h/mL). Elimination half-life was shorter with 100 mg of GS-9350 than with 100 mg of ritonavir (9.7 versus 15.7 h), and time to maximum concentration slightly longer (3.5 versus 3.0 h).
The Gilead team proposes that 150 mg of GS-9350 "may be a suitable alternative to ritonavir for boosting atazanavir."
References
1. Ramanathan S, Warren D, Wei L, Kearney BP. Pharmacokinetic boosting of atazanavir with the pharmacoenhancer GS-9350 versus ritonavir. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract AI-1301.
2. Xu L, Liu H, Murray BP, et al. Discovery of GS-9350: a novel pharmacoenhancer without anti-HIV activity. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract H-934.
49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 12-15, 2009, San Francisco
Mark Mascolini
from Jules: GS-9350 could be considered for boosting HCV protease inhibitors.
GS-9350, the "pharmacoenhancer" from Gilead Sciences, boosted the protease inhibitor (PI) atazanavir as well as ritonavir in a crossover study involving 42 healthy volunteers [1]. Gilead has already bundled GS-9350 with tenofovir/emtricitabine and its integrase inhibitor, elvitegravir, which until now relied on ritonavir for a pharmacokinetic kick [2]. The 4-in-1 pill, QUAD, is smaller than the 3-in-1 combo of efavirenz, tenofovir, and emtricitabine. QUAD is in a phase 2 trial.
Like ritonavir, GS-9350 strongly inhibits CYP3A. Gilead's booster appears not to threaten lipid metabolism and has properties that could make coformulation with other drugs simpler [2]. Gilead investigators tested that last proposition in a prelude to the ongoing phase 2 trial comparing atazanavir plus 150 mg of GS-9350 with atazanavir plus 100 mg of ritonavir--both with tenofovir and emtricitabine--in previously untreated people.
All healthy volunteers took once-daily atazanavir for 10 days with 100 mg of ritonavir, for 10 days with 100 mg of GS-9350, and for 10 days with 150 mg of GS-9350 in one of seven sequences [1]. Researchers measured atazanavir levels at the end of each 10-day stint, then the volunteers took 4 days off and returned for the next 10-day interval. Everyone took their drugs with a meal of about 400 kcal containing 13 grams of fat. The group included 28 men and 14 women, 28 whites, 10 blacks, 3 Asians, and 1 native American. Their ages averaged 28 years and ranged from 18 to 45.
Thirty-three people (79%) completed the study. Five dropped out because of adverse events, 2 withdrew consent, and 2 stopped at the investigator's discretion. The clinical problems that caused dropouts were all grade 2 in severity: anemia with atazanavir/ritonavir, paresthesia with atazanavir/ritonavir, and 3 rashes with atazanavir/GS-9350 (2 at 100 mg and 1 and 150 mg). All rashes resolved when the drugs stopped.
Total bilirubin rose by an average 3.1 mg/dL with 100 mg of GS-9350, 4.1 mg/dL with 150 mg of GS-9350, and 4.2 mg/dL with 100 mg of ritonavir. There were no changes in alanine aminotransferase, aspartate aminotransferase, or gamma glutamyl transferase. ECG showed no differences between GS-9350 and ritonavir in PR interval changes (3 people had grade 1 PR interval prolongations with all three treatments). There were no clinically relevant changes in GTcF or QRS intervals.
Atazanavir area under the concentration-time curve (AUC), maximum concentration, trough concentration, elimination half-life, and time to maximum concentration were nearly identical with 150 mg of GS-9350 and 100 mg of ritonavir. Atazanavir trough was lower with 100 mg of GS-9350 than with ritonavir (837 versus 1340 ng/mL), as were maximum concentration (4420 versus 5270 ng/mL) and AUC (45,100 versus 55,200 ng/h/mL). Elimination half-life was shorter with 100 mg of GS-9350 than with 100 mg of ritonavir (9.7 versus 15.7 h), and time to maximum concentration slightly longer (3.5 versus 3.0 h).
The Gilead team proposes that 150 mg of GS-9350 "may be a suitable alternative to ritonavir for boosting atazanavir."
References
1. Ramanathan S, Warren D, Wei L, Kearney BP. Pharmacokinetic boosting of atazanavir with the pharmacoenhancer GS-9350 versus ritonavir. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract AI-1301.
2. Xu L, Liu H, Murray BP, et al. Discovery of GS-9350: a novel pharmacoenhancer without anti-HIV activity. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract H-934.
Sunday, September 20, 2009
HBV Vaccination Cuts Liver Cancer Risk
HBV Vaccination Cuts Liver Cancer Risk
By Charles Bankhead, Staff Writer, MedPage Today
Published: September 17, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
for reading medical news
Action Points
Newborns vaccinated against hepatitis B infection had almost a 70% lower risk of hepatocellular carcinoma through early adulthood compared with an unvaccinated cohort, Taiwanese investigators reported.
Failure to control maternal HBV infection accounted for 95% of the cases of hepatocellular carcinoma in the vaccinated cohort, according to an article published online in the Journal of the National Cancer Institute.
"These data revealed that prenatal maternal HBsAG [hepatitis B surface antigen] status is the key factor affecting chronic HBV infection and hence hepatocellular carcinoma development," said Mei-Hwei Chang, MD, of Taiwan University Hospital in Taipei, and co-authors. "Vaccine failure and poor compliance with the HBV immunization protocol are the two most important causes of failure to block HBV transmission to children from high-risk mothers."
"Maternal transmission of HBV could not be eradicated by the current HBV immunization program," they added. "Further efforts to completely interrupt maternal transmission are crucial in eradicating HBV-related hepatocellular carcinoma."
Because the study did not consider factors other than HBV in liver cancer etiology, the authors cautioned against "concluding that HBV vaccination is the only factor contributing to the reduction of hepatocellular carcinoma."
In areas of endemic HBV infection, as many as 80% of adults with hepatocellular carcinoma are seropositive for HBsAg, and the cancer also occurs in children in areas of endemic infection. The authors previously reported near-100% seropositivity for HBsAg in children with hepatocellular carcinoma, as well as integration of HBV DNA into the host genome of tumor tissue (Cancer 1989; 64(11): 2377-80; Hepatology 1991; 13(2): 316-20).
In 1984, Taiwan implemented a universal HBV immunization program, which has been associated with a substantial decline in the incidence of liver cancer in children, the authors said.
Because most cases occur in people 40 and older, the vaccine's ability to protect against liver cancer beyond childhood is essential, they noted. Toward that end, they examined incidence in vaccinated and unvaccinated cohorts.
Review of two national cancer registries identified 1,958 cases of hepatocellular carcinoma diagnosed from 1983 through 2004 in Taiwan residents ages 6 to 29.
Among patients vaccinated after implementation of the universal HBV vaccination program (ages 6 to 19), investigators identified 64 cases from 37,709,304 person-years of follow-up. That compared with 444 cases in 78,496,406 person-years in unvaccinated patients.
The difference between cohorts translated into an age- and sex-adjusted relative risk of 0.31 for hepatocellular cancer in vaccinated versus unvaccinated patients (P<0.001).
Among vaccinated patients the risk of developing hepatocellular carcinoma was significantly associated with
* Incomplete vaccination (OR 4.32, 95% CI 2.34 to 7.91 for fewer than three doses of vaccine)
* Prenatal maternal HBsAg seropositivity (OR 29.5, 95% CI 13.98 to 62.6)
* Prenatal maternal seropositivity for hepatitis B envelope antigen (OR 5.13, 95% CI 2.24 to 11.71 with administration of HBV immunoglobulin at birth, and OR 9.43, 95% CI 3.54 to 25.11 without immunoglobulin administration)
A limitation of the study noted by the authors was the fact that the role of host factors, including genetic polymorphisms, was not studied, so the interpretation of data could have been affected.
The study was funded by the National Health Research Institutes of Taiwan.
The authors had no disclosures relevant to the study.
Primary source: Journal of the National Cancer Institute
Source reference:
Chang M-H, et al "Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study" J Natl Cancer Inst 2009; DOI: 10.1093/jnci/djp288.
By Charles Bankhead, Staff Writer, MedPage Today
Published: September 17, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
for reading medical news
Action Points
Newborns vaccinated against hepatitis B infection had almost a 70% lower risk of hepatocellular carcinoma through early adulthood compared with an unvaccinated cohort, Taiwanese investigators reported.
Failure to control maternal HBV infection accounted for 95% of the cases of hepatocellular carcinoma in the vaccinated cohort, according to an article published online in the Journal of the National Cancer Institute.
"These data revealed that prenatal maternal HBsAG [hepatitis B surface antigen] status is the key factor affecting chronic HBV infection and hence hepatocellular carcinoma development," said Mei-Hwei Chang, MD, of Taiwan University Hospital in Taipei, and co-authors. "Vaccine failure and poor compliance with the HBV immunization protocol are the two most important causes of failure to block HBV transmission to children from high-risk mothers."
"Maternal transmission of HBV could not be eradicated by the current HBV immunization program," they added. "Further efforts to completely interrupt maternal transmission are crucial in eradicating HBV-related hepatocellular carcinoma."
Because the study did not consider factors other than HBV in liver cancer etiology, the authors cautioned against "concluding that HBV vaccination is the only factor contributing to the reduction of hepatocellular carcinoma."
In areas of endemic HBV infection, as many as 80% of adults with hepatocellular carcinoma are seropositive for HBsAg, and the cancer also occurs in children in areas of endemic infection. The authors previously reported near-100% seropositivity for HBsAg in children with hepatocellular carcinoma, as well as integration of HBV DNA into the host genome of tumor tissue (Cancer 1989; 64(11): 2377-80; Hepatology 1991; 13(2): 316-20).
In 1984, Taiwan implemented a universal HBV immunization program, which has been associated with a substantial decline in the incidence of liver cancer in children, the authors said.
Because most cases occur in people 40 and older, the vaccine's ability to protect against liver cancer beyond childhood is essential, they noted. Toward that end, they examined incidence in vaccinated and unvaccinated cohorts.
Review of two national cancer registries identified 1,958 cases of hepatocellular carcinoma diagnosed from 1983 through 2004 in Taiwan residents ages 6 to 29.
Among patients vaccinated after implementation of the universal HBV vaccination program (ages 6 to 19), investigators identified 64 cases from 37,709,304 person-years of follow-up. That compared with 444 cases in 78,496,406 person-years in unvaccinated patients.
The difference between cohorts translated into an age- and sex-adjusted relative risk of 0.31 for hepatocellular cancer in vaccinated versus unvaccinated patients (P<0.001).
Among vaccinated patients the risk of developing hepatocellular carcinoma was significantly associated with
* Incomplete vaccination (OR 4.32, 95% CI 2.34 to 7.91 for fewer than three doses of vaccine)
* Prenatal maternal HBsAg seropositivity (OR 29.5, 95% CI 13.98 to 62.6)
* Prenatal maternal seropositivity for hepatitis B envelope antigen (OR 5.13, 95% CI 2.24 to 11.71 with administration of HBV immunoglobulin at birth, and OR 9.43, 95% CI 3.54 to 25.11 without immunoglobulin administration)
A limitation of the study noted by the authors was the fact that the role of host factors, including genetic polymorphisms, was not studied, so the interpretation of data could have been affected.
The study was funded by the National Health Research Institutes of Taiwan.
The authors had no disclosures relevant to the study.
Primary source: Journal of the National Cancer Institute
Source reference:
Chang M-H, et al "Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study" J Natl Cancer Inst 2009; DOI: 10.1093/jnci/djp288.
FDA Approves Vaccines for 2009 H1N1 Influenza Virus
FDA NEWS RELEASE
For Immediate Release: Sept. 15, 2009
Media Inquiries: Pat El-Hinnawy, 301-796-4763, patricia.el-hinnawy@fda.hhs.gov; Peper Long, 301-796-4671, mary.long@fda.hhs.gov
Consumer Inquiries: 1-888-INFO-FDA
FDA Approves Vaccines for 2009 H1N1 Influenza Virus
Approval Provides Important Tool to Fight Pandemic
The U.S. Food and Drug Administration announced today that it has approved four vaccines against the 2009 H1N1 influenza virus. The vaccines will be distributed nationally after the initial lots become available, which is expected within the next four weeks.
“Today's approval is good news for our nation's response to the 2009 H1N1 influenza virus,” said Commissioner of Food and Drugs Margaret A. Hamburg, M.D. “This vaccine will help protect individuals from serious illness and death from influenza.”
The vaccines are made by CSL Limited, MedImmune LLC, Novartis Vaccines and Diagnostics Limited, and sanofi pasteur Inc. All four firms manufacture the H1N1 vaccines using the same processes, which have a long record of producing safe seasonal influenza vaccines.
”The H1N1 vaccines approved today undergo the same rigorous FDA manufacturing oversight, product quality testing and lot release procedures that apply to seasonal influenza vaccines,” said Jesse Goodman, M.D., FDA acting chief scientist.
Based on preliminary data from adults participating in multiple clinical studies, the 2009 H1N1 vaccines induce a robust immune response in most healthy adults eight to 10 days after a single dose, as occurs with the seasonal influenza vaccine.
Clinical studies under way will provide additional information about the optimal dose in children. The recommendations for dosing will be updated if indicated by findings from those studies. The findings are expected in the near future.
As with the seasonal influenza vaccines, the 2009 H1N1 vaccines are being produced in formulations that contain thimerosal, a mercury-containing preservative, and in formulations that do not contain thimerosal.
People with severe or life-threatening allergies to chicken eggs, or to any other substance in the vaccine, should not be vaccinated.
In the ongoing clinical studies, the vaccines have been well tolerated. Potential side effects of the H1N1 vaccines are expected to be similar to those of seasonal flu vaccines.
For the injected vaccine, the most common side effect is soreness at the injection site. Other side effects may include mild fever, body aches, and fatigue for a few days after the inoculation. For the nasal spray vaccine, the most common side effects include runny nose or nasal congestion for all ages, sore throats in adults, and -- in children 2 to 6 years old -- fever.
As with any medical product, unexpected or rare serious adverse events may occur. The FDA is working closely with governmental and nongovernmental organizations to enhance the capacity for adverse event monitoring, information sharing and analysis during and after the 2009 H1N1 vaccination program. In the U.S. Department of Health and Human Services, these agencies include the Centers for Disease Control and Prevention.
Vaccines against three seasonal virus strains are already available and should be used (see information on the seasonal flu). However, they do not protect against the 2009 H1N1 virus (see information on H1N1 flu).
#
Additional Information
Influenza A (H1N1) 2009 Monovalent
For Immediate Release: Sept. 15, 2009
Media Inquiries: Pat El-Hinnawy, 301-796-4763, patricia.el-hinnawy@fda.hhs.gov; Peper Long, 301-796-4671, mary.long@fda.hhs.gov
Consumer Inquiries: 1-888-INFO-FDA
FDA Approves Vaccines for 2009 H1N1 Influenza Virus
Approval Provides Important Tool to Fight Pandemic
The U.S. Food and Drug Administration announced today that it has approved four vaccines against the 2009 H1N1 influenza virus. The vaccines will be distributed nationally after the initial lots become available, which is expected within the next four weeks.
“Today's approval is good news for our nation's response to the 2009 H1N1 influenza virus,” said Commissioner of Food and Drugs Margaret A. Hamburg, M.D. “This vaccine will help protect individuals from serious illness and death from influenza.”
The vaccines are made by CSL Limited, MedImmune LLC, Novartis Vaccines and Diagnostics Limited, and sanofi pasteur Inc. All four firms manufacture the H1N1 vaccines using the same processes, which have a long record of producing safe seasonal influenza vaccines.
”The H1N1 vaccines approved today undergo the same rigorous FDA manufacturing oversight, product quality testing and lot release procedures that apply to seasonal influenza vaccines,” said Jesse Goodman, M.D., FDA acting chief scientist.
Based on preliminary data from adults participating in multiple clinical studies, the 2009 H1N1 vaccines induce a robust immune response in most healthy adults eight to 10 days after a single dose, as occurs with the seasonal influenza vaccine.
Clinical studies under way will provide additional information about the optimal dose in children. The recommendations for dosing will be updated if indicated by findings from those studies. The findings are expected in the near future.
As with the seasonal influenza vaccines, the 2009 H1N1 vaccines are being produced in formulations that contain thimerosal, a mercury-containing preservative, and in formulations that do not contain thimerosal.
People with severe or life-threatening allergies to chicken eggs, or to any other substance in the vaccine, should not be vaccinated.
In the ongoing clinical studies, the vaccines have been well tolerated. Potential side effects of the H1N1 vaccines are expected to be similar to those of seasonal flu vaccines.
For the injected vaccine, the most common side effect is soreness at the injection site. Other side effects may include mild fever, body aches, and fatigue for a few days after the inoculation. For the nasal spray vaccine, the most common side effects include runny nose or nasal congestion for all ages, sore throats in adults, and -- in children 2 to 6 years old -- fever.
As with any medical product, unexpected or rare serious adverse events may occur. The FDA is working closely with governmental and nongovernmental organizations to enhance the capacity for adverse event monitoring, information sharing and analysis during and after the 2009 H1N1 vaccination program. In the U.S. Department of Health and Human Services, these agencies include the Centers for Disease Control and Prevention.
Vaccines against three seasonal virus strains are already available and should be used (see information on the seasonal flu). However, they do not protect against the 2009 H1N1 virus (see information on H1N1 flu).
#
Additional Information
Influenza A (H1N1) 2009 Monovalent
Monday, September 14, 2009
HCV Load Decay in First Day of PegIFN Treatment Predicts Long-Term Failure
HCV Load Decay in First Day of PegIFN Treatment Predicts Long-Term Failure
49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 12-15, 2009, San Francisco
Mark Mascolini
In a small study of people coinfected with HIV and hepatitis C virus (HCV), no one who failed to attain at least a 0.9-log drop in HCV load during the first 24 hours of pegylated interferon (PegIFN) plus ribavirin had a sustained virologic response (SVR) after completing treatment [1], or "Patients who do not reach 0.9 log decay at 24 hours will not achieve SVR". Pedro Cahn and colleagues at the Argentinean Reference Center for AIDS in Buenos Aires suggest that this cutoff may prove valuable in guiding treatment of HCV infection in people with HIV, especially in resource-poor settings. But results of this 20-person, single-center study require confirmation in larger, more diverse populations.
Up to 60% of HIV/HCV-coinfected people fail to respond to PegIFN/ribavirin, especially those with HCV genotypes 1 and 4 (from Jules: in a study but in the clinic coinfected genotype 1 patients often do much worse than 40% SVR, sometimes 15-20% SVR). To ascertain the impact of HCV dynamics on SVR, Cahn and coworkers collected HCV samples from 20 coinfected people before they started PegIFN/ribavirin, 24 hours after they started, and 4, 12, 24, 48, and 72 weeks after they started.
Nineteen of the 20 patients were taking antiretroviral therapy, 17 were men, 15 had HCV genotype 1, 10 had a Metavir score of F3-F4 (bridging fibrosis to cirrhosis), and CD4 count averaged 545.
HCV load at 24 hours was significantly greater in people with SVR than in those without SVR (1.6 +/- 0.2 versus 0.5 +/- 0.4 log). Receiver operating characteristic (ROC) curve analysis determined that a 0.9-log HCV decay was the best cutoff to discriminate between sustained virologic responders and nonresponders.
That cutoff had a 100% negative predictive value for SVR (95% confidence interval [CI] 66.2% to 100%), meaning no one without at least a 0.9-log decay in 24 hours reached an SVR. Positive predictive value of the 0.9-log cutoff was 71.4% (95% CI 29.3% to 95.5%). Sensitivity of the 0.9-log cutoff in predicting SVR was 100% (95% CI 48% to 100%) and specificity 81.8% (95% CI 48.2% to 97.2%).
Cahn and colleagues suggest that the 0.9-log 24-hour response cutoff could be particularly helpful in patients with other predictors of poor response or with a high risk of toxicity from PegIFN/ribavirin.
Reference
1. Laufer N, Bolcic F, Socias E, et al. Early changes in HCV viral load during the first 24 hours of treatment exhibit a very high negative predictive value of sustained virological response in HCV/HIV coinfected patients. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract H-213.
49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 12-15, 2009, San Francisco
Mark Mascolini
In a small study of people coinfected with HIV and hepatitis C virus (HCV), no one who failed to attain at least a 0.9-log drop in HCV load during the first 24 hours of pegylated interferon (PegIFN) plus ribavirin had a sustained virologic response (SVR) after completing treatment [1], or "Patients who do not reach 0.9 log decay at 24 hours will not achieve SVR". Pedro Cahn and colleagues at the Argentinean Reference Center for AIDS in Buenos Aires suggest that this cutoff may prove valuable in guiding treatment of HCV infection in people with HIV, especially in resource-poor settings. But results of this 20-person, single-center study require confirmation in larger, more diverse populations.
Up to 60% of HIV/HCV-coinfected people fail to respond to PegIFN/ribavirin, especially those with HCV genotypes 1 and 4 (from Jules: in a study but in the clinic coinfected genotype 1 patients often do much worse than 40% SVR, sometimes 15-20% SVR). To ascertain the impact of HCV dynamics on SVR, Cahn and coworkers collected HCV samples from 20 coinfected people before they started PegIFN/ribavirin, 24 hours after they started, and 4, 12, 24, 48, and 72 weeks after they started.
Nineteen of the 20 patients were taking antiretroviral therapy, 17 were men, 15 had HCV genotype 1, 10 had a Metavir score of F3-F4 (bridging fibrosis to cirrhosis), and CD4 count averaged 545.
HCV load at 24 hours was significantly greater in people with SVR than in those without SVR (1.6 +/- 0.2 versus 0.5 +/- 0.4 log). Receiver operating characteristic (ROC) curve analysis determined that a 0.9-log HCV decay was the best cutoff to discriminate between sustained virologic responders and nonresponders.
That cutoff had a 100% negative predictive value for SVR (95% confidence interval [CI] 66.2% to 100%), meaning no one without at least a 0.9-log decay in 24 hours reached an SVR. Positive predictive value of the 0.9-log cutoff was 71.4% (95% CI 29.3% to 95.5%). Sensitivity of the 0.9-log cutoff in predicting SVR was 100% (95% CI 48% to 100%) and specificity 81.8% (95% CI 48.2% to 97.2%).
Cahn and colleagues suggest that the 0.9-log 24-hour response cutoff could be particularly helpful in patients with other predictors of poor response or with a high risk of toxicity from PegIFN/ribavirin.
Reference
1. Laufer N, Bolcic F, Socias E, et al. Early changes in HCV viral load during the first 24 hours of treatment exhibit a very high negative predictive value of sustained virological response in HCV/HIV coinfected patients. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract H-213.
Open Invitation
Liver Support Group
I still attend the Liver Support Group at Mt. Sinai Hospital which meets at 1425 Madison Avenue East 98 street in New York City on the third Wednesday of every month in room 11-84 east building. It is open to anyone, with or without Hepatitis including friends, family members or anyone who wishes more knowledge on the subject. So please stop by if you're in the State of New York State on that day. It is from 6 P.M. till 7 30 P.M.
I still attend the Liver Support Group at Mt. Sinai Hospital which meets at 1425 Madison Avenue East 98 street in New York City on the third Wednesday of every month in room 11-84 east building. It is open to anyone, with or without Hepatitis including friends, family members or anyone who wishes more knowledge on the subject. So please stop by if you're in the State of New York State on that day. It is from 6 P.M. till 7 30 P.M.
Open Invitation St. Vincent's Hepatitis C Support Group
St. Vincent's Hepatitis C Support Group
Tuesday, September 15th at 6:30 PM
St. Vincent's Hospital, New York, NY
170 West 12th Street (off 7th Ave, SE Corner)
Reiss Conference Room-- for directions ask at the desk to the left of the revolving doors
At this months meeting Tracy Swan, the Hepatitis/HIV Project Director for TAG will be addressing the group.
Her expertise is in several areas of medication -- basically medications for HIV, HCV and Co-Infection. She's considered an expert and advocate in the area of clinical trials for meds for these conditions and is highly knowledgeable about not only the current meds but meds in the pipeline.
http://www.treatmentactiongroup.org/bio.aspx?id=330
If you've heard her before please trust me that once is not enough -- the information she has to impart could prove invaluable in terms of helping you make a decision re what, when, why now or best to wait.
Also, I'm suggesting that if you have someone who offers you support / helps you sort through info and decisions re HCV please encourage them to join you for this important meeting.
It's been established that a strong social support system helps people dealing with a difficult condition. Come join us to add to your support system. We try to offer education, information and a shoulder (with a network).
This meeting is free and open to anyone impacted by or interested in Hepatitis C.
Refreshments provided by Roche Pharmaceuticals through the efforts of Louis Colon
We meet the third Tuesday of each month. Next meeting will be October 20th, at 6:30 PM.
The facilitator of this meeting is Lillian de Mauro, she can be reached at lilliandem@gmail.com 607-746-7199 or 917-385-2480
Tuesday, September 15th at 6:30 PM
St. Vincent's Hospital, New York, NY
170 West 12th Street (off 7th Ave, SE Corner)
Reiss Conference Room-- for directions ask at the desk to the left of the revolving doors
At this months meeting Tracy Swan, the Hepatitis/HIV Project Director for TAG will be addressing the group.
Her expertise is in several areas of medication -- basically medications for HIV, HCV and Co-Infection. She's considered an expert and advocate in the area of clinical trials for meds for these conditions and is highly knowledgeable about not only the current meds but meds in the pipeline.
http://www.treatmentactiongroup.org/bio.aspx?id=330
If you've heard her before please trust me that once is not enough -- the information she has to impart could prove invaluable in terms of helping you make a decision re what, when, why now or best to wait.
Also, I'm suggesting that if you have someone who offers you support / helps you sort through info and decisions re HCV please encourage them to join you for this important meeting.
It's been established that a strong social support system helps people dealing with a difficult condition. Come join us to add to your support system. We try to offer education, information and a shoulder (with a network).
This meeting is free and open to anyone impacted by or interested in Hepatitis C.
Refreshments provided by Roche Pharmaceuticals through the efforts of Louis Colon
We meet the third Tuesday of each month. Next meeting will be October 20th, at 6:30 PM.
The facilitator of this meeting is Lillian de Mauro, she can be reached at lilliandem@gmail.com 607-746-7199 or 917-385-2480
Rate of Sustained Virologic Response in Relation to Baseline Hepatitis C Virus
Rate of Sustained Virologic Response in Relation to Baseline Hepatitis C Virus (HCV) RNA Level and Rapid Virologic Clearance in Persons with Acute HCV Infection: genotype 1 can achieve high SVR rate is treated during acute infection
The Journal of Infectious Diseases Sept 15 2009;200:877-881
Barbara H. McGovern,1,2 Ellen H. Nagami,1,5,6 Christopher E. Birch,1,5,6 Melinda J. Bowen,6,7 Laura L. Reyor,3,6 Raymond T. Chung,3,4 and Arthur Y. Kim4,5,6
1Lemuel Shattuck Hospital, Jamaica Plain, 2Tufts Medical School, 3Gastrointestinal Unit, Massachusetts General Hospital, 4Harvard Medical School, and 5Harvard University Center for AIDS Research, Boston, 6Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University (formerly known as Partners AIDS Research Center), Charlestown, and 7University of Massachusetts Medical School, Worcester, Massachusetts
ABSTRACT: Treatment of acute hepatitis C virus (HCV) infection leads to a sustained virologic response (SVR) in the vast majority of patients, although the clinical predictors of these favorable responses are not well understood. In chronic infection, the most potent predictor of a SVR is complete viral suppression after 4 weeks of treatment, also known as a rapid virologic response (RVR). However, few patients with HCV genotype 1 infection and high-level viremia ever achieve this benchmark. In 2 separate cohorts of patients with acute HCV infection, we demonstrate that rapid virologic clearance and low-level viremia (HCV RNA level, <400,000 IU/mL) are highly prevalent, regardless of HCV genotype.
Discussion
Treatment for acute HCV infection led to rapid virologic suppression in nearly all patients, regardless of genotype. Of the 17 patients with genotype 1 infection, 88.2% achieved rapid virologic clearance. This observation is in marked contrast to the low RVR rates of 16%-23% seen in persons with chronic HCV genotype-1 infection [1].
Studies involving patients with chronic HCV infection have demonstrated that low-level viremia (<400,000 IU/mL) and RVR are strongly linked. However, low-level viremia is distinctly uncommon among persons infected with the most difficult-to-treat genotypes. For example, in one retrospective study of 1550 HCV genotype 1-infected patients who were treated with pegylated interferon alfa-2a/ribavirin, only 13% met this criterion [4]. Low-level viremia, which is distinctly uncommon in HIV/HCV-coinfected patients, also informs RVR and ultimate clinical outcomes in this difficult-to-treat patient population [9].
In contrast to chronic disease, antiviral therapy leads to a sustained virologic response in the vast majority of patients with acute HCV infection [10]. The much higher RVR rates that are seen in acute HCV infection may be linked to prevalent low-level viremia, as demonstrated in our cohort of patients with acute infection. The only patient in the incarcerated cohort who did not attain a RVR had >1 log-fold increase in viremia (>500,000 IU/mL) before treatment; one may hypothesize that he may have had a better outcome with earlier initiation of therapy at the time of lower viremia. The change in viral set point to higher levels may signal a transition from acute to chronic HCV infection with onset of T cell immune dysfunction [11]. In this setting, treatment with an immunomodulatory agent (eg, interferon) may be less effective, particularly in patients infected with genotype 1. In contrast, the level of viremia may not be as important in patients infected with an HCV genotype (ie, genotype 2 or 3) that is more responsive to interferon.
Whether low-level viremia in acute infection is reflective of immunologic containment is unknown; patients with acute infection may have some relevant cellular responses, even if viremia persists [11, 12]. During acute infection, when acquired immunity is most likely to be detected, early treatment appears to facilitate a favorable balance between host-virus dynamics. In contrast, low-level viremia may be distinctly uncommon in chronic infection because of the loss of immunologic control, as suggested by in vitro data [13, 14]. Virally induced signaling pathways (through interferon regulatory factor 3) that are favorable to the host may be abolished over time through inactivation of interferon-responsive genes (such as the gene encoding RIG-1) [13]. Moreover, the serine protease of HCV has recently been found to cleave signaling molecules essential to innate immunity [14]; the exact in vivo timing of activation of viral evasion mechanisms is currently under investigation. Thus, acute-phase HCV may represent an immunologically favorable state before the virus has escaped from both innate and acquired immunity. Acute-phase HCV is also associated with less diversity and complexity of an individual's HCV quasispecies, which in the chronic phase has also been associated with favorable treatment outcomes [15]. The contribution of the immune system may be particularly important when administering the currently available antiviral therapies, which target upregulation of general antiviral genes rather than specific HCV viral proteins [16].
Limitations of the current study include the small number of patients with acute HCV infection; thus, our observations should be confirmed by others. One strength of our study is the large representation of injection drug users, who are often underrepresented in treatment studies of HCV infection. Furthermore, we were able to demonstrate the feasibility of treating acute HCV infection in the correctional setting.
In summary, in patients with acute HCV infection, rapid virologic clearance rates are commonly observed and are closely associated with SVR, regardless of genotype. High rates of RVR appear to be closely linked to low levels of viremia, which are more common in acute HCV infection. This virologic parameter may be particularly important in genotype 1-infected patients, who have generally lower rates of SVR in response to treatment.
Patients and methods.
We assessed 4-week HCV RNA responses among patients in 2 separate cohorts who were treated for acute HCV infection. The first cohort was identified prospectively beginning in October 2006 through the Massachusetts Department of Corrections. Within a week after admission to the correctional system, inmates were screened for a history of recent-onset injection drug use (IDU) and prior HCV testing. During the initial physical examination at 2 correctional intake sites, brief interviews of 3248 inmates were conducted by healthcare providers from the University of Massachusetts Healthcare Services. Of these inmates, 141 HCV-naive individuals who had a high risk for HCV infection were further screened by history and laboratory evaluation (eg, symptoms/signs of acute hepatitis, HCV seroconversion, elevations of aminotransferase levels to >7 times the upper limit of normal, and presence of HCV RNA). After diagnosis of acute HCV infection, we evaluated the HCV RNA level at baseline, 4 weeks, and 10 weeks and offered therapy only to patients with persistent viremia, based on our previously established screening protocol [6]. Full details of our diagnostic approach are described elsewhere [7].
Patients with viremia that persisted for >10 weeks from the time of diagnosis were offered 24 weeks of treatment with pegylated interferon alfa2b and ribavirin (800 mg daily for patients infected with genotype 2 or 3 and weight-based ribavirin therapy [13 mg/kg] for those infected with genotype 1). Patients with low-level viremia (HCV RNA level, <10,000 IU/mL) at week 10 underwent additional testing at week 14 to determine possible late clearance before initiation of treatment. Those who were administered combination therapy for persistent viremia had virologic monitoring performed with Versant HCV RNA 2.0 (Bayer Diagnostics) on a monthly basis until clearance was documented. HCV RNA was also assessed at the end of treatment and at the 6-month mark after discontinuation of therapy. HCV genotype was determined by Versant-LiPA HCV 2.0.
In the second cohort, we retrospectively reviewed 68 records from community-dwelling patients who received a diagnosis of acute HCV infection at a tertiary care center (Massachusetts General Hospital [Boston, MA]) from 1997 through 2007. Serial HCV RNA samples (mean, 5.4 samples/patient) were obtained to measure the HCV RNA level; the timing and frequency of sample collection were at the discretion of the 2 practitioners who provided care for these patients. The mean duration of sampling before treatment initiation was 17.6 weeks. From the overall cohort, 27 patients were treated for persistent viremia (6 patients were initially described in a previous report [8]. We selected 10 patients who had HCV RNA testing performed with the Cobas Amplicor HCV Monitor after 4 weeks of pegylated interferon and ribavirin for inclusion in this report.
All study subjects with acute HCV infection gave written informed consent for observational studies of the virologic, immunologic, and clinical courses of infection. These protocols conform to the 1975 Helsinki guidelines for the conduct of human research and were approved by each hospital's institutional review board. For incarcerated subjects, the Lemuel Shattuck Hospital Human Research Review Committee includes a prisoner advocate.
Results.
We identified 25 patients with acute HCV infection and persistent viremia who underwent combination therapy with pegylated interferon and ribavirin and had week 4 viral load testing performed. Fifteen patients were identified prospectively from the prison-based cohort, and 10 were identified retrospectively from the community-based cohort (table 1). Seventeen were men, and the mean age was 31 years. A total of 22 patients were white, and 1 was Hispanic; 1 person reported both white and African American ethnicity, and 1 reported both white and Hispanic ethnicity. Risk factors for HCV acquisition included IDU (for 20 patients) and sexual transmission (for 4 patients); the route of acquisition was unknown for 1 patient. Two patients in the community cohort were known to be HIV seropositive. No new diagnoses of HIV infection were made.
Nineteen patients were infected with HCV genotype 1 (n=17) or 4 (n=2), whereas 6 patients were infected with genotype 2 (n=1) or 3 (n=5). The mean HCV RNA level at enrollment was 329,210 IU/mL (range, 1004-1,745,260 IU/mL), whereas the mean HCV RNA level before treatment had increased to 391,747 IU/mL (range, 1385-1,665,560 IU/mL), although this trend was not statistically significant. Pretreatment low-level viremia was documented in 17 (68%) of 25 patients, including 12 (70.6%) of 17 with genotype 1 infection.
Rapid virologic clearance was achieved in 23 of 25 patients overall, including 2 patients with a history of HIV infection. The RVR rate was 89.5% (17 of 19) for patients infected with genotype 1 or 4 and 100% (6 of 6) for patients infected with genotype 2 or 3. On the assumption that treatment failure occurred in 3 patients who were lost to follow-up, the overall response rate was 72% (18 of 25) (figure 1).
The patients were treated for a mean duration of 22.8 weeks (range, 12-48 weeks); 1 patient was offered 48 weeks of therapy because of delayed therapeutic intervention secondary to uncontrolled depression. Adverse events were typical of combination therapy and included severe fatigue (for 5 patients), headache (for 4), loss of appetite (for 2), and new onset hypothyroidism (for 1). One patient received a single dose of erythropoietin because of anemia, and no patients required growth factors for neutropenia. Virologic breakthrough was documented in patients 10 and 11, both of whom had genotype 1 infection. Patient 10 stated that, during the last 2 months of ribavirin therapy, she had been poorly adherent. Although patient 11 was adherent to treatment, other factors may have contributed to his suboptimal response. These factors included a dramatic viral load increase between enrollment and pretreatment (from 22,635 to 546,478 IU/mL), as well as a marked increase in body weight from baseline obesity. A fasting insulin level and a glucose concentration were normal at the time of treatment discontinuation.
The Journal of Infectious Diseases Sept 15 2009;200:877-881
Barbara H. McGovern,1,2 Ellen H. Nagami,1,5,6 Christopher E. Birch,1,5,6 Melinda J. Bowen,6,7 Laura L. Reyor,3,6 Raymond T. Chung,3,4 and Arthur Y. Kim4,5,6
1Lemuel Shattuck Hospital, Jamaica Plain, 2Tufts Medical School, 3Gastrointestinal Unit, Massachusetts General Hospital, 4Harvard Medical School, and 5Harvard University Center for AIDS Research, Boston, 6Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University (formerly known as Partners AIDS Research Center), Charlestown, and 7University of Massachusetts Medical School, Worcester, Massachusetts
ABSTRACT: Treatment of acute hepatitis C virus (HCV) infection leads to a sustained virologic response (SVR) in the vast majority of patients, although the clinical predictors of these favorable responses are not well understood. In chronic infection, the most potent predictor of a SVR is complete viral suppression after 4 weeks of treatment, also known as a rapid virologic response (RVR). However, few patients with HCV genotype 1 infection and high-level viremia ever achieve this benchmark. In 2 separate cohorts of patients with acute HCV infection, we demonstrate that rapid virologic clearance and low-level viremia (HCV RNA level, <400,000 IU/mL) are highly prevalent, regardless of HCV genotype.
Discussion
Treatment for acute HCV infection led to rapid virologic suppression in nearly all patients, regardless of genotype. Of the 17 patients with genotype 1 infection, 88.2% achieved rapid virologic clearance. This observation is in marked contrast to the low RVR rates of 16%-23% seen in persons with chronic HCV genotype-1 infection [1].
Studies involving patients with chronic HCV infection have demonstrated that low-level viremia (<400,000 IU/mL) and RVR are strongly linked. However, low-level viremia is distinctly uncommon among persons infected with the most difficult-to-treat genotypes. For example, in one retrospective study of 1550 HCV genotype 1-infected patients who were treated with pegylated interferon alfa-2a/ribavirin, only 13% met this criterion [4]. Low-level viremia, which is distinctly uncommon in HIV/HCV-coinfected patients, also informs RVR and ultimate clinical outcomes in this difficult-to-treat patient population [9].
In contrast to chronic disease, antiviral therapy leads to a sustained virologic response in the vast majority of patients with acute HCV infection [10]. The much higher RVR rates that are seen in acute HCV infection may be linked to prevalent low-level viremia, as demonstrated in our cohort of patients with acute infection. The only patient in the incarcerated cohort who did not attain a RVR had >1 log-fold increase in viremia (>500,000 IU/mL) before treatment; one may hypothesize that he may have had a better outcome with earlier initiation of therapy at the time of lower viremia. The change in viral set point to higher levels may signal a transition from acute to chronic HCV infection with onset of T cell immune dysfunction [11]. In this setting, treatment with an immunomodulatory agent (eg, interferon) may be less effective, particularly in patients infected with genotype 1. In contrast, the level of viremia may not be as important in patients infected with an HCV genotype (ie, genotype 2 or 3) that is more responsive to interferon.
Whether low-level viremia in acute infection is reflective of immunologic containment is unknown; patients with acute infection may have some relevant cellular responses, even if viremia persists [11, 12]. During acute infection, when acquired immunity is most likely to be detected, early treatment appears to facilitate a favorable balance between host-virus dynamics. In contrast, low-level viremia may be distinctly uncommon in chronic infection because of the loss of immunologic control, as suggested by in vitro data [13, 14]. Virally induced signaling pathways (through interferon regulatory factor 3) that are favorable to the host may be abolished over time through inactivation of interferon-responsive genes (such as the gene encoding RIG-1) [13]. Moreover, the serine protease of HCV has recently been found to cleave signaling molecules essential to innate immunity [14]; the exact in vivo timing of activation of viral evasion mechanisms is currently under investigation. Thus, acute-phase HCV may represent an immunologically favorable state before the virus has escaped from both innate and acquired immunity. Acute-phase HCV is also associated with less diversity and complexity of an individual's HCV quasispecies, which in the chronic phase has also been associated with favorable treatment outcomes [15]. The contribution of the immune system may be particularly important when administering the currently available antiviral therapies, which target upregulation of general antiviral genes rather than specific HCV viral proteins [16].
Limitations of the current study include the small number of patients with acute HCV infection; thus, our observations should be confirmed by others. One strength of our study is the large representation of injection drug users, who are often underrepresented in treatment studies of HCV infection. Furthermore, we were able to demonstrate the feasibility of treating acute HCV infection in the correctional setting.
In summary, in patients with acute HCV infection, rapid virologic clearance rates are commonly observed and are closely associated with SVR, regardless of genotype. High rates of RVR appear to be closely linked to low levels of viremia, which are more common in acute HCV infection. This virologic parameter may be particularly important in genotype 1-infected patients, who have generally lower rates of SVR in response to treatment.
Patients and methods.
We assessed 4-week HCV RNA responses among patients in 2 separate cohorts who were treated for acute HCV infection. The first cohort was identified prospectively beginning in October 2006 through the Massachusetts Department of Corrections. Within a week after admission to the correctional system, inmates were screened for a history of recent-onset injection drug use (IDU) and prior HCV testing. During the initial physical examination at 2 correctional intake sites, brief interviews of 3248 inmates were conducted by healthcare providers from the University of Massachusetts Healthcare Services. Of these inmates, 141 HCV-naive individuals who had a high risk for HCV infection were further screened by history and laboratory evaluation (eg, symptoms/signs of acute hepatitis, HCV seroconversion, elevations of aminotransferase levels to >7 times the upper limit of normal, and presence of HCV RNA). After diagnosis of acute HCV infection, we evaluated the HCV RNA level at baseline, 4 weeks, and 10 weeks and offered therapy only to patients with persistent viremia, based on our previously established screening protocol [6]. Full details of our diagnostic approach are described elsewhere [7].
Patients with viremia that persisted for >10 weeks from the time of diagnosis were offered 24 weeks of treatment with pegylated interferon alfa2b and ribavirin (800 mg daily for patients infected with genotype 2 or 3 and weight-based ribavirin therapy [13 mg/kg] for those infected with genotype 1). Patients with low-level viremia (HCV RNA level, <10,000 IU/mL) at week 10 underwent additional testing at week 14 to determine possible late clearance before initiation of treatment. Those who were administered combination therapy for persistent viremia had virologic monitoring performed with Versant HCV RNA 2.0 (Bayer Diagnostics) on a monthly basis until clearance was documented. HCV RNA was also assessed at the end of treatment and at the 6-month mark after discontinuation of therapy. HCV genotype was determined by Versant-LiPA HCV 2.0.
In the second cohort, we retrospectively reviewed 68 records from community-dwelling patients who received a diagnosis of acute HCV infection at a tertiary care center (Massachusetts General Hospital [Boston, MA]) from 1997 through 2007. Serial HCV RNA samples (mean, 5.4 samples/patient) were obtained to measure the HCV RNA level; the timing and frequency of sample collection were at the discretion of the 2 practitioners who provided care for these patients. The mean duration of sampling before treatment initiation was 17.6 weeks. From the overall cohort, 27 patients were treated for persistent viremia (6 patients were initially described in a previous report [8]. We selected 10 patients who had HCV RNA testing performed with the Cobas Amplicor HCV Monitor after 4 weeks of pegylated interferon and ribavirin for inclusion in this report.
All study subjects with acute HCV infection gave written informed consent for observational studies of the virologic, immunologic, and clinical courses of infection. These protocols conform to the 1975 Helsinki guidelines for the conduct of human research and were approved by each hospital's institutional review board. For incarcerated subjects, the Lemuel Shattuck Hospital Human Research Review Committee includes a prisoner advocate.
Results.
We identified 25 patients with acute HCV infection and persistent viremia who underwent combination therapy with pegylated interferon and ribavirin and had week 4 viral load testing performed. Fifteen patients were identified prospectively from the prison-based cohort, and 10 were identified retrospectively from the community-based cohort (table 1). Seventeen were men, and the mean age was 31 years. A total of 22 patients were white, and 1 was Hispanic; 1 person reported both white and African American ethnicity, and 1 reported both white and Hispanic ethnicity. Risk factors for HCV acquisition included IDU (for 20 patients) and sexual transmission (for 4 patients); the route of acquisition was unknown for 1 patient. Two patients in the community cohort were known to be HIV seropositive. No new diagnoses of HIV infection were made.
Nineteen patients were infected with HCV genotype 1 (n=17) or 4 (n=2), whereas 6 patients were infected with genotype 2 (n=1) or 3 (n=5). The mean HCV RNA level at enrollment was 329,210 IU/mL (range, 1004-1,745,260 IU/mL), whereas the mean HCV RNA level before treatment had increased to 391,747 IU/mL (range, 1385-1,665,560 IU/mL), although this trend was not statistically significant. Pretreatment low-level viremia was documented in 17 (68%) of 25 patients, including 12 (70.6%) of 17 with genotype 1 infection.
Rapid virologic clearance was achieved in 23 of 25 patients overall, including 2 patients with a history of HIV infection. The RVR rate was 89.5% (17 of 19) for patients infected with genotype 1 or 4 and 100% (6 of 6) for patients infected with genotype 2 or 3. On the assumption that treatment failure occurred in 3 patients who were lost to follow-up, the overall response rate was 72% (18 of 25) (figure 1).
The patients were treated for a mean duration of 22.8 weeks (range, 12-48 weeks); 1 patient was offered 48 weeks of therapy because of delayed therapeutic intervention secondary to uncontrolled depression. Adverse events were typical of combination therapy and included severe fatigue (for 5 patients), headache (for 4), loss of appetite (for 2), and new onset hypothyroidism (for 1). One patient received a single dose of erythropoietin because of anemia, and no patients required growth factors for neutropenia. Virologic breakthrough was documented in patients 10 and 11, both of whom had genotype 1 infection. Patient 10 stated that, during the last 2 months of ribavirin therapy, she had been poorly adherent. Although patient 11 was adherent to treatment, other factors may have contributed to his suboptimal response. These factors included a dramatic viral load increase between enrollment and pretreatment (from 22,635 to 546,478 IU/mL), as well as a marked increase in body weight from baseline obesity. A fasting insulin level and a glucose concentration were normal at the time of treatment discontinuation.
September 2009 NYC Viral Hepatitis E-Newsletter
NYC Department of Health & Mental Hygiene ~ Office of Viral Hepatitis Coordination
September 2009 NYC Viral Hepatitis E-Newsletter
Contents ~ Click to jump to:
Upcoming Events
New Resources
In the News
NYC Viral Hepatitis Coalitions & Task Forces
NYC Viral Hepatitis Resources
Online Viral Hepatitis Information & Resources
Upcoming Events
* The Dawn of a New Era: Transforming Our Domestic Response to Hepatitis B & C. September 9th 6:30 pm – September 11th 2 pm. Washington , DC.
* HIV, Hepatitis C, Substance Abuse: The Incarcerated and the Community. September 10th 8 am – 3 pm. Multipurpose Room, Student Center 100, Hofstra University, Hempstead, NY.
* Syringe Exchange Services & Law Enforcement Training: Building a Positive Relationship. Harm Reduction Coalition, Thursday, Sept 10th • 10-5 PM.
* Basics of Community Organizing with Citizens Committee for NYC Neighborhood Leadership Institute. Saturday, September 12th 11 am -2 pm. 305 7th Ave , 15th Floor.
* Harlem Hepatitis C Task Force Meeting. September 15th 2:30-4:30. North General Hospital Cafeteria.
* NYC Hepatitis B Coalition Meeting. September 17th 3- 5:30. Beth Israel PACC Auditorium: 10 Union Square East , 2nd floor.
* Midwest Viral Hepatitis Summit. September 18th. Columbus , Ohio . Hepatitis Foundation International.
* Bronx Hepatitis C Task Force Meeting. September 21st 2:30 – 4:30. Lincoln Medical Center1st Floor Conference Center .
* 2009 National Medicare Train the Trainer Workshop: New York. September 23–25. The New Yorker Hotel, 481 8th Ave.
* NYC Adult Immunization Coalition Meeting. September 24th 10 am – 12 pm. 26 Federal Plaza, Room 38-110A, New York 10013. Contact: tbaker2@health.nyc.gov.
* NATAP Conference - Hepatitis C & HIV/HCV Co-infection; New HIV Drugs for Drug resistance; Managing HIV and Aging. Saturday Sept 26th (10am-1:30pm) NYU Medical Center-Schwartz Lecture Hall F. 550 First Ave. NY 10016 .
* HIV/HCV Coinfection and Use of Motivational Interviewing to Reduce Alcohol Use. NYS DOH. October 7. Manhattan .
* 5th Annual Asian American Health Conference “Reinvesting in Our Communities for Health Equity”. October 8th 12 -5. October 9th 9-11:30. NYU Langone Center .
* It's Time: Integrate Viral Hepatitis into Your Work. NYS DOH. October 14 -15. Rochester NY .
* ING New York City Marathon . Join the American Liver Foundation Liver Life Challenge Team and become eligible for guaranteed entry.
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New & Important Resources
Funding
* HIV Prevention Grants ~ CBOs are encouraged to incorporate hepatitis services into HIV Prevention Grants
o HIV Prevention Projects for Community-based Organizations (CBOs) # PS10-1003
* Black MSM Treatment Education Initiative ~ Request for Grant Applications
* Society for the Arts in Healthcare Partnership to Promote Arts and Healing Grant Program. 2009 Johnson & Johnson.
* Grants for grassroots community groups in economically under-resourced neighborhoods. Citizens Committee for NYC.
* NYS Recovery Funding ~ double check to see if your organization qualifies for Federal Stimulus & Recovery Funding
Advocacy Opportunities
* Trust for America’s Health ~ Health Reform website
* American Public Health Association ~ Advocacy & Policy website
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In the News
HBV ~ the hepatitis b vaccine is available from your own medical provider or Health Department Immunization Clinics
* Racial Differences in Liver Transplant Linked to Underlying Disease (CME/CE) Caucasian liver transplant recipients have a significantly greater risk of hepatitis B recurrence than Asian- and African-American recipients, according to a review of recent transplantation experience in HBV-infected patients.
* Bridging the Culture Gap. NY Times article about the significance of cultural issues and Hepatitis B in the Asian Community.
HCV
* Gene Variant Predicts HCV Treatment Success A small genetic change near the gene for interferon-lambda-3 doubles the chance of successful hepatitis C treatment, researchers said. The variant -- a cytosine for thymine switch on chromosome 19 -- is the first genetic marker that predicts response
§ 27 Cases of Hepatitis C Now Linked to Medical Technician’s Drug Theft Scheme. Denver
* Rate of Sustained Virologic Response in Relation to Baseline Hepatitis C Virus (HCV) RNA Level and Rapid Virologic Clearance in Persons with Acute HCV Infection: genotype 1 can achieve high SVR rate is treated during acute infection
HAV ~ the hepatitis A vaccine is available from your own medical provider or Health Department Immunization Clinics.
* Surfers Get Vaccines Against Hepatitis A. California Tijuana Border.
* Hepatitis A Death Traced to an Island. Maine .
High Risk Population Issues
· Two Acres of Hope for Recovering Addicts At Renewal Farm, the men tend to kale and lettuce and flowers by day, and then exorcise their worries at a rehabilitation center where they sleep.
· Medical Heroin Works to Beat Opioid Addiction Injectable diacetylmorphine, the active ingredient in heroin, was shown to be an effective alternative to oral methadone in treating opioid addiction that had not responded to previous treatment.
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NYC Viral Hepatitis Coalitions & Task Forces
A single bracelet does not jingle – African Proverb
The NYC Viral Hepatitis Coalitions and Task Forces are action oriented groups comprised of all types of health and human service providers as well as advocates and patients concerned with viral hepatitis. The groups come together to learn, network, and share existing resources. Through this process the groups for to identify and develop strategies to address unmet needs and disseminate their results with the greater network.
NYC Hepatitis B Coalition
Sign up for invitations to upcoming meetings & meeting highlights
September 17th from 3:30 – 5:30 PM. Beth Israel PACC Auditorium, 10 Union Square East , 2nd floor.
* Developing NYC Hepatitis Services Resource Directory
NYC Hepatitis C Task Forces
Sign up for invitations to upcoming meetings ~ view past meeting highlights online
Harlem ~ September 15 - November 17. (2:30 – 4:30)
North General Hospital ~ 1879 Madison Avenue (Between 121st & 122nd) Cafeteria (in the C level -Basement)
Bronx ~ September 21 - November 23. (2:30 – 4:30)
Lincoln Medical Center 234 East 149th Street , 1st Floor Conference Center
Brooklyn ~ October 19 - December 14. (2:30 – 4:30)
Brooklyn Borough Hall - 209 Jorelemon St. ~ Community Room
Queens ~ Schedule and Location TBD
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NYC Viral Hepatitis Resources ~ View Online
Patient Info & Resources
Health & Medical Information, Social, Mental and Spiritual Support, Hepatitis B & C Support Groups & Treatment Support
Provider Info & Resources
In Person Education, Online Education & Information
NYC Department of Health & Mental Hygiene Resources
Surveillance, Hepatitis A & B Vaccine, Testing & Partner Notification & Special Services
Viral Hepatitis Related Issues Resources
Mental Health Resources
Depression Screening tools, 24 hour mental health hotline & Support Groups
Harm Reduction & Recovery Resources
Syringe Exchange, Safer Sex & Substance Abuse Treatment
Complementary & Alternative Medicine
Information & resources for learning about safe complementary & alternative treatments
Health Care Access
Public Health Insurance Information and application procedures
Health Care Access for people who are not eligible for ANY health insurance
Health care access assistance programs
Hepatitis B & C Advocacy Opportunities
Organizations that work on making things better for people with viral hepatitis
Legal Resources
Immigration, Disability & Substance use related legal resources
Public Health Friendly Law Enforcement
Funding & Employment
Funding sources for viral hepatitis programs
Employment resources in the viral hepatitis field
Public Health Marketing and Media Resources
Affordable tools to create awareness
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Online Viral Hepatitis Information & Resources
* American Liver Foundation (ALF)
* American Cancer Society ~ Asian Initiatives
* Asian Liver Center at Stanford University
* B Free CEED: National Center of Excellence in the Elimination of Hepatitis B Disparities
* Centers for Disease Control & Prevention (CDC) ~ Hepatitis
* Social Determinants of Health
* Center for Drug Use and HIV Research
* Harm Reduction Coalition
* HBV Advocate
* HCV Advocate
* Hepatitis B Foundation
* Hepatitis C Information Central
* Hepatitis Foundation International
* Hepatitis Magazine
* HEP Team NYC
* HIVandHepatitis.com
* Immunization Action Coalition
* National AIDS Treatment Advocacy Project (NATAP)
* National Institutes of Health – Viral Hepatitis
* New York City Department of Health & Mental Hygiene (DOHMH) ~ Hepatitis
* New York State Department of Health ~ Hepatitis
* New York State Office of Alcoholism and Substance Abuse Services (OASAS) Wellness Website – Hepatitis C
* Office of Minority Health: Hepatitis
* PubMed
* Treatment Action Group (TAG)
* Veterans Affairs - National Hepatitis C Program
* World Hepatitis Alliance
* World Health Organization~ Hepatitis
* Hepatitis Outbreaks National Organization for Reform
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Contact:
Nirah Johnson, LMSW ~ Community Projects Specialist
NYC Department of Health & Mental Hygeine
125 Worth Street, Room 326. New York , NY 10013
(212) 341-0432 ~ njohnso2@health.nyc.gov
Office of Viral Hepatitis CoordinationWebsite ~ NYC Hepatitis C Task Force Resources & Services Map
The rock in the water does not know the pain of the rock in the sun - Haitian proverb
September 2009 NYC Viral Hepatitis E-Newsletter
Contents ~ Click to jump to:
Upcoming Events
New Resources
In the News
NYC Viral Hepatitis Coalitions & Task Forces
NYC Viral Hepatitis Resources
Online Viral Hepatitis Information & Resources
Upcoming Events
* The Dawn of a New Era: Transforming Our Domestic Response to Hepatitis B & C. September 9th 6:30 pm – September 11th 2 pm. Washington , DC.
* HIV, Hepatitis C, Substance Abuse: The Incarcerated and the Community. September 10th 8 am – 3 pm. Multipurpose Room, Student Center 100, Hofstra University, Hempstead, NY.
* Syringe Exchange Services & Law Enforcement Training: Building a Positive Relationship. Harm Reduction Coalition, Thursday, Sept 10th • 10-5 PM.
* Basics of Community Organizing with Citizens Committee for NYC Neighborhood Leadership Institute. Saturday, September 12th 11 am -2 pm. 305 7th Ave , 15th Floor.
* Harlem Hepatitis C Task Force Meeting. September 15th 2:30-4:30. North General Hospital Cafeteria.
* NYC Hepatitis B Coalition Meeting. September 17th 3- 5:30. Beth Israel PACC Auditorium: 10 Union Square East , 2nd floor.
* Midwest Viral Hepatitis Summit. September 18th. Columbus , Ohio . Hepatitis Foundation International.
* Bronx Hepatitis C Task Force Meeting. September 21st 2:30 – 4:30. Lincoln Medical Center1st Floor Conference Center .
* 2009 National Medicare Train the Trainer Workshop: New York. September 23–25. The New Yorker Hotel, 481 8th Ave.
* NYC Adult Immunization Coalition Meeting. September 24th 10 am – 12 pm. 26 Federal Plaza, Room 38-110A, New York 10013. Contact: tbaker2@health.nyc.gov.
* NATAP Conference - Hepatitis C & HIV/HCV Co-infection; New HIV Drugs for Drug resistance; Managing HIV and Aging. Saturday Sept 26th (10am-1:30pm) NYU Medical Center-Schwartz Lecture Hall F. 550 First Ave. NY 10016 .
* HIV/HCV Coinfection and Use of Motivational Interviewing to Reduce Alcohol Use. NYS DOH. October 7. Manhattan .
* 5th Annual Asian American Health Conference “Reinvesting in Our Communities for Health Equity”. October 8th 12 -5. October 9th 9-11:30. NYU Langone Center .
* It's Time: Integrate Viral Hepatitis into Your Work. NYS DOH. October 14 -15. Rochester NY .
* ING New York City Marathon . Join the American Liver Foundation Liver Life Challenge Team and become eligible for guaranteed entry.
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New & Important Resources
Funding
* HIV Prevention Grants ~ CBOs are encouraged to incorporate hepatitis services into HIV Prevention Grants
o HIV Prevention Projects for Community-based Organizations (CBOs) # PS10-1003
* Black MSM Treatment Education Initiative ~ Request for Grant Applications
* Society for the Arts in Healthcare Partnership to Promote Arts and Healing Grant Program. 2009 Johnson & Johnson.
* Grants for grassroots community groups in economically under-resourced neighborhoods. Citizens Committee for NYC.
* NYS Recovery Funding ~ double check to see if your organization qualifies for Federal Stimulus & Recovery Funding
Advocacy Opportunities
* Trust for America’s Health ~ Health Reform website
* American Public Health Association ~ Advocacy & Policy website
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In the News
HBV ~ the hepatitis b vaccine is available from your own medical provider or Health Department Immunization Clinics
* Racial Differences in Liver Transplant Linked to Underlying Disease (CME/CE) Caucasian liver transplant recipients have a significantly greater risk of hepatitis B recurrence than Asian- and African-American recipients, according to a review of recent transplantation experience in HBV-infected patients.
* Bridging the Culture Gap. NY Times article about the significance of cultural issues and Hepatitis B in the Asian Community.
HCV
* Gene Variant Predicts HCV Treatment Success A small genetic change near the gene for interferon-lambda-3 doubles the chance of successful hepatitis C treatment, researchers said. The variant -- a cytosine for thymine switch on chromosome 19 -- is the first genetic marker that predicts response
§ 27 Cases of Hepatitis C Now Linked to Medical Technician’s Drug Theft Scheme. Denver
* Rate of Sustained Virologic Response in Relation to Baseline Hepatitis C Virus (HCV) RNA Level and Rapid Virologic Clearance in Persons with Acute HCV Infection: genotype 1 can achieve high SVR rate is treated during acute infection
HAV ~ the hepatitis A vaccine is available from your own medical provider or Health Department Immunization Clinics.
* Surfers Get Vaccines Against Hepatitis A. California Tijuana Border.
* Hepatitis A Death Traced to an Island. Maine .
High Risk Population Issues
· Two Acres of Hope for Recovering Addicts At Renewal Farm, the men tend to kale and lettuce and flowers by day, and then exorcise their worries at a rehabilitation center where they sleep.
· Medical Heroin Works to Beat Opioid Addiction Injectable diacetylmorphine, the active ingredient in heroin, was shown to be an effective alternative to oral methadone in treating opioid addiction that had not responded to previous treatment.
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NYC Viral Hepatitis Coalitions & Task Forces
A single bracelet does not jingle – African Proverb
The NYC Viral Hepatitis Coalitions and Task Forces are action oriented groups comprised of all types of health and human service providers as well as advocates and patients concerned with viral hepatitis. The groups come together to learn, network, and share existing resources. Through this process the groups for to identify and develop strategies to address unmet needs and disseminate their results with the greater network.
NYC Hepatitis B Coalition
Sign up for invitations to upcoming meetings & meeting highlights
September 17th from 3:30 – 5:30 PM. Beth Israel PACC Auditorium, 10 Union Square East , 2nd floor.
* Developing NYC Hepatitis Services Resource Directory
NYC Hepatitis C Task Forces
Sign up for invitations to upcoming meetings ~ view past meeting highlights online
Harlem ~ September 15 - November 17. (2:30 – 4:30)
North General Hospital ~ 1879 Madison Avenue (Between 121st & 122nd) Cafeteria (in the C level -Basement)
Bronx ~ September 21 - November 23. (2:30 – 4:30)
Lincoln Medical Center 234 East 149th Street , 1st Floor Conference Center
Brooklyn ~ October 19 - December 14. (2:30 – 4:30)
Brooklyn Borough Hall - 209 Jorelemon St. ~ Community Room
Queens ~ Schedule and Location TBD
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NYC Viral Hepatitis Resources ~ View Online
Patient Info & Resources
Health & Medical Information, Social, Mental and Spiritual Support, Hepatitis B & C Support Groups & Treatment Support
Provider Info & Resources
In Person Education, Online Education & Information
NYC Department of Health & Mental Hygiene Resources
Surveillance, Hepatitis A & B Vaccine, Testing & Partner Notification & Special Services
Viral Hepatitis Related Issues Resources
Mental Health Resources
Depression Screening tools, 24 hour mental health hotline & Support Groups
Harm Reduction & Recovery Resources
Syringe Exchange, Safer Sex & Substance Abuse Treatment
Complementary & Alternative Medicine
Information & resources for learning about safe complementary & alternative treatments
Health Care Access
Public Health Insurance Information and application procedures
Health Care Access for people who are not eligible for ANY health insurance
Health care access assistance programs
Hepatitis B & C Advocacy Opportunities
Organizations that work on making things better for people with viral hepatitis
Legal Resources
Immigration, Disability & Substance use related legal resources
Public Health Friendly Law Enforcement
Funding & Employment
Funding sources for viral hepatitis programs
Employment resources in the viral hepatitis field
Public Health Marketing and Media Resources
Affordable tools to create awareness
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Online Viral Hepatitis Information & Resources
* American Liver Foundation (ALF)
* American Cancer Society ~ Asian Initiatives
* Asian Liver Center at Stanford University
* B Free CEED: National Center of Excellence in the Elimination of Hepatitis B Disparities
* Centers for Disease Control & Prevention (CDC) ~ Hepatitis
* Social Determinants of Health
* Center for Drug Use and HIV Research
* Harm Reduction Coalition
* HBV Advocate
* HCV Advocate
* Hepatitis B Foundation
* Hepatitis C Information Central
* Hepatitis Foundation International
* Hepatitis Magazine
* HEP Team NYC
* HIVandHepatitis.com
* Immunization Action Coalition
* National AIDS Treatment Advocacy Project (NATAP)
* National Institutes of Health – Viral Hepatitis
* New York City Department of Health & Mental Hygiene (DOHMH) ~ Hepatitis
* New York State Department of Health ~ Hepatitis
* New York State Office of Alcoholism and Substance Abuse Services (OASAS) Wellness Website – Hepatitis C
* Office of Minority Health: Hepatitis
* PubMed
* Treatment Action Group (TAG)
* Veterans Affairs - National Hepatitis C Program
* World Hepatitis Alliance
* World Health Organization~ Hepatitis
* Hepatitis Outbreaks National Organization for Reform
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Contact:
Nirah Johnson, LMSW ~ Community Projects Specialist
NYC Department of Health & Mental Hygeine
125 Worth Street, Room 326. New York , NY 10013
(212) 341-0432 ~ njohnso2@health.nyc.gov
Office of Viral Hepatitis CoordinationWebsite ~ NYC Hepatitis C Task Force Resources & Services Map
The rock in the water does not know the pain of the rock in the sun - Haitian proverb
Invitation to Harlem Hepatitis C Task Force Meeting Tuesday September 15th ~ 2:30 – 4:30
Harlem Hepatitis C Task Force Meeting
Tuesday September 15th ~ 2:30 – 4:30
NEW Location!! North General Hospital ~ 1879 Madison Avenue (Between 121st & 122nd) Cafeteria (in the C level -Basement) Map
* RSVP would be appreciated
* Open the attached Outlook Appointment and Save to add this event to your calendar
* This meeting and the first presentation will start promptly at 2:30! Please arrive on time!
Presentations
Mental Health Aspects of Hepatitis C Infection & Treatment
Jeffrey Weiss, PhD, Assistant Professor, Department of Psychiatry, Mount Sinai School of Medicine
§ Hepatitis C disease process and impact on mental health
§ Mental Health Issues related to Hepatitis C Treatment
§ HIV/HCV Coinfection & Mental Health
§ Introduction of Task Force Project to develop a standard mental health screening tool to assess HCV treatment candidacy and readiness
Bureau of Alcohol & Drug Use Prevention, Care & Treatment Hepatitis C Related Issues Update
Anne Siegler, MPH, NYC DOHMH Bureau of Alcohol & Drug Use Prevention, Care & Treatment
§ New overdose prevention materials
SEP & Law Enforcement: Building a Positive Relationship
Narelle Ellendon, RN, Syringe Access Expansion Coordinator, Harm Reduction Coalition
§ Syringe Access Services & Law Enforcement Training at HRC
§ SEP Participant Rights & Responsibilities Card
§ Incident Report Revision Progress
§ Hepatitis C Related Programs at HRC
Task Force Project Updates
* Harlem HCV Services Referral Pathway Map
* Bio-Hazard Disposal Expansion
* Medicaid – Medicare Training: Special Issues related to HCV & HBV Mono-Infection
* HCV Anti-Stigma Skit
* Faith Based Outreach Initiative
Community Announcements
Enhanced Networking Session
* There will be two brief program presentations by organizations that have needs or offerings for the Hepatitis C Service Community to facilitate opportunities for networking.
* Please bring business cards and Hepatitis C related program brochures or materials.
Nirah Johnson, LMSW ~ Community Projects Specialist
NYC Department of Health & Mental Hygeine
125 Worth Street, Room 326. New York , NY 10013
(212) 341-0432 ~ njohnso2@health.nyc.gov
Office of Viral Hepatitis CoordinationWebsite ~ NYC Hepatitis C Task Force Resources & Services Map
The rock in the water does not know the pain of the rock in the sun - Haitian proverb
**********************************************************************
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.
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.
Forwarded Message: Harlem HCV Task Force Meeting
Harlem HCV Task Force Meeting
Thursday, September 3, 2009 2:00 PM
From:
"Nirah Johnson"
To:
undisclosed-recipients
Harlem Hepatitis C Task Force Meeting
Tuesday September 15th ~ 2:30 – 4:30
NEW Location!! North General Hospital ~ 1879 Madison Avenue (Between 121st & 122nd) Cafeteria (in the C level -Basement) Map
o RSVP would be appreciated!
o This meeting and the first presentation will start promptly at 2:30! Please arrive on-time!
Presentations
Mental Health Aspects of Hepatitis C Infection & Treatment
Jeffrey Weiss, PhD, Assistant Professor, Department of Psychiatry, Mount Sinai School of Medicine
# Hepatitis C disease process and impact on mental health
# Mental Health Issues related to Hepatitis C Treatment
# HIV/HCV Coinfection & Mental Health
# Introduction of Task Force Project to develop a standard mental health screening tool to assess HCV treatment candidacy and readiness
Bureau of Alcohol & Drug Use Prevention, Care & Treatment Hepatitis C Related Issues Update
Anne Siegler, MPH, NYC DOHMH Bureau of Alcohol & Drug Use Prevention, Care & Treatment
# New overdose prevention materials
SEP & Law Enforcement: Building a Positive Relationship
Narelle Ellendon, RN, Syringe Access Expansion Coordinator, Harm Reduction Coalition
# Syringe Access Services & Law Enforcement Training at HRC
# SEP Participant Rights & Responsibilities Card
# Incident Report Revision Progress
# Hepatitis C Related Programs at HRC
Task Force Project Updates
o Harlem HCV Services Referral Pathway Map
o Bio-Hazard Disposal Expansion
o Medicaid – Medicare Training: Special Issues related to HCV & HBV Mono-Infection
o HCV Anti-Stigma Skit
o Faith Based Outreach Initiative
Community Announcements
Enhanced Networking Session
o There will be two brief program presentations by organizations that have needs or offerings for the Hepatitis C Service Community to facilitate opportunities for networking.
o Please bring business cards and Hepatitis C related program brochures or materials.
Nirah Johnson, LMSW ~ Community Projects Specialist
NYC Department of Health & Mental Hygeine
125 Worth Street, Room 326. New York, NY 10013
(212) 341-0432 ~ njohnso2@health.nyc.gov
Office of Viral Hepatitis CoordinationWebsite ~ NYC Hepatitis C Task Force Resources & Services Map
The rock in the water does not know the pain of the rock in the sun - Haitian proverb
Tuesday September 15th ~ 2:30 – 4:30
NEW Location!! North General Hospital ~ 1879 Madison Avenue (Between 121st & 122nd) Cafeteria (in the C level -Basement) Map
* RSVP would be appreciated
* Open the attached Outlook Appointment and Save to add this event to your calendar
* This meeting and the first presentation will start promptly at 2:30! Please arrive on time!
Presentations
Mental Health Aspects of Hepatitis C Infection & Treatment
Jeffrey Weiss, PhD, Assistant Professor, Department of Psychiatry, Mount Sinai School of Medicine
§ Hepatitis C disease process and impact on mental health
§ Mental Health Issues related to Hepatitis C Treatment
§ HIV/HCV Coinfection & Mental Health
§ Introduction of Task Force Project to develop a standard mental health screening tool to assess HCV treatment candidacy and readiness
Bureau of Alcohol & Drug Use Prevention, Care & Treatment Hepatitis C Related Issues Update
Anne Siegler, MPH, NYC DOHMH Bureau of Alcohol & Drug Use Prevention, Care & Treatment
§ New overdose prevention materials
SEP & Law Enforcement: Building a Positive Relationship
Narelle Ellendon, RN, Syringe Access Expansion Coordinator, Harm Reduction Coalition
§ Syringe Access Services & Law Enforcement Training at HRC
§ SEP Participant Rights & Responsibilities Card
§ Incident Report Revision Progress
§ Hepatitis C Related Programs at HRC
Task Force Project Updates
* Harlem HCV Services Referral Pathway Map
* Bio-Hazard Disposal Expansion
* Medicaid – Medicare Training: Special Issues related to HCV & HBV Mono-Infection
* HCV Anti-Stigma Skit
* Faith Based Outreach Initiative
Community Announcements
Enhanced Networking Session
* There will be two brief program presentations by organizations that have needs or offerings for the Hepatitis C Service Community to facilitate opportunities for networking.
* Please bring business cards and Hepatitis C related program brochures or materials.
Nirah Johnson, LMSW ~ Community Projects Specialist
NYC Department of Health & Mental Hygeine
125 Worth Street, Room 326. New York , NY 10013
(212) 341-0432 ~ njohnso2@health.nyc.gov
Office of Viral Hepatitis CoordinationWebsite ~ NYC Hepatitis C Task Force Resources & Services Map
The rock in the water does not know the pain of the rock in the sun - Haitian proverb
**********************************************************************
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.
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.
Forwarded Message: Harlem HCV Task Force Meeting
Harlem HCV Task Force Meeting
Thursday, September 3, 2009 2:00 PM
From:
"Nirah Johnson"
To:
undisclosed-recipients
Harlem Hepatitis C Task Force Meeting
Tuesday September 15th ~ 2:30 – 4:30
NEW Location!! North General Hospital ~ 1879 Madison Avenue (Between 121st & 122nd) Cafeteria (in the C level -Basement) Map
o RSVP would be appreciated!
o This meeting and the first presentation will start promptly at 2:30! Please arrive on-time!
Presentations
Mental Health Aspects of Hepatitis C Infection & Treatment
Jeffrey Weiss, PhD, Assistant Professor, Department of Psychiatry, Mount Sinai School of Medicine
# Hepatitis C disease process and impact on mental health
# Mental Health Issues related to Hepatitis C Treatment
# HIV/HCV Coinfection & Mental Health
# Introduction of Task Force Project to develop a standard mental health screening tool to assess HCV treatment candidacy and readiness
Bureau of Alcohol & Drug Use Prevention, Care & Treatment Hepatitis C Related Issues Update
Anne Siegler, MPH, NYC DOHMH Bureau of Alcohol & Drug Use Prevention, Care & Treatment
# New overdose prevention materials
SEP & Law Enforcement: Building a Positive Relationship
Narelle Ellendon, RN, Syringe Access Expansion Coordinator, Harm Reduction Coalition
# Syringe Access Services & Law Enforcement Training at HRC
# SEP Participant Rights & Responsibilities Card
# Incident Report Revision Progress
# Hepatitis C Related Programs at HRC
Task Force Project Updates
o Harlem HCV Services Referral Pathway Map
o Bio-Hazard Disposal Expansion
o Medicaid – Medicare Training: Special Issues related to HCV & HBV Mono-Infection
o HCV Anti-Stigma Skit
o Faith Based Outreach Initiative
Community Announcements
Enhanced Networking Session
o There will be two brief program presentations by organizations that have needs or offerings for the Hepatitis C Service Community to facilitate opportunities for networking.
o Please bring business cards and Hepatitis C related program brochures or materials.
Nirah Johnson, LMSW ~ Community Projects Specialist
NYC Department of Health & Mental Hygeine
125 Worth Street, Room 326. New York, NY 10013
(212) 341-0432 ~ njohnso2@health.nyc.gov
Office of Viral Hepatitis CoordinationWebsite ~ NYC Hepatitis C Task Force Resources & Services Map
The rock in the water does not know the pain of the rock in the sun - Haitian proverb
Thursday, September 10, 2009
Population-based Surveillance for Hepatitis C Virus, United States, 2006–2007
Our study had 2 objectives. The first objective was to describe findings from 6 US state or county health departments that have been funded by CDC to perform enhanced surveillance for HCV infection. The second objective was to discuss the limitations and challenges of conducting population-based surveillance for HCV infection in the United States.....The 6 sites reported a total of 20,285 cases of confirmed HCV infection that were previously unreported in their respective jurisdictions.
The authors, which include the CDC, conclude "we lack evidence that surveillance results in a lower incidence of illness & death".
from Jules: this thinking comes from out public officials at the CDC --
"Local health departments need chronic HCV infection surveillance to document effects of disease, identify persons in need of linkage to care, and prevent complications among persons infected (13). However, accurately collecting the necessary information is challenging for health departments, and we currently lack evidence that obtaining these data will result in a lower incidence of illness and death. A full assessment of the benefits and costs of conducting comprehensive surveillance for chronic HCV infection is overdue. Currently, the enhanced hepatitis surveillance sites are developing recommendations for best practices and plan to share methods and tools with all interested health departments. Future studies should evaluate what level of surveillance for chronic HCV is feasible and whether the prevention benefit is worth the effort."
Population-based Surveillance for Hepatitis C Virus, United States, 2006–2007
Emerging Infectious Diseases Sept 2009
R. Monina Klevens, Comments to Author Jeremy Miller, Candace Vonderwahl, Suzanne Speers, Karen Alelis, Kristin Sweet, Elena Rocchio, Tasha Poissant, Tara M. Vogt, and Kathleen Gallagher
Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA (R.M. Klevens, J. Miller, T.M. Vogt, K. Gallagher); Colorado Department of Health, Denver, Colorado, USA (C. Vonderwahl); Connecticut Department of Public Health, Hartford, Connecticut, USA (S. Speers); Florida Health Department of Pinellas County, St. Petersburg, Florida, USA (K. Alelis); Minnesota Department of Health, St. Paul, Minnesota, USA (K. Sweet); New York State Department of Health, Albany, New York, USA (E. Rocchio); and Oregon Public Health Division, Portland, Oregon, USA (T. Poissant)
Dr Klevens is a medical epidemiologist in the Division of Viral Hepatitis at CDC. She is the CDC principal investigator for hepatitis surveillance in the Emerging Infections Program. She also provides epidemiologic support for hepatitis surveillance in the National Notifiable Diseases Surveillance System.
R. Monina Klevens, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Mailstop G37, Atlanta GA, 30329, USA; email: rmk2@cdc.gov
Abstract
Surveillance for hepatitis C virus infection in 6 US sites identified 20,285 newly reported cases in 12 months (report rate 69 cases/100,000 population, range 25–108/100,000). Staff reviewed 4 laboratory reports per new case. Local surveillance data can document the effects of disease, support linkage to care, and help prevent secondary transmission.
Hepatitis C virus (HCV) infection is a serious public health problem in the United States and throughout the world. At least 80% of acute infections become chronic (1); an estimated 3.2 million persons in the United States alone have chronic HCV infection (2). In 2004, an HCV diagnosis was made in 936 of 100,000 outpatient visits for healthcare and in 143 of 100,000 hospital discharges (3). This is a chronic infection in which complications are manifested decades after the initial infection. Complications and costs associated with chronic HCV infection are anticipated to increase during 2010–2019 (4), because the incidence of new infections peaked from the late 1960s to early 1980s (5).
Although identifying persons with HCV infection, including asymptomatic persons, is challenging, the benefits for overall public health make it worthwhile. Infected persons can be referred to care (6), treated (if appropriate) (7), and counseled to prevent complications. The Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists recognized these benefits, and in 2003, recommended that past or present infections with HCV (hereafter referred to as HCV infection because most of these cases likely represent chronic rather than acute or resolved HCV infections) become a nationally reportable condition. Surveillance for acute non-A, non-B hepatitis, which was mostly HCV infection, has been performed in the United States since 1982, but in 2007, a total of 33 states also conducted surveillance for HCV infection and reported 133,520 cases to CDC; however, these data remain unpublished.
The Study
Our study had 2 objectives. The first objective was to describe findings from 6 US state or county health departments that have been funded by CDC to perform enhanced surveillance for HCV infection. The second objective was to discuss the limitations and challenges of conducting population-based surveillance for HCV infection in the United States.
The sites where enhanced hepatitis surveillance was conducted during 2006–2007 were Colorado, Connecticut, Minnesota, New York (excluding New York City), and Oregon; Pinellas County, Florida, a sentinel counties (8) site, also contributed hepatitis C reports. The combined population under surveillance from the 5 states and 1 county was an estimated 29.3 million in 2007 (Table). In each of these jurisdictions, clinical laboratories are required to report positive results from HCV assays. For this analysis, a confirmed case of HCV infection was identified in any person who, from July 1, 2006 through June 30, 2007, had at least 1 of the following: 1) a positive result for an HCV recombinant immunoblot assay (RIBA), 2) a positive nucleic acid test (NAT) result for HCV RNA, 3) a documented HCV genotype, or 4) a positive result for a screening test for antibodies against HCV (anti-HCV) with a signal-to-cutoff (s:co) ratio predictive of a true positive result for the given assay.
Laboratories and providers continuously reported positive results for HCV markers (e.g., anti-HCV, RIBA, NAT, genotype) to state or local health departments. Health department staff checked patients' names and dates of birth from each report against a surveillance database to determine whether a case had been previously reported. Newly reported cases (i.e., previously not captured in the database of this jurisdiction) were entered into this database along with hepatitis test results. Health department staff investigated cases and collected basic demographic and clinical information to confirm the case definition and to epidemiologically describe the case. We calculated rates of newly reported cases by using denominators available from the 2007 population estimates from the US Bureau of the Census (www.census.gov/compendia/statab).
Two supplemental assessments were conducted. The first assessment measured the number of laboratory reports associated with each new case. Staff at each site monitored a convenience sample of laboratory reports and measured the number excluded, reasons for exclusion, and the number that eventually were classified as newly reported cases. The second assessment determined the validity of basic epidemiologic information. For this task, CDC drew a random sample of 10 cases per site from among those reported during the 12-month reporting period (n = 60) and extracted the following variables: date of birth, county of residence, sex, race, and clinical test results associated with HCV infection. Surveillance staff contacted at least 1 healthcare provider to independently collect this information. We measured agreement between the information initially reported and the information collected during the validation using a κ statistic (9).
The 6 sites reported a total of 20,285 cases of confirmed HCV infection that were previously unreported in their respective jurisdictions (Table). Of these, 66% of case-patients were male and 56% were 40–54 years of age (men and women combined) (Table). More than half (52%) of the reports lacked information on race or ethnicity. Most cases (89%) were reported by clinical laboratories. The laboratory criterion most frequently reported was a positive result for HCV RNA (53%). The rate of new reports of past or present HCV infection was 69/100,000 population (range 25–108/100,000).
Sites monitored all incoming reports on average for 8 days (range 5–16 days). A total of 2,180 reports were received and, among these, 491 (23%, range 13%–52%) met the case definition and were considered newly reported cases; Oregon had the highest proportion of newly reported cases (52%) and the newest registry. The remaining reports fell into the following categories: already in the database (68%, range 30%–78%), lacking value for s:co ratio (5%, range 3%–13%), negative test results for an HCV marker (2%, range 1%–4%), or missing key demographic data (1%, range 0%–2%).
All cases were confirmed to meet the case definition. Agreement was high for age (κ = 1.0, p<0.001), sex (κ = 0.96; p<0.001), and county of residence (κ = 1.0; p<0.001); county data were missing for 6 (10%) cases.
Conclusions
We documented that for every 4 laboratory reports, ≈1 newly reported case of HCV infection was identified. The overall annual rate of new case reports was 69/100,000 population in 6 sites that were conducting enhanced surveillance. In the 4 states (Colorado, Connecticut, Minnesota, Oregon) for which comparable data were available, the number of newly reported cases of HCV infection was at least 4× the number of newly reported HIV infections in 2006 (10). The 1 county in Florida was not included in the comparison because no HIV data were available.
Two limitations must be mentioned. First, we do not know how many of the newly reported cases represent current infections. In the United States, 80% of prevalent anti-HCV–positive cases are HCV RNA positive (2); thus, most laboratory confirmed cases reported to surveillance are likely chronic infections, but could also represent acute or resolved infections. Electronic laboratory reporting is the most efficient way to identify potential cases (11), but because no current laboratory test can distinguish acute from chronic HCV infections, identification of acute-phase cases requires contacting the provider or patient to determine whether acute symptoms were present. Due to the high volume of reports received, this level of follow-up was not routinely conducted.
The second major limitation is that testing patterns in the community are unknown. Providers are inconsistent about eliciting risk factor information and about testing and referring patients to specialists (12). Patient access to care and structural factors in institutions (e.g., incentives and disincentives for testing at jails, prisons, and drug treatment programs) and in the community (e.g., screenings) also affect testing and, therefore, the reporting rate.
The greatest value of conducting surveillance for chronic HCV at the state and local level is to measure local frequency of disease. Local and state health departments share information such that changes of residence of cases within the state over time would not result in a duplicate case count. However, in aggregating these data at the national level, an infected person who moved from 1 state to another would likely trigger a new report in another state, thus resulting in an overestimate of the national prevalence. Therefore, as a coordinated surveillance system for chronic HCV is developed, a mechanism to prevent duplication of cases across states will need to be developed.
Many factors affect case reporting, such as, local public health reporting requirements, the sophistication and capacity of laboratories to electronically report de-duplicated positive test results, availability of health department staff to conduct investigations and follow-up on reports, time since registry was initiated, and the capacity of the system to maintain ongoing surveillance efforts. Without an understanding of these factors, interpreting the meaning of new HCV infection case reports is difficult.
Local health departments need chronic HCV infection surveillance to document effects of disease, identify persons in need of linkage to care, and prevent complications among persons infected (13). However, accurately collecting the necessary information is challenging for health departments, and we currently lack evidence that obtaining these data will result in a lower incidence of illness and death. A full assessment of the benefits and costs of conducting comprehensive surveillance for chronic HCV infection is overdue. Currently, the enhanced hepatitis surveillance sites are developing recommendations for best practices and plan to share methods and tools with all interested health departments. Future studies should evaluate what level of surveillance for chronic HCV is feasible and whether the prevention benefit is worth the effort.
References
1. Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ, et al. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic Non-A, Non-B Hepatitis Study Team. N Engl J Med. 1992;327:1899–905.
2. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705–14.
3. Everhart JE. Viral hepatitis. In: Everhart JE, editor. The burden of digestive diseases in the United States. Washington: National Institute of Diabetes and Digestive and Kidney Diseases. Washington: Government Printing Office; 2008. NIH publication no. 09-6443. p. 13–23.
4. Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health. 2000;90:1562–9. PubMed DOI
5. Armstrong GL, Alter MJ, McQuillan GM, Margolis HS. The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States. Hepatology. 2000;31:777–82. PubMed DOI
6. Yawn BP, Gazzuola L, Wollan PC, Kim WR. Development and maintenance of a community-based hepatitis C registry. Am J Manag Care. 2002;8:253–61.
7. Strader DB, Wright T, Thomas DL, Seef LB. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147–71. PubMed DOI
8. Bell BP, Shapiro C, Alter MJ, Moyer LA, Judson FN, Mottram K, et al. The diverse patterns of hepatitis A epidemiology in the United States: implications for vaccination strategies. J Infect Dis. 1998;178:1579–84. PubMed DOI
9. Fleiss J. The measurement of interrater agreement. In: Statistical methods for rates and proportions, 2nd ed. New York: Wiley Interscience; 1981. p. 212–36.
10. Centers for Disease Control and Prevention. HIV/AIDS surveillance report 2007;18 [cited 2009 Jan 14]. Available from http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2006report/default.htm
11. Centers for Disease Control and Prevention. Automated detection and reporting of notifiable diseases using electronic medical records versus passive surveillance—Massachusetts, June 2006–July 2007. MMWR Morb Mortal Wkly Rep. 2008;57:373–6.
12. Shehab TM, Sonnad SS, Lok AS. Management of hepatitis C patients by primary care physicians in the USA: results of a national survey. J Viral Hepat. 2001;8:377–83. PubMed DOI
13. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Recomm Rep. 1998;47(RR-19):1–39
The authors, which include the CDC, conclude "we lack evidence that surveillance results in a lower incidence of illness & death".
from Jules: this thinking comes from out public officials at the CDC --
"Local health departments need chronic HCV infection surveillance to document effects of disease, identify persons in need of linkage to care, and prevent complications among persons infected (13). However, accurately collecting the necessary information is challenging for health departments, and we currently lack evidence that obtaining these data will result in a lower incidence of illness and death. A full assessment of the benefits and costs of conducting comprehensive surveillance for chronic HCV infection is overdue. Currently, the enhanced hepatitis surveillance sites are developing recommendations for best practices and plan to share methods and tools with all interested health departments. Future studies should evaluate what level of surveillance for chronic HCV is feasible and whether the prevention benefit is worth the effort."
Population-based Surveillance for Hepatitis C Virus, United States, 2006–2007
Emerging Infectious Diseases Sept 2009
R. Monina Klevens, Comments to Author Jeremy Miller, Candace Vonderwahl, Suzanne Speers, Karen Alelis, Kristin Sweet, Elena Rocchio, Tasha Poissant, Tara M. Vogt, and Kathleen Gallagher
Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA (R.M. Klevens, J. Miller, T.M. Vogt, K. Gallagher); Colorado Department of Health, Denver, Colorado, USA (C. Vonderwahl); Connecticut Department of Public Health, Hartford, Connecticut, USA (S. Speers); Florida Health Department of Pinellas County, St. Petersburg, Florida, USA (K. Alelis); Minnesota Department of Health, St. Paul, Minnesota, USA (K. Sweet); New York State Department of Health, Albany, New York, USA (E. Rocchio); and Oregon Public Health Division, Portland, Oregon, USA (T. Poissant)
Dr Klevens is a medical epidemiologist in the Division of Viral Hepatitis at CDC. She is the CDC principal investigator for hepatitis surveillance in the Emerging Infections Program. She also provides epidemiologic support for hepatitis surveillance in the National Notifiable Diseases Surveillance System.
R. Monina Klevens, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Mailstop G37, Atlanta GA, 30329, USA; email: rmk2@cdc.gov
Abstract
Surveillance for hepatitis C virus infection in 6 US sites identified 20,285 newly reported cases in 12 months (report rate 69 cases/100,000 population, range 25–108/100,000). Staff reviewed 4 laboratory reports per new case. Local surveillance data can document the effects of disease, support linkage to care, and help prevent secondary transmission.
Hepatitis C virus (HCV) infection is a serious public health problem in the United States and throughout the world. At least 80% of acute infections become chronic (1); an estimated 3.2 million persons in the United States alone have chronic HCV infection (2). In 2004, an HCV diagnosis was made in 936 of 100,000 outpatient visits for healthcare and in 143 of 100,000 hospital discharges (3). This is a chronic infection in which complications are manifested decades after the initial infection. Complications and costs associated with chronic HCV infection are anticipated to increase during 2010–2019 (4), because the incidence of new infections peaked from the late 1960s to early 1980s (5).
Although identifying persons with HCV infection, including asymptomatic persons, is challenging, the benefits for overall public health make it worthwhile. Infected persons can be referred to care (6), treated (if appropriate) (7), and counseled to prevent complications. The Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists recognized these benefits, and in 2003, recommended that past or present infections with HCV (hereafter referred to as HCV infection because most of these cases likely represent chronic rather than acute or resolved HCV infections) become a nationally reportable condition. Surveillance for acute non-A, non-B hepatitis, which was mostly HCV infection, has been performed in the United States since 1982, but in 2007, a total of 33 states also conducted surveillance for HCV infection and reported 133,520 cases to CDC; however, these data remain unpublished.
The Study
Our study had 2 objectives. The first objective was to describe findings from 6 US state or county health departments that have been funded by CDC to perform enhanced surveillance for HCV infection. The second objective was to discuss the limitations and challenges of conducting population-based surveillance for HCV infection in the United States.
The sites where enhanced hepatitis surveillance was conducted during 2006–2007 were Colorado, Connecticut, Minnesota, New York (excluding New York City), and Oregon; Pinellas County, Florida, a sentinel counties (8) site, also contributed hepatitis C reports. The combined population under surveillance from the 5 states and 1 county was an estimated 29.3 million in 2007 (Table). In each of these jurisdictions, clinical laboratories are required to report positive results from HCV assays. For this analysis, a confirmed case of HCV infection was identified in any person who, from July 1, 2006 through June 30, 2007, had at least 1 of the following: 1) a positive result for an HCV recombinant immunoblot assay (RIBA), 2) a positive nucleic acid test (NAT) result for HCV RNA, 3) a documented HCV genotype, or 4) a positive result for a screening test for antibodies against HCV (anti-HCV) with a signal-to-cutoff (s:co) ratio predictive of a true positive result for the given assay.
Laboratories and providers continuously reported positive results for HCV markers (e.g., anti-HCV, RIBA, NAT, genotype) to state or local health departments. Health department staff checked patients' names and dates of birth from each report against a surveillance database to determine whether a case had been previously reported. Newly reported cases (i.e., previously not captured in the database of this jurisdiction) were entered into this database along with hepatitis test results. Health department staff investigated cases and collected basic demographic and clinical information to confirm the case definition and to epidemiologically describe the case. We calculated rates of newly reported cases by using denominators available from the 2007 population estimates from the US Bureau of the Census (www.census.gov/compendia/statab).
Two supplemental assessments were conducted. The first assessment measured the number of laboratory reports associated with each new case. Staff at each site monitored a convenience sample of laboratory reports and measured the number excluded, reasons for exclusion, and the number that eventually were classified as newly reported cases. The second assessment determined the validity of basic epidemiologic information. For this task, CDC drew a random sample of 10 cases per site from among those reported during the 12-month reporting period (n = 60) and extracted the following variables: date of birth, county of residence, sex, race, and clinical test results associated with HCV infection. Surveillance staff contacted at least 1 healthcare provider to independently collect this information. We measured agreement between the information initially reported and the information collected during the validation using a κ statistic (9).
The 6 sites reported a total of 20,285 cases of confirmed HCV infection that were previously unreported in their respective jurisdictions (Table). Of these, 66% of case-patients were male and 56% were 40–54 years of age (men and women combined) (Table). More than half (52%) of the reports lacked information on race or ethnicity. Most cases (89%) were reported by clinical laboratories. The laboratory criterion most frequently reported was a positive result for HCV RNA (53%). The rate of new reports of past or present HCV infection was 69/100,000 population (range 25–108/100,000).
Sites monitored all incoming reports on average for 8 days (range 5–16 days). A total of 2,180 reports were received and, among these, 491 (23%, range 13%–52%) met the case definition and were considered newly reported cases; Oregon had the highest proportion of newly reported cases (52%) and the newest registry. The remaining reports fell into the following categories: already in the database (68%, range 30%–78%), lacking value for s:co ratio (5%, range 3%–13%), negative test results for an HCV marker (2%, range 1%–4%), or missing key demographic data (1%, range 0%–2%).
All cases were confirmed to meet the case definition. Agreement was high for age (κ = 1.0, p<0.001), sex (κ = 0.96; p<0.001), and county of residence (κ = 1.0; p<0.001); county data were missing for 6 (10%) cases.
Conclusions
We documented that for every 4 laboratory reports, ≈1 newly reported case of HCV infection was identified. The overall annual rate of new case reports was 69/100,000 population in 6 sites that were conducting enhanced surveillance. In the 4 states (Colorado, Connecticut, Minnesota, Oregon) for which comparable data were available, the number of newly reported cases of HCV infection was at least 4× the number of newly reported HIV infections in 2006 (10). The 1 county in Florida was not included in the comparison because no HIV data were available.
Two limitations must be mentioned. First, we do not know how many of the newly reported cases represent current infections. In the United States, 80% of prevalent anti-HCV–positive cases are HCV RNA positive (2); thus, most laboratory confirmed cases reported to surveillance are likely chronic infections, but could also represent acute or resolved infections. Electronic laboratory reporting is the most efficient way to identify potential cases (11), but because no current laboratory test can distinguish acute from chronic HCV infections, identification of acute-phase cases requires contacting the provider or patient to determine whether acute symptoms were present. Due to the high volume of reports received, this level of follow-up was not routinely conducted.
The second major limitation is that testing patterns in the community are unknown. Providers are inconsistent about eliciting risk factor information and about testing and referring patients to specialists (12). Patient access to care and structural factors in institutions (e.g., incentives and disincentives for testing at jails, prisons, and drug treatment programs) and in the community (e.g., screenings) also affect testing and, therefore, the reporting rate.
The greatest value of conducting surveillance for chronic HCV at the state and local level is to measure local frequency of disease. Local and state health departments share information such that changes of residence of cases within the state over time would not result in a duplicate case count. However, in aggregating these data at the national level, an infected person who moved from 1 state to another would likely trigger a new report in another state, thus resulting in an overestimate of the national prevalence. Therefore, as a coordinated surveillance system for chronic HCV is developed, a mechanism to prevent duplication of cases across states will need to be developed.
Many factors affect case reporting, such as, local public health reporting requirements, the sophistication and capacity of laboratories to electronically report de-duplicated positive test results, availability of health department staff to conduct investigations and follow-up on reports, time since registry was initiated, and the capacity of the system to maintain ongoing surveillance efforts. Without an understanding of these factors, interpreting the meaning of new HCV infection case reports is difficult.
Local health departments need chronic HCV infection surveillance to document effects of disease, identify persons in need of linkage to care, and prevent complications among persons infected (13). However, accurately collecting the necessary information is challenging for health departments, and we currently lack evidence that obtaining these data will result in a lower incidence of illness and death. A full assessment of the benefits and costs of conducting comprehensive surveillance for chronic HCV infection is overdue. Currently, the enhanced hepatitis surveillance sites are developing recommendations for best practices and plan to share methods and tools with all interested health departments. Future studies should evaluate what level of surveillance for chronic HCV is feasible and whether the prevention benefit is worth the effort.
References
1. Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ, et al. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic Non-A, Non-B Hepatitis Study Team. N Engl J Med. 1992;327:1899–905.
2. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705–14.
3. Everhart JE. Viral hepatitis. In: Everhart JE, editor. The burden of digestive diseases in the United States. Washington: National Institute of Diabetes and Digestive and Kidney Diseases. Washington: Government Printing Office; 2008. NIH publication no. 09-6443. p. 13–23.
4. Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health. 2000;90:1562–9. PubMed DOI
5. Armstrong GL, Alter MJ, McQuillan GM, Margolis HS. The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States. Hepatology. 2000;31:777–82. PubMed DOI
6. Yawn BP, Gazzuola L, Wollan PC, Kim WR. Development and maintenance of a community-based hepatitis C registry. Am J Manag Care. 2002;8:253–61.
7. Strader DB, Wright T, Thomas DL, Seef LB. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147–71. PubMed DOI
8. Bell BP, Shapiro C, Alter MJ, Moyer LA, Judson FN, Mottram K, et al. The diverse patterns of hepatitis A epidemiology in the United States: implications for vaccination strategies. J Infect Dis. 1998;178:1579–84. PubMed DOI
9. Fleiss J. The measurement of interrater agreement. In: Statistical methods for rates and proportions, 2nd ed. New York: Wiley Interscience; 1981. p. 212–36.
10. Centers for Disease Control and Prevention. HIV/AIDS surveillance report 2007;18 [cited 2009 Jan 14]. Available from http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2006report/default.htm
11. Centers for Disease Control and Prevention. Automated detection and reporting of notifiable diseases using electronic medical records versus passive surveillance—Massachusetts, June 2006–July 2007. MMWR Morb Mortal Wkly Rep. 2008;57:373–6.
12. Shehab TM, Sonnad SS, Lok AS. Management of hepatitis C patients by primary care physicians in the USA: results of a national survey. J Viral Hepat. 2001;8:377–83. PubMed DOI
13. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Recomm Rep. 1998;47(RR-19):1–39
Monday, September 7, 2009
The many faces of hepatitis C: Liver disease and type 2 diabetes
The many faces of hepatitis C: Liver disease and type 2 diabetes
Editorial
Hepatology Sept 2009
Kerry-Lee Milner 1, Donald Chisholm 1, Jacob George 2 *§
1Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia
2Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Sydney, Australia
Article Text
Epidemiological, clinical, and laboratory data indicate that apart from causing chronic liver injury, hepatitis C virus (HCV) infection is associated with extrahepatic disease. Foremost among the systemic consequences of chronic hepatitis C (CHC) is evidence that infection results in metabolic sequelae with the virus interacting with lipid and glucose metabolism resulting in hepatic steatosis, insulin resistance (IR), type 2 diabetes, and hypocholesterolemia. Multiple cross-sectional and longitudinal[1] studies have identified the association between CHC, IR, and type 2 diabetes. The prevalence of diabetes in CHC is between 19%-33%,[2][3] is specific to hepatitis C compared to other chronic liver diseases such as chronic hepatitis B, is independent of the severity of liver fibrosis, and its incidence is increased in patients with CHC after liver transplantation.[4] A causative association is further suggested by the knowledge that treatment-induced viral eradication results in improvements in insulin sensitivity.[5]
Abbreviations
CHC, chronic hepatitis C; HCV, hepatitis C virus; HOMA-IR, homeostasis model of insulin resistance; HOMA-B, homeostasis model of cell function; IR, insulin resistance; IL, interleukin; TNF-, tumor necrosis factor-alpha.
In type 2 diabetes not associated with CHC, impairments in insulin action (insulin resistance) and pancreatic -cell failure normally precede diabetes development. In these individuals, the primary sites of insulin action and resistance are muscle and adipose tissue (peripheral compartment) and the liver. With regard to IR in CHC, a number of studies using HOMA-IR (homeostasis model of IR, based on a fasting plasma glucose and insulin level) have found reduced insulin sensitivity in nondiabetic subjects with minimal liver fibrosis;[6] HOMA-B (homeostasis model of cell function, also based on fasting glucose and insulin levels) has not suggested an insulin secretory defect, but this needs more adequate assessment. The association between CHC and IR is of clinical significance to hepatologists, because IR is a predictor of fibrosis progression[7] and a reduced response to antiviral therapy, irrespective of genotype.[8]
Our understanding of the pathophysiology of IR in CHC has been limited by a number of factors. For example, HOMA-IR reflects the fasting state, does not distinguish between peripheral and hepatic IR, and has not been validated in populations with liver disease where insulin clearance rates may be affected. Moreover, factors that contribute to IR such as ethnicity, hepatic steatosis, body fat distribution, and family history of type 2 diabetes have not always been assessed. To date, the pathophysiology of IR in CHC is not well defined, and it is unclear if derangements in insulin action are a direct consequence of the virus or if they arise through indirect mechanisms such as lipid accumulation or cytokine secretion. Finally, there has also been some suggestion that IR in CHC may be genotype-specific, with one study showing lower HOMA-IR scores in genotype 3 infection; the mechanism of any such effect has not been elucidated.[6]
CHC infection results in a chronic inflammatory process in the liver where there is close proximity between hepatocytes, Kupffer cells, and infiltrating cells of the immune system. This inflammatory state with activation of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-) and interleukin-6 (IL-6), together with the effects of the virus on hepatic lipid metabolism, may inhibit insulin signaling pathways in the liver, increase steatosis, and induce hepatic IR. A hepatic locus of IR is also suggested by a transgenic mouse model of HCV core protein. These transgenic mice develop hepatic IR (prior to development of hepatic steatosis) with elevated intrahepatic TNF- levels.[9] Additionally, in vitro experiments in hepatocytes transfected with HCV proteins demonstrate postreceptor impairments in the insulin signaling cascade, with defects of insulin receptor substrate-1 and insulin receptor substrate-2 content or phosphorylation,[10] and up-regulation of suppressor of cytokine signaling-3.[11] Accumulation of lipid in the liver resulting from virus-induced changes in lipogenic genes[12] and mitochondrial dysfunction[13] has also been proposed to contribute to the inhibition of insulin signaling. Several human studies demonstrate elevated TNF-a levels (in serum and liver) in CHC[14] that may contribute to hepatic IR. However, TNF-a levels have not been strongly correlated with IR and similarly, elevated TNF-a levels are found in other chronic liver diseases such as chronic hepatitis B which are not associated with IR. Other adipokine disturbances in CHC include elevated IL-6 and retinol-binding protein 4,[15] and possibly alterations in adiponectin; these could contribute to hepatic IR, but correlative data does not support their importance.
In this issue of HEPATOLOGY, Vanni et al.[16] have used the gold standard measurement of IR - the hyperinsulinemic-euglycemic clamp with tracer glucose infusion - to more clearly define the site of IR in nonobese, normoglycemic subjects with CHC, compared to controls matched for body mass index and sex. The site of the IR was unexpectedly both peripheral and hepatic. Hepatic glucose production was increased basally and less suppressed with insulin in the subjects with hepatitis C compared to controls. Liver fat and the extent of liver disease were not associated with IR. The authors further suggest that the IR may primarily relate to increased intrahepatic and peripheral fat oxidation and increased hepatic expression of suppressor of cytokine signaling-3 and IL-18. Although this hypothesis is attractive, their data would indicate that a significant component of the IR in the subjects with CHC occurs in the peripheral compartment, although the mechanisms by which this occurs remain elusive (Fig 1). The similar suppression of lipolysis by insulin in all subjects (as measured by glycerol turnover and nonesterified free fatty acids) argues against adipocyte IR and infers that the peripheral IR is predominantly in muscle. However, it should be noted that alterations in lipid oxidation can be a consequence rather than a cause of IR. Of interest, there was no correlation between IR and viral load. A separate analysis of subjects with genotype 3 and subjects infected with other than genotype 3 would have been useful in evaluating whether, as previously suggested, genotype-specific differences occur in CHC-associated IR. Furthermore, such a study would have clarified the relationship between liver fat and IR, because IR is thought to be greater in genotype 1 infection, yet paradoxically, greater hepatic steatosis is present in genotype 3 disease. In the study by Vanni et al., small numbers precluded such an analysis. It should also be noted that liver fat was not significantly different, although the mean level in genotype 3 was 50% greater than in non-genotype 3 subjects.
Picture 2.png
Figure 1. Possible mechanisms by which chronic hepatitis C might cause insulin resistance. The hepatitis C virus is known to affect lipid metabolism and increase cytokine production in the liver, both of which could contribute to hepatic insulin resistance. The mechanisms by which the virus contributes to peripheral insulin resistance are unclear, but might involve direct effects on muscle and indirect effects via free fatty acid flux or adipokine production from adipose tissue.
[Normal View 37K | Magnified View 86K]
What is it then in a viral liver disease that causes skeletal muscle IR? Given that HCV alters lipid metabolism, a simple explanation would be an increased fatty acid supply to muscle, which is a proven cause of muscle IR. This or previous studies have not measured intramyocellular lipid, but the relatively normal circulating fatty acid and glycerol levels and normal suppression with insulin do not lend support for this mechanism. Another likely mediator is via circulating cytokine levels, which were not measured in this study. In this regard, TNF-a and other adipokines including adiponectin, IL-6, and retinol-binding protein 4 might contribute to peripheral IR, but they have not consistently correlated with HOMA-IR measurements.[17] Could the virus affect muscle directly? HCV has a very high circulating load but has not been shown to replicate in muscle.[18] Therefore, one could postulate that a local muscle effect of the virus would likely be mediated by receptors or other molecules on muscle cell membranes, perhaps exciting c-Jun N-terminal kinase-related pathways, or by influencing neighboring cells (e.g., adipocytes) to generate a paracrine effect. Muscle biopsy would not resolve the issue as to whether the virus is present in muscle because of inevitable blood contamination, but might identify activation of pathways known to interfere with insulin signaling. Clearly, whereas much has been learned by this important study, future reports will need to include detailed measurements of lipid compartments, body composition, and more extensive measurements of adipocytokines.
Chronic hepatitis C, although predominantly a liver disease, has protean manifestations. Although the pathophysiology of hepatic injury in CHC is now better understood, that of its other faces is still being elucidated. The study by Vanni et al.[16] significantly increases our understanding of the physiology of IR in CHC. However, like most things in science, their findings raise interesting questions and much food for further study.
References
1 Mehta SH, Brancati FL, Strathdee SA, Pankow JS, Netski D, Coresh J, et al. Hepatitis C virus infection and incident type 2 diabetes. HEPATOLOGY 2003; 38: 50-56. Links
2 Mason AL, Lau JY, Hoang N, Qian K, Alexander GJ, Xu L, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. HEPATOLOGY 1999; 29: 328-333. Links
3 Fraser GM, Harman I, Meller N, Niv Y, Porath A. Diabetes mellitus is associated with chronic hepatitis C but not chronic hepatitis B infection. Isr J Med Sci 1996; 32: 526-530. Links
4 Knobler H, Stagnaro-Green A, Wallenstein S, Schwartz M, Roman SH. Higher incidence of diabetes in liver transplant recipients with hepatitis C. J Clin Gastroenterol 1998; 26: 30-33. Links
5 Romero-Gomez M, Fernandez-Rodriguez CM, Andrade RJ, Diago M, Alonso S, Planas R, et al. Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol 2008; 48: 721-727. Links
6 Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 2003; 125: 1695-1704. Links
7 Petta S, Camma C, Marco VD, Alessi N, Cabibi D, Caldarella R, et al. Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection. Am J Gastroenterol 2008; 103: 1136-1144. Links
8 Poustchi H, Negro F, Hui J, Cua IH, Brandt LR, Kench JG, et al. Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3. J Hepatol 2008; 48: 28-34. Links
9 Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 2004; 126: 840-848. Links
10 Aytug S, Reich D, Sapiro LE, Bernstein D, Begum N. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. HEPATOLOGY 2003; 38: 1384-1392. Links
11 Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol 2004; 165: 1499-1508. Links
12 Su AI, Pezacki JP, Wodicka L, Brideau AD, Supekova L, Thimme R, et al. Genomic analysis of the host response to hepatitis C virus infection. Proc Natl Acad Sci U S A 2002; 99: 15669-15674. Links
13 Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, et al. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 2002; 122: 366-375. Links
14 Nelson DR, Lim HL, Marousis CG, Fang JW, Davis GL, Shen L, et al. Activation of tumor necrosis factor-alpha system in chronic hepatitis C virus infection. Dig Dis Sci 1997; 42: 2487-2494. Links
15 Petta S, Camma C, Di Marco V, Alessi N, Barbaria F, Cabibi D, et al. Retinol-binding protein 4: a new marker of virus-induced steatosis in patients infected with hepatitis c virus genotype 1. HEPATOLOGY 2008; 48: 28-37. Links
16 Vanni E, Abate ML, Gentilcore E, Hickman IJ, Gambino R, Cassader M, et al. Sites and mechanisms of insulin resistance in non-obese, non-diabetic patients with chronic hepatitis C. HEPATOLOGY 2009; doi:10.1002/hep.23031. Links
17 Cua IH, Hui JM, Bandara P, Kench JG, Farrell GC, McCaughan GW, et al. Insulin resistance and liver injury in hepatitis C is not associated with virus-specific changes in adipocytokines. HEPATOLOGY 2007; 46: 66-73. Links
18 Laskus T, Radkowski M, Wang LF, Vargas H, Rakela J. Search for hepatitis C virus extrahepatic replication sites in patients with acquired immunodeficiency syndrome: specific detection of negative-strand viral RNA in various tissues. HEPATOLOGY 1998; 28: 1398-1401. Links
Editorial
Hepatology Sept 2009
Kerry-Lee Milner 1, Donald Chisholm 1, Jacob George 2 *§
1Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia
2Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Sydney, Australia
Article Text
Epidemiological, clinical, and laboratory data indicate that apart from causing chronic liver injury, hepatitis C virus (HCV) infection is associated with extrahepatic disease. Foremost among the systemic consequences of chronic hepatitis C (CHC) is evidence that infection results in metabolic sequelae with the virus interacting with lipid and glucose metabolism resulting in hepatic steatosis, insulin resistance (IR), type 2 diabetes, and hypocholesterolemia. Multiple cross-sectional and longitudinal[1] studies have identified the association between CHC, IR, and type 2 diabetes. The prevalence of diabetes in CHC is between 19%-33%,[2][3] is specific to hepatitis C compared to other chronic liver diseases such as chronic hepatitis B, is independent of the severity of liver fibrosis, and its incidence is increased in patients with CHC after liver transplantation.[4] A causative association is further suggested by the knowledge that treatment-induced viral eradication results in improvements in insulin sensitivity.[5]
Abbreviations
CHC, chronic hepatitis C; HCV, hepatitis C virus; HOMA-IR, homeostasis model of insulin resistance; HOMA-B, homeostasis model of cell function; IR, insulin resistance; IL, interleukin; TNF-, tumor necrosis factor-alpha.
In type 2 diabetes not associated with CHC, impairments in insulin action (insulin resistance) and pancreatic -cell failure normally precede diabetes development. In these individuals, the primary sites of insulin action and resistance are muscle and adipose tissue (peripheral compartment) and the liver. With regard to IR in CHC, a number of studies using HOMA-IR (homeostasis model of IR, based on a fasting plasma glucose and insulin level) have found reduced insulin sensitivity in nondiabetic subjects with minimal liver fibrosis;[6] HOMA-B (homeostasis model of cell function, also based on fasting glucose and insulin levels) has not suggested an insulin secretory defect, but this needs more adequate assessment. The association between CHC and IR is of clinical significance to hepatologists, because IR is a predictor of fibrosis progression[7] and a reduced response to antiviral therapy, irrespective of genotype.[8]
Our understanding of the pathophysiology of IR in CHC has been limited by a number of factors. For example, HOMA-IR reflects the fasting state, does not distinguish between peripheral and hepatic IR, and has not been validated in populations with liver disease where insulin clearance rates may be affected. Moreover, factors that contribute to IR such as ethnicity, hepatic steatosis, body fat distribution, and family history of type 2 diabetes have not always been assessed. To date, the pathophysiology of IR in CHC is not well defined, and it is unclear if derangements in insulin action are a direct consequence of the virus or if they arise through indirect mechanisms such as lipid accumulation or cytokine secretion. Finally, there has also been some suggestion that IR in CHC may be genotype-specific, with one study showing lower HOMA-IR scores in genotype 3 infection; the mechanism of any such effect has not been elucidated.[6]
CHC infection results in a chronic inflammatory process in the liver where there is close proximity between hepatocytes, Kupffer cells, and infiltrating cells of the immune system. This inflammatory state with activation of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-) and interleukin-6 (IL-6), together with the effects of the virus on hepatic lipid metabolism, may inhibit insulin signaling pathways in the liver, increase steatosis, and induce hepatic IR. A hepatic locus of IR is also suggested by a transgenic mouse model of HCV core protein. These transgenic mice develop hepatic IR (prior to development of hepatic steatosis) with elevated intrahepatic TNF- levels.[9] Additionally, in vitro experiments in hepatocytes transfected with HCV proteins demonstrate postreceptor impairments in the insulin signaling cascade, with defects of insulin receptor substrate-1 and insulin receptor substrate-2 content or phosphorylation,[10] and up-regulation of suppressor of cytokine signaling-3.[11] Accumulation of lipid in the liver resulting from virus-induced changes in lipogenic genes[12] and mitochondrial dysfunction[13] has also been proposed to contribute to the inhibition of insulin signaling. Several human studies demonstrate elevated TNF-a levels (in serum and liver) in CHC[14] that may contribute to hepatic IR. However, TNF-a levels have not been strongly correlated with IR and similarly, elevated TNF-a levels are found in other chronic liver diseases such as chronic hepatitis B which are not associated with IR. Other adipokine disturbances in CHC include elevated IL-6 and retinol-binding protein 4,[15] and possibly alterations in adiponectin; these could contribute to hepatic IR, but correlative data does not support their importance.
In this issue of HEPATOLOGY, Vanni et al.[16] have used the gold standard measurement of IR - the hyperinsulinemic-euglycemic clamp with tracer glucose infusion - to more clearly define the site of IR in nonobese, normoglycemic subjects with CHC, compared to controls matched for body mass index and sex. The site of the IR was unexpectedly both peripheral and hepatic. Hepatic glucose production was increased basally and less suppressed with insulin in the subjects with hepatitis C compared to controls. Liver fat and the extent of liver disease were not associated with IR. The authors further suggest that the IR may primarily relate to increased intrahepatic and peripheral fat oxidation and increased hepatic expression of suppressor of cytokine signaling-3 and IL-18. Although this hypothesis is attractive, their data would indicate that a significant component of the IR in the subjects with CHC occurs in the peripheral compartment, although the mechanisms by which this occurs remain elusive (Fig 1). The similar suppression of lipolysis by insulin in all subjects (as measured by glycerol turnover and nonesterified free fatty acids) argues against adipocyte IR and infers that the peripheral IR is predominantly in muscle. However, it should be noted that alterations in lipid oxidation can be a consequence rather than a cause of IR. Of interest, there was no correlation between IR and viral load. A separate analysis of subjects with genotype 3 and subjects infected with other than genotype 3 would have been useful in evaluating whether, as previously suggested, genotype-specific differences occur in CHC-associated IR. Furthermore, such a study would have clarified the relationship between liver fat and IR, because IR is thought to be greater in genotype 1 infection, yet paradoxically, greater hepatic steatosis is present in genotype 3 disease. In the study by Vanni et al., small numbers precluded such an analysis. It should also be noted that liver fat was not significantly different, although the mean level in genotype 3 was 50% greater than in non-genotype 3 subjects.
Picture 2.png
Figure 1. Possible mechanisms by which chronic hepatitis C might cause insulin resistance. The hepatitis C virus is known to affect lipid metabolism and increase cytokine production in the liver, both of which could contribute to hepatic insulin resistance. The mechanisms by which the virus contributes to peripheral insulin resistance are unclear, but might involve direct effects on muscle and indirect effects via free fatty acid flux or adipokine production from adipose tissue.
[Normal View 37K | Magnified View 86K]
What is it then in a viral liver disease that causes skeletal muscle IR? Given that HCV alters lipid metabolism, a simple explanation would be an increased fatty acid supply to muscle, which is a proven cause of muscle IR. This or previous studies have not measured intramyocellular lipid, but the relatively normal circulating fatty acid and glycerol levels and normal suppression with insulin do not lend support for this mechanism. Another likely mediator is via circulating cytokine levels, which were not measured in this study. In this regard, TNF-a and other adipokines including adiponectin, IL-6, and retinol-binding protein 4 might contribute to peripheral IR, but they have not consistently correlated with HOMA-IR measurements.[17] Could the virus affect muscle directly? HCV has a very high circulating load but has not been shown to replicate in muscle.[18] Therefore, one could postulate that a local muscle effect of the virus would likely be mediated by receptors or other molecules on muscle cell membranes, perhaps exciting c-Jun N-terminal kinase-related pathways, or by influencing neighboring cells (e.g., adipocytes) to generate a paracrine effect. Muscle biopsy would not resolve the issue as to whether the virus is present in muscle because of inevitable blood contamination, but might identify activation of pathways known to interfere with insulin signaling. Clearly, whereas much has been learned by this important study, future reports will need to include detailed measurements of lipid compartments, body composition, and more extensive measurements of adipocytokines.
Chronic hepatitis C, although predominantly a liver disease, has protean manifestations. Although the pathophysiology of hepatic injury in CHC is now better understood, that of its other faces is still being elucidated. The study by Vanni et al.[16] significantly increases our understanding of the physiology of IR in CHC. However, like most things in science, their findings raise interesting questions and much food for further study.
References
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