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State Health Department Launches Media Campaign To Increase Public Awareness About Hepatitis C
- Campaign Urges Hepatitis C Prevention,Testing
ALBANY, N.Y. (August 6, 2009) - The New York State Department of Health (DOH) has launched a statewide public awareness campaign to urge New Yorkers to learn about the hepatitis C virus and to take appropriate preventive steps. Under Governor David A. Paterson's leadership, nearly $1.6 million was appropriated in the 2008-2009 Executive Budget for the first time ever to establish a comprehensive hepatitis C program in New York State. Included in the program is a $270,000 campaign using billboards, subway and bus shelter advertisements to promote the theme: "Over 200,000 New Yorkers have hepatitis C. Are you one of them?"
A toll-free English/Spanish hotline is available 24 hours a day, seven days a week to provide basic hepatitis C information, locations for testing and hepatitis A and B vaccination, and other resources available to consumers. The hotline number is 1-800-522-5006.
"This campaign draws attention to the fact that thousands of New Yorkers living with chronic hepatitis C are unaware that they have it, because individuals in the early stages of hepatitis C often show no symptoms and are not diagnosed until the disease has advanced," said State Health Commissioner Richard F. Daines, M.D. "For that reason, hepatitis C is called the silent epidemic. It's time to break the silence and raise the volume on awareness, prevention and action about this disease."
Viral hepatitis includes three different viruses than can cause inflammation of the liver. Hepatitis A virus is spread by putting something in the mouth that has been contaminated with the stool of a person who has hepatitis A. Hepatitis B is spread through contact with blood and body fluids of a hepatitis B-infected person. There are vaccines available to prevent infection from hepatitis A and B.
Hepatitis C is spread when blood from an infected person enters the body of a person who is not infected. For example, the virus can be spread by sharing needles or "works" when injecting drugs or having sex with an infected person without using a condom. Hepatitis C can also be spread through needle sticks or "sharps" exposure on the job and from an infected mother to her baby during birth.
Currently there is no vaccine to prevent hepatitis C. However, people living with hepatitis C should be vaccinated for hepatitis A and B. If left untreated, hepatitis C can damage the liver, leading to cirrhosis, liver cancer or even death. Because of the danger to the liver, it's also important to avoid alcohol. "It's important that all New Yorkers know that hepatitis C can be prevented," said Commissioner Daines. "There is no reason we can not drastically reduce or even eliminate the occurrence of hepatitis C in our communities. Anyone who thinks they may have put themselves at risk for hepatitis C should get a blood test and talk with their health care provider."
An estimated 304,000 New Yorkers have been infected with hepatitis C. Of these, nearly 240,000 people are currently living with chronic infections. Up to 5 percent of people with chronic hepatitis C die. Hepatitis C is the leading reason for liver transplants.
Nearly 50 percent of people with chronic hepatitis C are unaware they are infected because they often show no symptoms until advanced liver damage develops. Those who do have symptoms may experience fatigue, loss of appetite, nausea, abdominal discomfort, dark urine, clay-colored bowel movements, and yellowing of the skin and eyes (jaundice).
There are drugs licensed for the treatment of chronic hepatitis. However, treatment is not for everyone, and a specialist should be consulted to determine the appropriate course of action.
More information on hepatitis C is available on the DOH website at
http://www.nyhealth.gov/diseases/communicable/hepatitis/
Links to the campaign images can be found at:
http://www.health.state.ny.us/diseases/communicable/hepatitis/campaign_images.htm
Monday, August 24, 2009
Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance; for African-Americans, Hispanics, East Asians
Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance; for African-Americans, Hispanics, East Asians - (08/15/09)
New biomarker predicts response to hepatitis C treatment
22 Aug 2009
http://www.virtualmedicalcentre.com
Researchers have identified the first genetic marker that predicts response to hepatitis C treatments, and a single letter of DNA code appears to make a huge difference. Duke University Medical Center scientists says the biomarker not only predicts who is most likely to respond to treatment and who isn't, but also may explain why there are such different rates of response among racial and ethnic groups, a phenomenon that has puzzled physicians for years.
"For geneticists, understanding response to treatment for hepatitis C infection has been almost like a holy grail," says David Goldstein, PhD, director of the Center for Human Genome Variation in Duke's Institute for Genome Sciences & Policy and the senior author of the study. "The side effects of hepatitis treatment can be brutal, and about half the time, the treatment fails to eradicate the virus. This discovery enables us to give patients valuable information that will help them and their doctors decide what is best for them. This is what personalised medicine is all about."
The discovery is reported online in the journal Nature.
Hepatitis C is one of the most common infections in the world, affecting an estimated 170 million people. Many can live with the disease for years without any serious complications. About a quarter of the time, however, the infection leads to cirrhosis of the liver, which, in turn, can lead to liver cancer or death or the need for a transplant. Hepatitis C is the leading cause for liver transplants in the US.
Treatment typically involves 48 weeks of interferon plus the antiviral drug ribavirin. Some patients develop such taxing side effects that they stop treatment. Physicians have long observed that African-Americans are less likely to respond to treatments than Caucasians, while East Asian patients seem to respond the best. But until now, no one has known why.
"This discovery appears to explain a large part of it. It is most certainly a triumph of translational medicine," says John McHutchison, MD, associate director of the Duke Clinical Research Institute, a member of the Division of Gastroenterology in the School of Medicine at Duke and study co-author. "This is a perfect example of bedside to bench and back to bedside investigation."
The new marker is a single letter change – a C instead of a T – in a tiny segment of DNA near the IL28B gene. Researchers found it by studying 1,671 individuals who participated in the IDEAL study, a multicentre clinical trial that compared the two most widely used therapies among patients with the most common form of the disease in the US and Europe. McHutchison was the lead investigator of the recently published IDEAL study, which found no clinically meaningful differences in overall viral response among the regimens.
In conducting the current study, Goldstein and his colleagues found that the patients who had the single-letter change in their DNA were significantly more likely to respond to treatment than those who did not have it. "Eighty percent of those with the favourable response genotype eradicated the virus, while only about 30 percent with the less favourable response genotype did so. With differences of that magnitude, patients considering therapy may want to know what their genotype is before they start treatment," says Goldstein.
Goldstein says they were struck by the finding that the "good" genotype proved beneficial to patients in all population subgroups. "But because it appears significantly more often among Caucasian populations than it does among African populations, we feel it explains much of the difference in response rates we see between African Americans and those of European ancestry," says Goldstein. "This tells us that individual genetic makeup is much more important determinant of response to treatment than is race or ethnicity."
Researchers found that African Americans with the favourable (CC) genotype had a significantly higher rate of response to treatment (53.3 percent) than did individuals of European ancestry who had the less favourable (TT) genotype (33.3 percent).
The researchers also ran tests to see if the presence of the biomarker was related in any way to viral load, a measure of how much virus was circulating in the patient before treatment started. They found a significant association in all groups. "Interestingly, we found that the C allele, although associated with better treatment response, was associated with a higher viral load at baseline – something we have traditionally viewed as a negative prognostic marker when it comes to treatment response," says McHutchison.
That finding, along with other evidence gleaned in the research, suggests that patients who have the beneficial genetic marker might be especially adept at spontaneously clearing the virus through some as yet unknown mechanism, says McHutchison. "It was thrilling to discover such an important biological marker related to response to hepatitis C treatments, but at the same time, the findings tell us there is a lot more work to do before we can fully understand how patients' immune systems protect them from the virus."
"This stunning finding supports the integration of research efforts that previously were not connected," says Robert Califf, MD, vice chancellor for clinical research and director of the Duke Translational Medicine Institute. "Drs Goldstein, McHutchison and colleagues have combined world class genotyping and clinical trials management in an academic medical center with an industry sponsored clinical trial to produce a set of findings that are likely to change practice. Their focus on modification of clinical outcomes is especially important to note as we design future studies."
Some members of the research team are interested in finding a way to routinely test for the new marker, but McHutchison says important work still needs to be done. "This study only pertains to patients with genotype 1 infection. We still need to evaluate the polymorphism among patients with less common genotypes of hepatitis C."
The study was funded by the Schering-Plough Research Institute.
(Source: Duke University Medical Center: Nature: August 2009)
New biomarker predicts response to hepatitis C treatment
22 Aug 2009
http://www.virtualmedicalcentre.com
Researchers have identified the first genetic marker that predicts response to hepatitis C treatments, and a single letter of DNA code appears to make a huge difference. Duke University Medical Center scientists says the biomarker not only predicts who is most likely to respond to treatment and who isn't, but also may explain why there are such different rates of response among racial and ethnic groups, a phenomenon that has puzzled physicians for years.
"For geneticists, understanding response to treatment for hepatitis C infection has been almost like a holy grail," says David Goldstein, PhD, director of the Center for Human Genome Variation in Duke's Institute for Genome Sciences & Policy and the senior author of the study. "The side effects of hepatitis treatment can be brutal, and about half the time, the treatment fails to eradicate the virus. This discovery enables us to give patients valuable information that will help them and their doctors decide what is best for them. This is what personalised medicine is all about."
The discovery is reported online in the journal Nature.
Hepatitis C is one of the most common infections in the world, affecting an estimated 170 million people. Many can live with the disease for years without any serious complications. About a quarter of the time, however, the infection leads to cirrhosis of the liver, which, in turn, can lead to liver cancer or death or the need for a transplant. Hepatitis C is the leading cause for liver transplants in the US.
Treatment typically involves 48 weeks of interferon plus the antiviral drug ribavirin. Some patients develop such taxing side effects that they stop treatment. Physicians have long observed that African-Americans are less likely to respond to treatments than Caucasians, while East Asian patients seem to respond the best. But until now, no one has known why.
"This discovery appears to explain a large part of it. It is most certainly a triumph of translational medicine," says John McHutchison, MD, associate director of the Duke Clinical Research Institute, a member of the Division of Gastroenterology in the School of Medicine at Duke and study co-author. "This is a perfect example of bedside to bench and back to bedside investigation."
The new marker is a single letter change – a C instead of a T – in a tiny segment of DNA near the IL28B gene. Researchers found it by studying 1,671 individuals who participated in the IDEAL study, a multicentre clinical trial that compared the two most widely used therapies among patients with the most common form of the disease in the US and Europe. McHutchison was the lead investigator of the recently published IDEAL study, which found no clinically meaningful differences in overall viral response among the regimens.
In conducting the current study, Goldstein and his colleagues found that the patients who had the single-letter change in their DNA were significantly more likely to respond to treatment than those who did not have it. "Eighty percent of those with the favourable response genotype eradicated the virus, while only about 30 percent with the less favourable response genotype did so. With differences of that magnitude, patients considering therapy may want to know what their genotype is before they start treatment," says Goldstein.
Goldstein says they were struck by the finding that the "good" genotype proved beneficial to patients in all population subgroups. "But because it appears significantly more often among Caucasian populations than it does among African populations, we feel it explains much of the difference in response rates we see between African Americans and those of European ancestry," says Goldstein. "This tells us that individual genetic makeup is much more important determinant of response to treatment than is race or ethnicity."
Researchers found that African Americans with the favourable (CC) genotype had a significantly higher rate of response to treatment (53.3 percent) than did individuals of European ancestry who had the less favourable (TT) genotype (33.3 percent).
The researchers also ran tests to see if the presence of the biomarker was related in any way to viral load, a measure of how much virus was circulating in the patient before treatment started. They found a significant association in all groups. "Interestingly, we found that the C allele, although associated with better treatment response, was associated with a higher viral load at baseline – something we have traditionally viewed as a negative prognostic marker when it comes to treatment response," says McHutchison.
That finding, along with other evidence gleaned in the research, suggests that patients who have the beneficial genetic marker might be especially adept at spontaneously clearing the virus through some as yet unknown mechanism, says McHutchison. "It was thrilling to discover such an important biological marker related to response to hepatitis C treatments, but at the same time, the findings tell us there is a lot more work to do before we can fully understand how patients' immune systems protect them from the virus."
"This stunning finding supports the integration of research efforts that previously were not connected," says Robert Califf, MD, vice chancellor for clinical research and director of the Duke Translational Medicine Institute. "Drs Goldstein, McHutchison and colleagues have combined world class genotyping and clinical trials management in an academic medical center with an industry sponsored clinical trial to produce a set of findings that are likely to change practice. Their focus on modification of clinical outcomes is especially important to note as we design future studies."
Some members of the research team are interested in finding a way to routinely test for the new marker, but McHutchison says important work still needs to be done. "This study only pertains to patients with genotype 1 infection. We still need to evaluate the polymorphism among patients with less common genotypes of hepatitis C."
The study was funded by the Schering-Plough Research Institute.
(Source: Duke University Medical Center: Nature: August 2009)
Carvedilol Reduces Esophageal Bleeding in Cirrhosis Patients
Carvedilol Reduces Esophageal Bleeding in Cirrhosis Patients
By Chris Emery, Contributing Writer, MedPage Today
Published: August 20, 2009
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
for reading medical news
Action Points
* Explain to interested patients that carvedilol has been shown to prevent variceal bleeding in cirrhosis patients.
* Note that the researchers urged caution interpretation of the comparison to carvedilol, due to poor adherence to variceal band ligation in the study population.
The beta-blocker carvedilol was more effective at preventing esophageal bleeding in cirrhosis patients than variceal band ligation (VBL), without increasing mortality risk, a new study found.
Cirrhosis patients who received carvedilol had lower rates of initial bleeding from abnormally dilated submucosal veins in the lower esophagus, known as varices, compared with patients who received variceal banding ligation (RH 0.41; 95% CI 0.19 to 0.96; P<0.04), according to the report published online Aug. 19 in Hepatology.
Six patients who underwent banding ligation, an endoscopic procedure in which rubber bands are looped around the dilated veins in the esophagus, bled from ulcers that resulted from the banding.
"This study is the first randomized, controlled trial to assess the role of carvedilol in the prevention of the first variceal bleed in patients with high-risk varices," Peter C. Hayes, MD, PhD, FRCP, of the Royal Infirmary of Edinburgh, and colleagues wrote. "We have found carvedilol to have lower bleeding rates than VBL, with no difference in survival."
Variceal hemorrhages are the most most serious complication of high blood pressure in the portal vein (portal hypertension), which is often related to chronic liver disease. About 5% of cirrhosis patients will suffer from esophageal varices annually, with bleeding in about a third of those cases.
Two recent reviews of 16 previous trials comparing VB and beta-blockers for primary prevention of bleeding found that VBL was more effective, although the difference in effectiveness disappeared in one meta-analysis studies when potentially biased studies were excluded.
However, none of the trials on variceal hemorrhages investigated the effectiveness of carvedilol, a noncardioselective beta-blocker with weak vasodilating properties that is sold as a generic drug and under brand names such as Coreg, Dilatrend, Eucardic and Carloc.
In this study, Hayes and colleagues sought to compare carvedilol and VBL for the prevention of the first variceal bleed in a randomized, controlled multicenter trial.
They randomly assigned 152 cirrhosis patients (median age 54) from five different medical centers to receive either 12.5 milligrams of carvedilol once daily or VBL performed every two weeks using an endoscopic banding device until the serious (worse than grade 1) varices disappeared.
Of the patients in the study, 75% suffered from alcoholic cirrhosis and all had grade II or larger esophageal varices.
After randomization, the patients were followed for a median of 20 months. Among the patients who received carvedilol, 39 experienced side effects, most of which were minor and resolved with continued use.
However, 10 patients could not tolerate persistent side effects, including shortness of breath, impotence, nausea and vomiting, and symptomatic hypotension, and they discontinued the treatment. A total of 13 patients discontinued the banding treatment as well, often because they found the procedure uncomfortable.
Variceal bleeding occurred in eight patients (10%) in the carvedilol group and 17 patients (23%) in the banding group during the follow-up period. The researchers found no difference in overall mortality or bleeding-related mortality between the two treatments.
The researchers concluded that carvedilol was effective at preventing the first variceal bleed and is well tolerated but cautioned that difficulties in adherence to the banding protocol in their study may have effected the results.
"Further studies should aim to increase compliance with VBL protocols, with particular emphasis on variceal eradication," they wrote. "However, we believe that carvedilol can be considered a treatment option for primary prophylaxis of variceal bleeding."
The study was supported by the University of Edinburgh.
The researchers reported no financial conflicts of interest.
Primary source: Hepatology
Source reference:
Hayes P, et al "Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed" Hepatology 2009; DOI: 10.1002/hep.23045.
By Chris Emery, Contributing Writer, MedPage Today
Published: August 20, 2009
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
for reading medical news
Action Points
* Explain to interested patients that carvedilol has been shown to prevent variceal bleeding in cirrhosis patients.
* Note that the researchers urged caution interpretation of the comparison to carvedilol, due to poor adherence to variceal band ligation in the study population.
The beta-blocker carvedilol was more effective at preventing esophageal bleeding in cirrhosis patients than variceal band ligation (VBL), without increasing mortality risk, a new study found.
Cirrhosis patients who received carvedilol had lower rates of initial bleeding from abnormally dilated submucosal veins in the lower esophagus, known as varices, compared with patients who received variceal banding ligation (RH 0.41; 95% CI 0.19 to 0.96; P<0.04), according to the report published online Aug. 19 in Hepatology.
Six patients who underwent banding ligation, an endoscopic procedure in which rubber bands are looped around the dilated veins in the esophagus, bled from ulcers that resulted from the banding.
"This study is the first randomized, controlled trial to assess the role of carvedilol in the prevention of the first variceal bleed in patients with high-risk varices," Peter C. Hayes, MD, PhD, FRCP, of the Royal Infirmary of Edinburgh, and colleagues wrote. "We have found carvedilol to have lower bleeding rates than VBL, with no difference in survival."
Variceal hemorrhages are the most most serious complication of high blood pressure in the portal vein (portal hypertension), which is often related to chronic liver disease. About 5% of cirrhosis patients will suffer from esophageal varices annually, with bleeding in about a third of those cases.
Two recent reviews of 16 previous trials comparing VB and beta-blockers for primary prevention of bleeding found that VBL was more effective, although the difference in effectiveness disappeared in one meta-analysis studies when potentially biased studies were excluded.
However, none of the trials on variceal hemorrhages investigated the effectiveness of carvedilol, a noncardioselective beta-blocker with weak vasodilating properties that is sold as a generic drug and under brand names such as Coreg, Dilatrend, Eucardic and Carloc.
In this study, Hayes and colleagues sought to compare carvedilol and VBL for the prevention of the first variceal bleed in a randomized, controlled multicenter trial.
They randomly assigned 152 cirrhosis patients (median age 54) from five different medical centers to receive either 12.5 milligrams of carvedilol once daily or VBL performed every two weeks using an endoscopic banding device until the serious (worse than grade 1) varices disappeared.
Of the patients in the study, 75% suffered from alcoholic cirrhosis and all had grade II or larger esophageal varices.
After randomization, the patients were followed for a median of 20 months. Among the patients who received carvedilol, 39 experienced side effects, most of which were minor and resolved with continued use.
However, 10 patients could not tolerate persistent side effects, including shortness of breath, impotence, nausea and vomiting, and symptomatic hypotension, and they discontinued the treatment. A total of 13 patients discontinued the banding treatment as well, often because they found the procedure uncomfortable.
Variceal bleeding occurred in eight patients (10%) in the carvedilol group and 17 patients (23%) in the banding group during the follow-up period. The researchers found no difference in overall mortality or bleeding-related mortality between the two treatments.
The researchers concluded that carvedilol was effective at preventing the first variceal bleed and is well tolerated but cautioned that difficulties in adherence to the banding protocol in their study may have effected the results.
"Further studies should aim to increase compliance with VBL protocols, with particular emphasis on variceal eradication," they wrote. "However, we believe that carvedilol can be considered a treatment option for primary prophylaxis of variceal bleeding."
The study was supported by the University of Edinburgh.
The researchers reported no financial conflicts of interest.
Primary source: Hepatology
Source reference:
Hayes P, et al "Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed" Hepatology 2009; DOI: 10.1002/hep.23045.
Anadys Moves Hepatitis C Drug Ahead on its Own
Anadys Moves Hepatitis C Drug Ahead on its Own
Bruce V. Bigelow 8/20/09
http://www.xconomy.com
It’s been relatively slow for San Diego life sciences news, except for a flurry of funding deals for local drug development companies. Get the scoop on who’s getting money, along with some biotech profiles and more.
—CEO Steve Worland of San Diego’s Anadys Pharmaceuticals(NASDAQ: ANDS) says the company has stabilized following some mercurial advances and declines in the price of its shares. Whether or not Wall Street has been overreacting to Anadys’ announcements concerning its experimental drug for treating hepatitis C, Worland has put his efforts to find a drug development partner on hold. Instead, he’s cut payroll and raised more than $16 million so the company can carry out the next stage of its drug development plan on its own.
Anadys, Biotech’s Roller Coaster Story, Gears Up for Next Big Step with Hepatitis C Drug
Luke Timmerman 8/19/09
If there were a prize for the whiplash-inducing roller coaster story of the year in San Diego biotech, Anadys Pharmaceuticals would have to be a contender. But if CEO Steve Worland has his way, some of that stomach-turning drama of the past eight months will soon just be a memory.
“You might say we’ve been stabilized, but I’m not sure we were really unstable before,” Worland says. “We’ve turned an important corner.”
Anadys got to this position, talking about stability, after it dropped bombshells on investors twice this year—once in a good way, and once not so good. The positive one came in January, when the company (NASDAQ: ANDS) shocked Wall Street by dribbling out data from the first eight patients with hepatitis C who got the lowest dose of its experimental drug, ANA598. The patients had 99 percent of their virus wiped out within the first 72 hours, which was a far better anti-viral punch than any other drug in its class. The stock, which had been on practically no one’s trading screen the day before, with just 68,000 shares changing hands, rocketed on the news from $1.91 to $4.10 on volume of more than six million shares.
This was just the beginning. The preliminary results were from the lowest of three doses studied in a clinical trial, and Anadys suggested the data would only look better a couple months later, at a key research meeting, the European Association for the Study of the Liver. Anticipation was in the air: Anadys engaged in talks with potential partners about the data. The hepatitis C space was hot. Cambridge, MA-based Vertex Pharmaceuticals built a legion of fans on Wall Street for its industry-leading drug, and then Vertex paid more than $375 million in March to acquire another hepatitis C drug developer at a similar stage of development as Anadys. Shortly after, Worland talked about how his company and others were changing the paradigm for treating hepatitis C, following the cocktail-drug approach pioneered by HIV treatments.
Then came the plunge. Anadys presented full results from the clinical trial, which showed that, as predicted, the company’s ANA598 product had even stronger anti-viral activity at higher doses. There were no serious side effects, no signs of patients developing drug resistance, or of the virus bouncing back.
Anadys CEO Steve Worland
Anadys CEO Steve Worland
What was the problem? A separate study of 24 healthy volunteers showed that three patients dropped out of the study because they had developed Grade 2 rashes, measured on a scale of one to four, with four being the most severe. The price of Anadys shares fell, even though hepatitis C patients on the drug had no severe rashes, other drugs in the class have the same side effect, and healthy volunteers essentially have no reason to stay in a study if they see any side effects at all. Such nuances were lost on the fast-money crowd. Anadys shares fell 40 percent that day, making it the biggest decliner on the Nasdaq, and shares kept falling. “People thought the rash was more severe than it was,” Worland says. “It was an extreme reaction.”
Regardless of which interpretation you prefer to believe, Anadys had to deal with the consequences. It wasn’t able to find a partner to help take ANA598 through the next phases of clinical development on its preferred terms, and cash began to run low. By June, Worland had to act, by shedding
an expensive office lease, cutting 40 percent of the staff, and swallowing hard, by selling new shares and warrants at bargain prices in order to collect net proceeds of $16.2 million. That was a tiny fraction of what he could have raised a few months earlier, when the stock hit its 52-week high of $8.43. The company was left with 29 employees.
Then, slowly, the roller coaster started climbing again for Anadys. The company announced on July 30, as part of its second-quarter financial report, its revamped game plan as a stand-alone company: It had agreed with the FDA on a clear next step for development of ANA598. If this trial goes according to plan, it will keep control of the drug during a critical value-building phase, and still have enough cash in the bank to run into 2011.
Even though agreeing to a clinical trial design with the FDA is usually a perfunctory event at most biotech companies, investors suddenly got excited. Volume skyrocketed again, and 25 million shares changed hands the following day as Anadys stock shot up 44 percent, from $1.80 to $2.60.
The market moved up this time because investors were impressed at the rigor of the trial design, which should give Anadys a clearer idea, in a short period of time, of ANA598’s prospects, Worland says. The trial will randomly assign patients to get ANA598 along with the standard two drugs, pegylated interferon alpha and ribavirin, or the two standard drugs alone. It will enroll 90 patients, and monitor their viral levels at weeks four and 12.
In the past, the FDA has asked companies at Anadys’ stage of the game to take more modest steps with a four-week trial, not a more in-depth 12-week study, Worland says. The long-term effectiveness is of key importance to partners. If it can stick to its timelines, Anadys could get the first signs of effectiveness from this trial by the end of the year, with more details to follow in the first half of 2010, Worland says.
“People asked ‘can you really do that? Is the FDA going to allow you to do that? The answer is yes. They encouraged it,” Worland says.
So where does this leave Anadys now? The company has put its partnership talks on “hiatus” because it has enough money in the bank to carry out the next phase of ANA598’s development. If the drug passes that test, Anadys should be able to command better terms from a potential partner or acquirer. (Worland said he discussed with partners the possibility of selling the company in the spring, but the feedback he got was that the company first needed to gather more data.)
Anadys still hasn’t enrolled the first patient in the mid-stage clinical trial, and it sounds like it is still getting its ducks in a row for the study, which will likely have 15 to 20 sites in the U.S., Worland says. The next really big news will be when Anadys has preliminary results on the anti-viral activity of its drug, which could come out by the end of this year.
“We’re in the driver’s seat now,” Worland says. “We’re well-positioned.”
Bruce V. Bigelow 8/20/09
http://www.xconomy.com
It’s been relatively slow for San Diego life sciences news, except for a flurry of funding deals for local drug development companies. Get the scoop on who’s getting money, along with some biotech profiles and more.
—CEO Steve Worland of San Diego’s Anadys Pharmaceuticals(NASDAQ: ANDS) says the company has stabilized following some mercurial advances and declines in the price of its shares. Whether or not Wall Street has been overreacting to Anadys’ announcements concerning its experimental drug for treating hepatitis C, Worland has put his efforts to find a drug development partner on hold. Instead, he’s cut payroll and raised more than $16 million so the company can carry out the next stage of its drug development plan on its own.
Anadys, Biotech’s Roller Coaster Story, Gears Up for Next Big Step with Hepatitis C Drug
Luke Timmerman 8/19/09
If there were a prize for the whiplash-inducing roller coaster story of the year in San Diego biotech, Anadys Pharmaceuticals would have to be a contender. But if CEO Steve Worland has his way, some of that stomach-turning drama of the past eight months will soon just be a memory.
“You might say we’ve been stabilized, but I’m not sure we were really unstable before,” Worland says. “We’ve turned an important corner.”
Anadys got to this position, talking about stability, after it dropped bombshells on investors twice this year—once in a good way, and once not so good. The positive one came in January, when the company (NASDAQ: ANDS) shocked Wall Street by dribbling out data from the first eight patients with hepatitis C who got the lowest dose of its experimental drug, ANA598. The patients had 99 percent of their virus wiped out within the first 72 hours, which was a far better anti-viral punch than any other drug in its class. The stock, which had been on practically no one’s trading screen the day before, with just 68,000 shares changing hands, rocketed on the news from $1.91 to $4.10 on volume of more than six million shares.
This was just the beginning. The preliminary results were from the lowest of three doses studied in a clinical trial, and Anadys suggested the data would only look better a couple months later, at a key research meeting, the European Association for the Study of the Liver. Anticipation was in the air: Anadys engaged in talks with potential partners about the data. The hepatitis C space was hot. Cambridge, MA-based Vertex Pharmaceuticals built a legion of fans on Wall Street for its industry-leading drug, and then Vertex paid more than $375 million in March to acquire another hepatitis C drug developer at a similar stage of development as Anadys. Shortly after, Worland talked about how his company and others were changing the paradigm for treating hepatitis C, following the cocktail-drug approach pioneered by HIV treatments.
Then came the plunge. Anadys presented full results from the clinical trial, which showed that, as predicted, the company’s ANA598 product had even stronger anti-viral activity at higher doses. There were no serious side effects, no signs of patients developing drug resistance, or of the virus bouncing back.
Anadys CEO Steve Worland
Anadys CEO Steve Worland
What was the problem? A separate study of 24 healthy volunteers showed that three patients dropped out of the study because they had developed Grade 2 rashes, measured on a scale of one to four, with four being the most severe. The price of Anadys shares fell, even though hepatitis C patients on the drug had no severe rashes, other drugs in the class have the same side effect, and healthy volunteers essentially have no reason to stay in a study if they see any side effects at all. Such nuances were lost on the fast-money crowd. Anadys shares fell 40 percent that day, making it the biggest decliner on the Nasdaq, and shares kept falling. “People thought the rash was more severe than it was,” Worland says. “It was an extreme reaction.”
Regardless of which interpretation you prefer to believe, Anadys had to deal with the consequences. It wasn’t able to find a partner to help take ANA598 through the next phases of clinical development on its preferred terms, and cash began to run low. By June, Worland had to act, by shedding
an expensive office lease, cutting 40 percent of the staff, and swallowing hard, by selling new shares and warrants at bargain prices in order to collect net proceeds of $16.2 million. That was a tiny fraction of what he could have raised a few months earlier, when the stock hit its 52-week high of $8.43. The company was left with 29 employees.
Then, slowly, the roller coaster started climbing again for Anadys. The company announced on July 30, as part of its second-quarter financial report, its revamped game plan as a stand-alone company: It had agreed with the FDA on a clear next step for development of ANA598. If this trial goes according to plan, it will keep control of the drug during a critical value-building phase, and still have enough cash in the bank to run into 2011.
Even though agreeing to a clinical trial design with the FDA is usually a perfunctory event at most biotech companies, investors suddenly got excited. Volume skyrocketed again, and 25 million shares changed hands the following day as Anadys stock shot up 44 percent, from $1.80 to $2.60.
The market moved up this time because investors were impressed at the rigor of the trial design, which should give Anadys a clearer idea, in a short period of time, of ANA598’s prospects, Worland says. The trial will randomly assign patients to get ANA598 along with the standard two drugs, pegylated interferon alpha and ribavirin, or the two standard drugs alone. It will enroll 90 patients, and monitor their viral levels at weeks four and 12.
In the past, the FDA has asked companies at Anadys’ stage of the game to take more modest steps with a four-week trial, not a more in-depth 12-week study, Worland says. The long-term effectiveness is of key importance to partners. If it can stick to its timelines, Anadys could get the first signs of effectiveness from this trial by the end of the year, with more details to follow in the first half of 2010, Worland says.
“People asked ‘can you really do that? Is the FDA going to allow you to do that? The answer is yes. They encouraged it,” Worland says.
So where does this leave Anadys now? The company has put its partnership talks on “hiatus” because it has enough money in the bank to carry out the next phase of ANA598’s development. If the drug passes that test, Anadys should be able to command better terms from a potential partner or acquirer. (Worland said he discussed with partners the possibility of selling the company in the spring, but the feedback he got was that the company first needed to gather more data.)
Anadys still hasn’t enrolled the first patient in the mid-stage clinical trial, and it sounds like it is still getting its ducks in a row for the study, which will likely have 15 to 20 sites in the U.S., Worland says. The next really big news will be when Anadys has preliminary results on the anti-viral activity of its drug, which could come out by the end of this year.
“We’re in the driver’s seat now,” Worland says. “We’re well-positioned.”
Roche, InterMune Commence Mid-Stage Trial Of Hepatitis C Drug
Roche, InterMune Commence Mid-Stage Trial Of Hepatitis C Drug
8/19/2009 7:37 PM ET
(RTTNews) - Swiss drug giant Roche Holding AG (RHHBY.PK: News , RHHVF.PK) and InterMune Inc. (ITMN: News ) Wednesday announced the start of a mid-stage trial to evaluate hepatitis C virus protease inhibitor, RG7227/ ITMN-191, in combination with Pegasys and Copegus.
The study is to be conducted at 45 sites globally, and will enroll about 300 patients. The study will further define the safety and efficacy profile of RG7227/ITMN-191 for a treatment duration of up to 24 weeks.
RG7227/ITMN-191 is being developed in partnership by Roche and InterMune. With the initiation of the phase 2b trial, InterMune will receive a $20 million event payment from Roche under a collaboration agreement.
The objective of the Phase 2b randomized, double-blind, placebo-controlled study is to further characterize the safety, tolerability, and antiviral effects of RG7227/ITMN-191 in triple combination, compared with standard of care, PEGASYS plus COPEGUS.
Roche and InterMune also plan to initiate a phase 1 trial combining RG7227/ITMN-191 with low dose ritonavir to examine the virologic effect of ritonavir-boosted RG7227/ITMN-191 in once-daily and twice-daily regimens in combination with standard dosing of PEGASYS and COPEGUS in patients chronically infected with HCV genotype 1.
RG7227/ITMN-191 is also being investigated in combination with the NS5B polymerase inhibitor RG7128 in the INFORM-1 study.
ITMN closed Wednesday's regular trading session at $14.49, up 58 cents or 4.17%. However, in the after-hours, the share lost 58 cents or 4.00%.
Roche and InterMune Initiate Phase 2b Clinical Trial of RG7227/ ITMN-191 in Patients With Chronic Hepatitis C
- Study will further define the safety and efficacy profile -, - Parallel Phase 1 trial will assess ritonavir-boosted dosing -, - INFORM-1 study with polymerase inhibitor RG7128 ongoing -
BASEL, Switzerland and BRISBANE, Calif., Aug. 19 /PRNewswire-FirstCall/ -- Roche and InterMune, Inc. today announced that the first patient has been dosed in a Phase 2b study evaluating the hepatitis C virus (HCV) protease inhibitor, RG7227/ ITMN-191, in combination with PEGASYS(R) (pegylated interferon alfa-2a) and COPEGUS(R) (ribavirin). The study, to be conducted at 45 sites globally, will further define the safety and efficacy profile of RG7227/ ITMN-191, for a treatment duration of up to 24 weeks. Approximately 300 treatment-naive patients chronically infected with HCV genotype 1 - the most difficult to treat form of the virus - will participate.
RG7227/ ITMN-191 is being developed in partnership by Roche and InterMune. Initiation of the Phase 2b trial triggered a $20 million event payment from Roche to InterMune under the companies' collaboration agreement.
Frank Duff, M.D., Head of Roche's Clinical Development for Virology, said, "This trial represents an important step forward in the development of this oral direct-acting antiviral (DAA), and builds on the encouraging clinical safety and efficacy data generated to date."
Dan Welch, Chairman, Chief Executive Officer and President of InterMune, said, "We are very pleased to announce with our colleagues, Roche, the start of the global Phase 2b program of RG7227/ ITMN-191 in treatment-naive HCV patients. This study will significantly expand the clinical efficacy and safety database for RG7227/ ITMN-191, and in the first quarter of next year provide our first look at the rapid virologic response (RVR) rates associated with this triple therapy."
Phase 2b Triple Combination Trial Design
The objective of the Phase 2b randomized, double-blind, placebo-controlled study is to further characterize the safety, tolerability, and antiviral effects of RG7227/ ITMN-191 in triple combination, compared with standard of care (PEGASYS plus COPEGUS).
The two-part study will evaluate treatment regimens of both 12 and 24 weeks. In Part 1 of the study, approximately 210 patients will be randomized to one of four study arms - three of which will receive a 12-week regimen of RG7227/ ITMN-191 at either 300 mg every 8 hours, 600 mg every 12 hours or 900 mg every 12 hours, in combination with PEGASYS and COPEGUS, followed by 12 weeks of therapy with PEGASYS and COPEGUS.* The fourth group will be a control arm receiving PEGASYS and COPEGUS dosed for 48 weeks.
Part 2 of the study, which is expected to begin in the first quarter of 2010, will further evaluate RG7227/ ITMN-191 in a 24-week triple combination regimen with PEGASYS and COPEGUS. Approximately 90 patients will be randomized to one of two study arms in Part 2, either a 24-week regimen of RG7227/ ITMN-191 in combination with PEGASYS and COPEGUS, or a control arm of PEGASYS and COPEGUS dosed for 48 weeks.** Dose selection for Part 2 will be informed by week 4 results generated in Part 1.
RVR results from Part 1 of the study are expected in the first quarter of 2010.
RG7227/ ITMN-191 - Next Steps in Development Program
Roche and InterMune will also initiate in the third quarter a Phase 1 trial combining RG7227/ ITMN-191 with low dose ritonavir to examine the virologic effect of ritonavir-boosted RG7227/ ITMN-191 in once-daily and twice-daily regimens in combination with standard dosing of PEGASYS and COPEGUS in patients chronically infected with HCV genotype 1.
This study builds on promising drug-drug interaction data recently generated in healthy volunteers; a low dose of ritonavir significantly improved RG7227/ ITMN-191 AUC and plasma concentrations at later times. There were no remarkable safety findings.
The Phase 1 study will evaluate the safety, tolerability, pharmacokinetics and antiviral activity of once-daily and twice-daily ritonavir-boosted RG7227/ ITMN-191 regimens administered with PEGASYS and ribavirin for 14 days.
Dr. Duff commented, "Combining RG7227/ ITMN-191 with low dose ritonavir has the potential to deliver additional benefits to patients, including the requirement for less frequent dosing and fewer tablets per day. Data generated from this Phase 1 trial may pave the way for larger studies investigating this treatment combination."
RG7227/ ITMN-191 is also being investigated in combination with the NS5B polymerase inhibitor RG7128 in the INFORM-1 study. This innovative study has recently been expanded to examine regimens in which both RG7227/ ITMN-191 and RG7128 are dosed twice daily in treatment-experienced patients. Results from all cohorts of this study will be presented in an oral presentation in Presidential Plenary Session III on the morning of November 3 at the 2009 AASLD meeting. Additional abstracts regarding pharmacokinetic/pharmacodynamics and resistance have been accepted for poster presentation.
Notes to Editors
* Patients who achieve RVR, defined as undetectable viral levels (less than 15 IU/mL) by the end of week 4, will stop all treatment at week 24 and will be followed post treatment to evaluate whether they achieve SVR. Patients in the treatment arms who do not achieve RVR will continue with PEGASYS and COPEGUS treatment for a total duration of 48 weeks.
** As in Part 1, patients who achieve RVR by the end of week 4 will stop all treatment at week 24 and will be followed post treatment to evaluate whether they achieve SVR. Patients who do not achieve RVR will continue with PEGASYS and COPEGUS treatment for a total of 48 weeks.
About RG7227/ ITMN-191
RG7227/ ITMN-191 is a potent, macrocyclic inhibitor of HCV NS3/4A protease activity, and has produced multi-log10 reductions in HCV levels in chronic HCV patients, when administered for 14 days as monotherapy. When RG7227/ ITMN-191 is combined with PEGASYS and COPEGUS, or the NS5B polymerase inhibitor RG7128, it reduced viral loads below the limit of detection in a majority of study-treated patients. RG7227/ ITMN-191 was safe and well tolerated in these studies.
About PEGASYS
PEGASYS, in combination with COPEGUS (ribavirin), is indicated for the treatment of adults with chronic HCV who have compensated liver disease and have not previously been treated with interferon alpha. Efficacy has been demonstrated in patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that are clinically stable (e.g., antiretroviral therapy not required or receiving stable antiretroviral therapy). In addition, PEGASYS in combination with COPEGUS is the first and only FDA-approved regimen for the treatment of chronic HCV in patients coinfected with HCV and HIV. PEGASYS is the only pegylated interferon indicated for the treatment of adult patients with chronic hepatitis B (HBeAg positive and HBeAg negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and liver inflammation).
PEGASYS is dosed at 180mcg as a subcutaneous injection taken once a week. COPEGUS is available as a 200mg tablet, and is administered orally two times a day as a split dose. Roche has backed PEGASYS with the most extensive clinical research program ever undertaken in HCV, with major studies initiated to advance treatment for HCV patients with unmet needs, including patients co-infected with HIV and HCV, African Americans, patients with cirrhosis, and patients who have failed to respond to previous therapy.
Important Safety Information About PEGASYS
PEGASYS, alone or in combination with COPEGUS, is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A).
Alpha interferons, including PEGASYS, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
Use with Ribavirin. Ribavirin, including COPEGUS, may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
PEGASYS is contraindicated in patients with hypersensitivity to PEGASYS or any of its components, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment. PEGASYS is also contraindicated in hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before or during treatment. PEGASYS is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal. PEGASYS and COPEGUS therapy is additionally contraindicated in patients with a hypersensitivity to COPEGUS or any of its components, in women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).
COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. If pregnancy should occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. Healthcare providers and patients are strongly encouraged to immediately report any pregnancy in a patient or partner of a patient during treatment or during 6 months after treatment cessation to the Ribavirin Pregnancy Registry at 1-800-593-2214.
Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. During treatment, patients' clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score greater than or equal to 6) is observed. Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including PEGASYS. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and causal relationship between interferon alfa-based therapies and these events is difficult to establish.
The most common adverse events reported for PEGASYS and COPEGUS combination therapy observed in clinical trials were fatigue/asthenia (65 percent), headache (43 percent), pyrexia (41 percent), myalgia (40 percent), irritability/anxiety/nervousness (33 percent), insomnia (30 percent), alopecia (28 percent), neutropenia (27 percent), nausea/vomiting (25 percent), rigors (25 percent), anorexia (24 percent), injection site reaction (23 percent), arthralgia (22 percent), depression (20 percent), pruritus (19 percent) and dermatitis (16 percent).
Serious adverse events in hepatitis C trials included neuropsychiatric disorders (homicidal ideation, suicidal ideation, suicide attempt, suicide, psychotic disorder and hallucinations), serious and severe bacterial infections (sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, supraventricular arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, psoriasis, lupus, rheumatoid arthritis and interstitial nephritis), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemic colitis), pancreatitis, and ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema).
Adverse reactions reported during post-approval use of PEGASYS therapy, with and without ribavirin, include hearing impairment, hearing loss, serious skin reactions, including erythema multiforme major, and infections (bacterial, viral and fungal).
Full prescribing information is available at www.rocheusa.com.
About Roche
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche's personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2008, Roche had over 80,000 employees worldwide and invested almost 9 billion Swiss francs in R&D. The Group posted sales of 45.6 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.
About InterMune
InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and hepatology. InterMune has a pipeline portfolio addressing idiopathic pulmonary fibrosis (IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio includes the completed Phase 3 CAPACITY program, now in pre-registration, which evaluated pirfenidone for the treatment of patients with IPF; RECAP, an open-label extension study from CAPACITY and a research program focused on small molecules for the treatment of pulmonary disease. The hepatology portfolio includes the HCV protease inhibitor compound RG7227/ ITMN-191 in Phase 2b, a second-generation HCV protease inhibitor research program, and a research program evaluating new targets in hepatology. For additional information about InterMune and its R&D pipeline, please visit www.intermune.com.
Forward-Looking Statements
This news release contains forward-looking statements within the meaning of section 21E of the Securities Exchange Act of 1934, as amended, that reflect InterMune's judgment and involve risks and uncertainties as of the date of this release, including without limitation the statements related to anticipated product development timelines. All forward-looking statements and other information included in this press release are based on information available to InterMune as of the date hereof, and InterMune assumes no obligation to update any such forward-looking statements or information. InterMune's actual results could differ materially from those described in InterMune's forward-looking statements.
Factors that could cause or contribute to such differences include, but are not limited to, those discussed in detail under the heading "Risk Factors" in InterMune's most recent annual report on Form 10-K filed with the SEC on March 16, 2009 (the "Form 10-K") and other periodic reports filed with the SEC, including the following: (i) risks related to the long, expensive and uncertain clinical development and regulatory process, including having no unexpected safety, toxicology, clinical or other issues or delays in anticipated timing of the regulatory approval process; (ii) risks related to failure to achieve the clinical trial results required to commercialize our product candidates; and (iii) risks related to timely patient enrollment and retention in clinical trials. The risks and other factors discussed above should be considered only in connection with the fully discussed risks and other factors discussed in detail in the Form 10-K and InterMune's other periodic reports filed with the SEC, all of which are available via InterMune's web site at www.intermune.com.
All trademarks used or mentioned in this release are protected by law.
SOURCE InterMune, Inc.
8/19/2009 7:37 PM ET
(RTTNews) - Swiss drug giant Roche Holding AG (RHHBY.PK: News , RHHVF.PK) and InterMune Inc. (ITMN: News ) Wednesday announced the start of a mid-stage trial to evaluate hepatitis C virus protease inhibitor, RG7227/ ITMN-191, in combination with Pegasys and Copegus.
The study is to be conducted at 45 sites globally, and will enroll about 300 patients. The study will further define the safety and efficacy profile of RG7227/ITMN-191 for a treatment duration of up to 24 weeks.
RG7227/ITMN-191 is being developed in partnership by Roche and InterMune. With the initiation of the phase 2b trial, InterMune will receive a $20 million event payment from Roche under a collaboration agreement.
The objective of the Phase 2b randomized, double-blind, placebo-controlled study is to further characterize the safety, tolerability, and antiviral effects of RG7227/ITMN-191 in triple combination, compared with standard of care, PEGASYS plus COPEGUS.
Roche and InterMune also plan to initiate a phase 1 trial combining RG7227/ITMN-191 with low dose ritonavir to examine the virologic effect of ritonavir-boosted RG7227/ITMN-191 in once-daily and twice-daily regimens in combination with standard dosing of PEGASYS and COPEGUS in patients chronically infected with HCV genotype 1.
RG7227/ITMN-191 is also being investigated in combination with the NS5B polymerase inhibitor RG7128 in the INFORM-1 study.
ITMN closed Wednesday's regular trading session at $14.49, up 58 cents or 4.17%. However, in the after-hours, the share lost 58 cents or 4.00%.
Roche and InterMune Initiate Phase 2b Clinical Trial of RG7227/ ITMN-191 in Patients With Chronic Hepatitis C
- Study will further define the safety and efficacy profile -, - Parallel Phase 1 trial will assess ritonavir-boosted dosing -, - INFORM-1 study with polymerase inhibitor RG7128 ongoing -
BASEL, Switzerland and BRISBANE, Calif., Aug. 19 /PRNewswire-FirstCall/ -- Roche and InterMune, Inc. today announced that the first patient has been dosed in a Phase 2b study evaluating the hepatitis C virus (HCV) protease inhibitor, RG7227/ ITMN-191, in combination with PEGASYS(R) (pegylated interferon alfa-2a) and COPEGUS(R) (ribavirin). The study, to be conducted at 45 sites globally, will further define the safety and efficacy profile of RG7227/ ITMN-191, for a treatment duration of up to 24 weeks. Approximately 300 treatment-naive patients chronically infected with HCV genotype 1 - the most difficult to treat form of the virus - will participate.
RG7227/ ITMN-191 is being developed in partnership by Roche and InterMune. Initiation of the Phase 2b trial triggered a $20 million event payment from Roche to InterMune under the companies' collaboration agreement.
Frank Duff, M.D., Head of Roche's Clinical Development for Virology, said, "This trial represents an important step forward in the development of this oral direct-acting antiviral (DAA), and builds on the encouraging clinical safety and efficacy data generated to date."
Dan Welch, Chairman, Chief Executive Officer and President of InterMune, said, "We are very pleased to announce with our colleagues, Roche, the start of the global Phase 2b program of RG7227/ ITMN-191 in treatment-naive HCV patients. This study will significantly expand the clinical efficacy and safety database for RG7227/ ITMN-191, and in the first quarter of next year provide our first look at the rapid virologic response (RVR) rates associated with this triple therapy."
Phase 2b Triple Combination Trial Design
The objective of the Phase 2b randomized, double-blind, placebo-controlled study is to further characterize the safety, tolerability, and antiviral effects of RG7227/ ITMN-191 in triple combination, compared with standard of care (PEGASYS plus COPEGUS).
The two-part study will evaluate treatment regimens of both 12 and 24 weeks. In Part 1 of the study, approximately 210 patients will be randomized to one of four study arms - three of which will receive a 12-week regimen of RG7227/ ITMN-191 at either 300 mg every 8 hours, 600 mg every 12 hours or 900 mg every 12 hours, in combination with PEGASYS and COPEGUS, followed by 12 weeks of therapy with PEGASYS and COPEGUS.* The fourth group will be a control arm receiving PEGASYS and COPEGUS dosed for 48 weeks.
Part 2 of the study, which is expected to begin in the first quarter of 2010, will further evaluate RG7227/ ITMN-191 in a 24-week triple combination regimen with PEGASYS and COPEGUS. Approximately 90 patients will be randomized to one of two study arms in Part 2, either a 24-week regimen of RG7227/ ITMN-191 in combination with PEGASYS and COPEGUS, or a control arm of PEGASYS and COPEGUS dosed for 48 weeks.** Dose selection for Part 2 will be informed by week 4 results generated in Part 1.
RVR results from Part 1 of the study are expected in the first quarter of 2010.
RG7227/ ITMN-191 - Next Steps in Development Program
Roche and InterMune will also initiate in the third quarter a Phase 1 trial combining RG7227/ ITMN-191 with low dose ritonavir to examine the virologic effect of ritonavir-boosted RG7227/ ITMN-191 in once-daily and twice-daily regimens in combination with standard dosing of PEGASYS and COPEGUS in patients chronically infected with HCV genotype 1.
This study builds on promising drug-drug interaction data recently generated in healthy volunteers; a low dose of ritonavir significantly improved RG7227/ ITMN-191 AUC and plasma concentrations at later times. There were no remarkable safety findings.
The Phase 1 study will evaluate the safety, tolerability, pharmacokinetics and antiviral activity of once-daily and twice-daily ritonavir-boosted RG7227/ ITMN-191 regimens administered with PEGASYS and ribavirin for 14 days.
Dr. Duff commented, "Combining RG7227/ ITMN-191 with low dose ritonavir has the potential to deliver additional benefits to patients, including the requirement for less frequent dosing and fewer tablets per day. Data generated from this Phase 1 trial may pave the way for larger studies investigating this treatment combination."
RG7227/ ITMN-191 is also being investigated in combination with the NS5B polymerase inhibitor RG7128 in the INFORM-1 study. This innovative study has recently been expanded to examine regimens in which both RG7227/ ITMN-191 and RG7128 are dosed twice daily in treatment-experienced patients. Results from all cohorts of this study will be presented in an oral presentation in Presidential Plenary Session III on the morning of November 3 at the 2009 AASLD meeting. Additional abstracts regarding pharmacokinetic/pharmacodynamics and resistance have been accepted for poster presentation.
Notes to Editors
* Patients who achieve RVR, defined as undetectable viral levels (less than 15 IU/mL) by the end of week 4, will stop all treatment at week 24 and will be followed post treatment to evaluate whether they achieve SVR. Patients in the treatment arms who do not achieve RVR will continue with PEGASYS and COPEGUS treatment for a total duration of 48 weeks.
** As in Part 1, patients who achieve RVR by the end of week 4 will stop all treatment at week 24 and will be followed post treatment to evaluate whether they achieve SVR. Patients who do not achieve RVR will continue with PEGASYS and COPEGUS treatment for a total of 48 weeks.
About RG7227/ ITMN-191
RG7227/ ITMN-191 is a potent, macrocyclic inhibitor of HCV NS3/4A protease activity, and has produced multi-log10 reductions in HCV levels in chronic HCV patients, when administered for 14 days as monotherapy. When RG7227/ ITMN-191 is combined with PEGASYS and COPEGUS, or the NS5B polymerase inhibitor RG7128, it reduced viral loads below the limit of detection in a majority of study-treated patients. RG7227/ ITMN-191 was safe and well tolerated in these studies.
About PEGASYS
PEGASYS, in combination with COPEGUS (ribavirin), is indicated for the treatment of adults with chronic HCV who have compensated liver disease and have not previously been treated with interferon alpha. Efficacy has been demonstrated in patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that are clinically stable (e.g., antiretroviral therapy not required or receiving stable antiretroviral therapy). In addition, PEGASYS in combination with COPEGUS is the first and only FDA-approved regimen for the treatment of chronic HCV in patients coinfected with HCV and HIV. PEGASYS is the only pegylated interferon indicated for the treatment of adult patients with chronic hepatitis B (HBeAg positive and HBeAg negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and liver inflammation).
PEGASYS is dosed at 180mcg as a subcutaneous injection taken once a week. COPEGUS is available as a 200mg tablet, and is administered orally two times a day as a split dose. Roche has backed PEGASYS with the most extensive clinical research program ever undertaken in HCV, with major studies initiated to advance treatment for HCV patients with unmet needs, including patients co-infected with HIV and HCV, African Americans, patients with cirrhosis, and patients who have failed to respond to previous therapy.
Important Safety Information About PEGASYS
PEGASYS, alone or in combination with COPEGUS, is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A).
Alpha interferons, including PEGASYS, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
Use with Ribavirin. Ribavirin, including COPEGUS, may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
PEGASYS is contraindicated in patients with hypersensitivity to PEGASYS or any of its components, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment. PEGASYS is also contraindicated in hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before or during treatment. PEGASYS is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal. PEGASYS and COPEGUS therapy is additionally contraindicated in patients with a hypersensitivity to COPEGUS or any of its components, in women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).
COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. If pregnancy should occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. Healthcare providers and patients are strongly encouraged to immediately report any pregnancy in a patient or partner of a patient during treatment or during 6 months after treatment cessation to the Ribavirin Pregnancy Registry at 1-800-593-2214.
Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. During treatment, patients' clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score greater than or equal to 6) is observed. Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including PEGASYS. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and causal relationship between interferon alfa-based therapies and these events is difficult to establish.
The most common adverse events reported for PEGASYS and COPEGUS combination therapy observed in clinical trials were fatigue/asthenia (65 percent), headache (43 percent), pyrexia (41 percent), myalgia (40 percent), irritability/anxiety/nervousness (33 percent), insomnia (30 percent), alopecia (28 percent), neutropenia (27 percent), nausea/vomiting (25 percent), rigors (25 percent), anorexia (24 percent), injection site reaction (23 percent), arthralgia (22 percent), depression (20 percent), pruritus (19 percent) and dermatitis (16 percent).
Serious adverse events in hepatitis C trials included neuropsychiatric disorders (homicidal ideation, suicidal ideation, suicide attempt, suicide, psychotic disorder and hallucinations), serious and severe bacterial infections (sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, supraventricular arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, psoriasis, lupus, rheumatoid arthritis and interstitial nephritis), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemic colitis), pancreatitis, and ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema).
Adverse reactions reported during post-approval use of PEGASYS therapy, with and without ribavirin, include hearing impairment, hearing loss, serious skin reactions, including erythema multiforme major, and infections (bacterial, viral and fungal).
Full prescribing information is available at www.rocheusa.com.
About Roche
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche's personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2008, Roche had over 80,000 employees worldwide and invested almost 9 billion Swiss francs in R&D. The Group posted sales of 45.6 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.
About InterMune
InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and hepatology. InterMune has a pipeline portfolio addressing idiopathic pulmonary fibrosis (IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio includes the completed Phase 3 CAPACITY program, now in pre-registration, which evaluated pirfenidone for the treatment of patients with IPF; RECAP, an open-label extension study from CAPACITY and a research program focused on small molecules for the treatment of pulmonary disease. The hepatology portfolio includes the HCV protease inhibitor compound RG7227/ ITMN-191 in Phase 2b, a second-generation HCV protease inhibitor research program, and a research program evaluating new targets in hepatology. For additional information about InterMune and its R&D pipeline, please visit www.intermune.com.
Forward-Looking Statements
This news release contains forward-looking statements within the meaning of section 21E of the Securities Exchange Act of 1934, as amended, that reflect InterMune's judgment and involve risks and uncertainties as of the date of this release, including without limitation the statements related to anticipated product development timelines. All forward-looking statements and other information included in this press release are based on information available to InterMune as of the date hereof, and InterMune assumes no obligation to update any such forward-looking statements or information. InterMune's actual results could differ materially from those described in InterMune's forward-looking statements.
Factors that could cause or contribute to such differences include, but are not limited to, those discussed in detail under the heading "Risk Factors" in InterMune's most recent annual report on Form 10-K filed with the SEC on March 16, 2009 (the "Form 10-K") and other periodic reports filed with the SEC, including the following: (i) risks related to the long, expensive and uncertain clinical development and regulatory process, including having no unexpected safety, toxicology, clinical or other issues or delays in anticipated timing of the regulatory approval process; (ii) risks related to failure to achieve the clinical trial results required to commercialize our product candidates; and (iii) risks related to timely patient enrollment and retention in clinical trials. The risks and other factors discussed above should be considered only in connection with the fully discussed risks and other factors discussed in detail in the Form 10-K and InterMune's other periodic reports filed with the SEC, all of which are available via InterMune's web site at www.intermune.com.
All trademarks used or mentioned in this release are protected by law.
SOURCE InterMune, Inc.
Gene Variant Predicts HCV Treatment Success
Gene Variant Predicts HCV Treatment Success
By Michael Smith, North American Correspondent, MedPage Today
Published: August 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
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 to treatment for genotype 1 hepatitis C, according to David Goldstein, PhD, of Duke University, and colleagues.
The alteration is also more common among people of European ancestry than those of African background, which may explain much of the difference in treatment response between the two ethnic groups, Goldstein and colleagues wrote online in Nature.
"This is what personalized medicine is all about," Goldstein said in a statement. "This discovery enables us to give patients valuable information that will help them and their doctors decide what is best for them."
Action Points
* Explain to interested patients that treatment for hepatitis C is not uniformly successful.
* Note that this study found a small genetic variation that explains much of the difference in treatment success rates, which may allow for better prognostic assessments.
The finding comes from a genome-wide association study of more than 1,600 patients involved in the so-called IDEAL trial, which compared three treatment regimens for the disease. (See Head-to-Head Trial Finds HCV Regimens Equal)
Across all ethnic groups, the polymorphism was significantly associated (at P=1.37x10-28) with sustained virological response (SVR), defined as the absence of detectable virus at the end of follow-up.
In patients of European ancestry who carry two copies of the C variant, the genotype was associated with a twofold greater rate of SVR than the TT genotype.
The ratios were similar in both the African-American and the Hispanic populations in the study – threefold and twofold, respectively, the researchers said.
Interestingly, African-Americans with two copies of the C allele had a 53.3% SVR rate, significantly higher (at P<0.05) than the 33.3% seen in Europeans with two copies of the T allele.
That finding, Goldstein and colleagues said, "emphasizes the greater importance of individual genotype compared with ethnicity in predicting treatment response."
In a random, multi-ethnic sample, whose hepatitis C status was not known, the C allele appeared in about 40% of African-Americans, compared with between 70% and 80% for European-Americans and Hispanics, Goldstein and colleagues said.
East Asians, who are known to have even better SVR rates than Europeans, had the C allele more than 90% of the time, the researchers found.
The researchers said they were struck by the finding that the CC genotype was beneficial to all subgroups, Goldstein said.
"But because it appears significantly more often among Caucasian populations than it does among African populations, we feel it explains much of the difference in response rates we see between African-Americans and those of European ancestry," he said.
He and colleagues cautioned that the finding only applies to genotype 1 hepatitis C, which is the most common form. They said more research is needed to see if it applies to less common forms of the disease.
The study was supported by the Schering-Plough Research Institute.
Goldstein reported financial links with Schering-Plough, and several authors are employees of the company.
Goldstein and other authors are inventors of a patent application based on this finding.
Primary source: Nature
Source reference:
Ge D, et al "Genetic variation in IL28B predicts hepatitis C
treatment-induced viral clearance" Nature 2009; DOI: 10.1038/nature08309.
By Michael Smith, North American Correspondent, MedPage Today
Published: August 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
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 to treatment for genotype 1 hepatitis C, according to David Goldstein, PhD, of Duke University, and colleagues.
The alteration is also more common among people of European ancestry than those of African background, which may explain much of the difference in treatment response between the two ethnic groups, Goldstein and colleagues wrote online in Nature.
"This is what personalized medicine is all about," Goldstein said in a statement. "This discovery enables us to give patients valuable information that will help them and their doctors decide what is best for them."
Action Points
* Explain to interested patients that treatment for hepatitis C is not uniformly successful.
* Note that this study found a small genetic variation that explains much of the difference in treatment success rates, which may allow for better prognostic assessments.
The finding comes from a genome-wide association study of more than 1,600 patients involved in the so-called IDEAL trial, which compared three treatment regimens for the disease. (See Head-to-Head Trial Finds HCV Regimens Equal)
Across all ethnic groups, the polymorphism was significantly associated (at P=1.37x10-28) with sustained virological response (SVR), defined as the absence of detectable virus at the end of follow-up.
In patients of European ancestry who carry two copies of the C variant, the genotype was associated with a twofold greater rate of SVR than the TT genotype.
The ratios were similar in both the African-American and the Hispanic populations in the study – threefold and twofold, respectively, the researchers said.
Interestingly, African-Americans with two copies of the C allele had a 53.3% SVR rate, significantly higher (at P<0.05) than the 33.3% seen in Europeans with two copies of the T allele.
That finding, Goldstein and colleagues said, "emphasizes the greater importance of individual genotype compared with ethnicity in predicting treatment response."
In a random, multi-ethnic sample, whose hepatitis C status was not known, the C allele appeared in about 40% of African-Americans, compared with between 70% and 80% for European-Americans and Hispanics, Goldstein and colleagues said.
East Asians, who are known to have even better SVR rates than Europeans, had the C allele more than 90% of the time, the researchers found.
The researchers said they were struck by the finding that the CC genotype was beneficial to all subgroups, Goldstein said.
"But because it appears significantly more often among Caucasian populations than it does among African populations, we feel it explains much of the difference in response rates we see between African-Americans and those of European ancestry," he said.
He and colleagues cautioned that the finding only applies to genotype 1 hepatitis C, which is the most common form. They said more research is needed to see if it applies to less common forms of the disease.
The study was supported by the Schering-Plough Research Institute.
Goldstein reported financial links with Schering-Plough, and several authors are employees of the company.
Goldstein and other authors are inventors of a patent application based on this finding.
Primary source: Nature
Source reference:
Ge D, et al "Genetic variation in IL28B predicts hepatitis C
treatment-induced viral clearance" Nature 2009; DOI: 10.1038/nature08309.
Tuesday, August 18, 2009
ANA773 HCV Toll-Receptor Reduced Viral Load
ANA773 HCV Toll-Receptor Reduced Viral Load, oral inducer of endogenous interferons that acts via the toll like receptor 7 (TLR7) pathway, 10-day monotherapy study
Proof of Concept Achieved for Second Anadys HCV Product Candidate SAN DIEGO, Aug. 11SAN DIEGO, Aug. 11 /PRNewswire-FirstCall/ -- Anadys Pharmaceuticals, Inc. (Nasdaq: ANDS) today announced viral load data for the final cohort of hepatitis C patients in a Phase I clinical trial of ANA773, the Company's oral inducer of endogenous interferons that acts via the toll-like receptor 7 (TLR7) pathway. In patients who received 2000 mg ANA773 every other day over 10 days, the mean (+/-SEM) maximal decline in viral load was 1.3 (+/-0.4) log10, compared to a mean maximal decline of 0.3 (+/-0.1) log10 in patients who received placebo (p=0.037). Five of the eight patients who received 2000 mg ANA773 experienced a maximal decline of greater than 1 log, while none of the eight patients who received placebo experienced a decline of greater than 1 log (p<0.001 for the proportion of patients with maximal response greater than 1 log compared to placebo). The mean end-of-treatment decline was 0.6 log10 in patients who received 2000 mg ANA773 compared to 0.1 log10 in patients who received placebo. ANA773 was well-tolerated in patients throughout the course of the study and there were no serious adverse events reported."ANA773 has demonstrated a significant short-term antiviral response in HCV patients, comparable to many historical reports of interferon as a single agent," commented Steve Worland, Ph.D., Anadys' President and CEO. "Given its oral delivery and favorable tolerability profile to date, we believe that ANA773 holds promise as a potential replacement for injectable interferon products in HCV therapy. We intend to seek partnership opportunities to continue advancing the development of ANA773, with the objective of creating well-tolerated, all oral combination regimens to treat hepatitis C." James L. Freddo, M.D., Anadys' Senior Vice President, Drug Development and Chief Medical Officer added, "We are very encouraged by this data and the potential to further improve response by combining ANA773 with other agents, including ribavirin, an agent that improves response to interferon. Additionally, alternative dosing schedules may further improve pharmacological response to TLR7 activation, as was seen in preclinical studies of ANA773."In an earlier cohort in which six patients received 1600 mg ANA773 every other day over 28 days, the mean (+/-SEM) maximal decline was 1.0 (+/-0.3) log10 (p>0.1 compared to placebo), with two patients experiencing a maximal decline of greater than 1 log during treatment. The mean end-of-treatment decline was 0.5 log10 at 1600 mg. Patients who received lower doses than 1600 mg showed correspondingly less antiviral response. The Company intends to present complete results from this study at the upcoming Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), Oct. 30 - Nov. 3 in Boston. ANA773 Phase I Clinical Trial in HCV The Phase I clinical trial of ANA773 in HCV was conducted in the Netherlands under a two-part protocol. Part A of the study included both single and multiple doses of ANA773 in healthy volunteers. Successive cohorts of volunteers received ascending dose levels of ANA773. The primary objectives of Part A of the study were to assess safety and tolerability. Full results from Part A of the study were presented at the EASL Conference in April of this year. In Part B of the study, HCV patients received ANA773 every other day for either 28 or 10 days. The primary objectives of Part B were to assess safety, tolerability and viral load decline. Doses initially explored in Part B of the study were 800 mg, 1200 mg, and 1600 mg dosed every other day for a period of 28 days. Based on the viral load data from the 1600 mg cohort, in April of this year Anadys amended the protocol to include a fourth cohort of HCV patients who received 2000 mg of ANA773 dosed every other day over a period of 10 days. About ANA773 and TLR PharmacologyANA773 is the Company's oral inducer of endogenous interferons that acts via the toll like receptor 7 (TLR7) pathway. Results from preclinical pharmacology studies have shown that ANA773 can elicit desired immune responses and that the profile of response can be modulated by both dose and schedule of administration. Results of completed 13-week GLP toxicology studies have shown that with every-other-day dosing of ANA773, immune stimulation of a magnitude believed to confer therapeutic potential can be achieved without adverse toxicology findings. The immune stimulation observed with every-other-day dosing of ANA773 in preclinical studies included induction of interferon-alpha and interferon dependent responses at levels that are sustained over 13 weeks of dosing. Furthermore, dose-dependent stimulation of innate immune response in healthy volunteers was observed in Part A of the Phase I clinical trial with ANA773 (presented at EASL, 2009).About AnadysAnadys Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to improving patient care by developing novel medicines for the treatment of hepatitis C. The Company believes hepatitis C represents a large unmet medical need in which meaningful improvements in treatment outcomes may be attainable with the introduction of new medicines. The Company is developing ANA598, a non-nucleoside polymerase inhibitor for the treatment of hepatitis C. The Company has also investigated the potential of ANA773, an oral, small-molecule inducer of endogenous interferons that acts via the Toll-like receptor 7, or TLR7, pathway in hepatitis C.Safe Harbor Statement Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to (i) Anadys' belief that ANA773 holds promise as a potential replacement for injectable interferon products in HCV therapy; (ii) Anadys' ability to seek and obtain partnership opportunities to further the development of ANA773; (iii) the ability to create well-tolerated, all oral combination regimens to treat hepatitis C; (iv) the potential to further improve response by combining ANA773 with other agents, including ribavirin; and (v) the potential for alternative dosing schedules to further improve pharmacological response to TLR7 activation. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause Anadys' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements. For example, the results of preclinical and early clinical studies may not be predictive of future results, and Anadys cannot provide any assurances that ANA773 will not have unforeseen safety issues or will have favorable results in future clinical studies. Furthermore, Anadys cannot provide any assurances that it will be able to obtain a partnership around ANA773 or that the development of the program will be continued. In addition, Anadys' results may be affected by risks related to competition from other biotechnology and pharmaceutical companies, its effectiveness at managing its financial resources, its ability to enter into collaborations around its product candidates, its ability to successfully develop and market products, difficulties or delays in its preclinical studies or clinical trials, difficulties or delays in manufacturing its clinical trials materials, the scope and validity of patent protection for its product candidates, regulatory developments involving its product candidates and its ability to obtain additional funding to support its operations. Risk factors that may cause actual results to differ are more fully discussed in Anadys' SEC filings, including Anadys' Form 10-K for the year ended December 31, 2008 and its Form 10-Q for the quarter ended June 30, 2009. All forward-looking statements are qualified in their entirety by this cautionary statement. Anadys is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.SOURCE Anadys Pharmaceuticals, Inc.
Proof of Concept Achieved for Second Anadys HCV Product Candidate SAN DIEGO, Aug. 11SAN DIEGO, Aug. 11 /PRNewswire-FirstCall/ -- Anadys Pharmaceuticals, Inc. (Nasdaq: ANDS) today announced viral load data for the final cohort of hepatitis C patients in a Phase I clinical trial of ANA773, the Company's oral inducer of endogenous interferons that acts via the toll-like receptor 7 (TLR7) pathway. In patients who received 2000 mg ANA773 every other day over 10 days, the mean (+/-SEM) maximal decline in viral load was 1.3 (+/-0.4) log10, compared to a mean maximal decline of 0.3 (+/-0.1) log10 in patients who received placebo (p=0.037). Five of the eight patients who received 2000 mg ANA773 experienced a maximal decline of greater than 1 log, while none of the eight patients who received placebo experienced a decline of greater than 1 log (p<0.001 for the proportion of patients with maximal response greater than 1 log compared to placebo). The mean end-of-treatment decline was 0.6 log10 in patients who received 2000 mg ANA773 compared to 0.1 log10 in patients who received placebo. ANA773 was well-tolerated in patients throughout the course of the study and there were no serious adverse events reported."ANA773 has demonstrated a significant short-term antiviral response in HCV patients, comparable to many historical reports of interferon as a single agent," commented Steve Worland, Ph.D., Anadys' President and CEO. "Given its oral delivery and favorable tolerability profile to date, we believe that ANA773 holds promise as a potential replacement for injectable interferon products in HCV therapy. We intend to seek partnership opportunities to continue advancing the development of ANA773, with the objective of creating well-tolerated, all oral combination regimens to treat hepatitis C." James L. Freddo, M.D., Anadys' Senior Vice President, Drug Development and Chief Medical Officer added, "We are very encouraged by this data and the potential to further improve response by combining ANA773 with other agents, including ribavirin, an agent that improves response to interferon. Additionally, alternative dosing schedules may further improve pharmacological response to TLR7 activation, as was seen in preclinical studies of ANA773."In an earlier cohort in which six patients received 1600 mg ANA773 every other day over 28 days, the mean (+/-SEM) maximal decline was 1.0 (+/-0.3) log10 (p>0.1 compared to placebo), with two patients experiencing a maximal decline of greater than 1 log during treatment. The mean end-of-treatment decline was 0.5 log10 at 1600 mg. Patients who received lower doses than 1600 mg showed correspondingly less antiviral response. The Company intends to present complete results from this study at the upcoming Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), Oct. 30 - Nov. 3 in Boston. ANA773 Phase I Clinical Trial in HCV The Phase I clinical trial of ANA773 in HCV was conducted in the Netherlands under a two-part protocol. Part A of the study included both single and multiple doses of ANA773 in healthy volunteers. Successive cohorts of volunteers received ascending dose levels of ANA773. The primary objectives of Part A of the study were to assess safety and tolerability. Full results from Part A of the study were presented at the EASL Conference in April of this year. In Part B of the study, HCV patients received ANA773 every other day for either 28 or 10 days. The primary objectives of Part B were to assess safety, tolerability and viral load decline. Doses initially explored in Part B of the study were 800 mg, 1200 mg, and 1600 mg dosed every other day for a period of 28 days. Based on the viral load data from the 1600 mg cohort, in April of this year Anadys amended the protocol to include a fourth cohort of HCV patients who received 2000 mg of ANA773 dosed every other day over a period of 10 days. About ANA773 and TLR PharmacologyANA773 is the Company's oral inducer of endogenous interferons that acts via the toll like receptor 7 (TLR7) pathway. Results from preclinical pharmacology studies have shown that ANA773 can elicit desired immune responses and that the profile of response can be modulated by both dose and schedule of administration. Results of completed 13-week GLP toxicology studies have shown that with every-other-day dosing of ANA773, immune stimulation of a magnitude believed to confer therapeutic potential can be achieved without adverse toxicology findings. The immune stimulation observed with every-other-day dosing of ANA773 in preclinical studies included induction of interferon-alpha and interferon dependent responses at levels that are sustained over 13 weeks of dosing. Furthermore, dose-dependent stimulation of innate immune response in healthy volunteers was observed in Part A of the Phase I clinical trial with ANA773 (presented at EASL, 2009).About AnadysAnadys Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to improving patient care by developing novel medicines for the treatment of hepatitis C. The Company believes hepatitis C represents a large unmet medical need in which meaningful improvements in treatment outcomes may be attainable with the introduction of new medicines. The Company is developing ANA598, a non-nucleoside polymerase inhibitor for the treatment of hepatitis C. The Company has also investigated the potential of ANA773, an oral, small-molecule inducer of endogenous interferons that acts via the Toll-like receptor 7, or TLR7, pathway in hepatitis C.Safe Harbor Statement Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to (i) Anadys' belief that ANA773 holds promise as a potential replacement for injectable interferon products in HCV therapy; (ii) Anadys' ability to seek and obtain partnership opportunities to further the development of ANA773; (iii) the ability to create well-tolerated, all oral combination regimens to treat hepatitis C; (iv) the potential to further improve response by combining ANA773 with other agents, including ribavirin; and (v) the potential for alternative dosing schedules to further improve pharmacological response to TLR7 activation. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause Anadys' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements. For example, the results of preclinical and early clinical studies may not be predictive of future results, and Anadys cannot provide any assurances that ANA773 will not have unforeseen safety issues or will have favorable results in future clinical studies. Furthermore, Anadys cannot provide any assurances that it will be able to obtain a partnership around ANA773 or that the development of the program will be continued. In addition, Anadys' results may be affected by risks related to competition from other biotechnology and pharmaceutical companies, its effectiveness at managing its financial resources, its ability to enter into collaborations around its product candidates, its ability to successfully develop and market products, difficulties or delays in its preclinical studies or clinical trials, difficulties or delays in manufacturing its clinical trials materials, the scope and validity of patent protection for its product candidates, regulatory developments involving its product candidates and its ability to obtain additional funding to support its operations. Risk factors that may cause actual results to differ are more fully discussed in Anadys' SEC filings, including Anadys' Form 10-K for the year ended December 31, 2008 and its Form 10-Q for the quarter ended June 30, 2009. All forward-looking statements are qualified in their entirety by this cautionary statement. Anadys is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.SOURCE Anadys Pharmaceuticals, Inc.
Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance; for African-Americans, Hispanics, East Asians
Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance; for African-Americans, Hispanics, East Asians
Letter
Nature advance online publication 16 August 2009 | doi:10.1038/nature08309; Received 27 May 2009; Accepted 17 July 2009; Published online 16 August 2009
Dongliang Ge1, Jacques Fellay1, Alexander J. Thompson2, Jason S. Simon3, Kevin V. Shianna1, Thomas J. Urban1, Erin L. Heinzen1, Ping Qiu3, Arthur H. Bertelsen3, Andrew J. Muir2, Mark Sulkowski4, John G. McHutchison2 & David B. Goldstein1
1. Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, North Carolina 27708, USA
2. Duke Clinical Research Institute and Division of Gastroenterology, School of Medicine, Duke University, Durham, North Carolina 27705, USA
3. Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
4. Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
Correspondence to: David B. Goldstein1 Correspondence and requests for materials should be addressed to D.B.G. (Email: d.goldstein@duke.edu).
Abstract
Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America1. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or -alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 times 10-25) and African-Americans (P = 2.06 times 10-3). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.
To identify human genetic contributions to anti-HCV treatment response, we have performed a genome-wide association study of more than 1,600 individuals who were part of the IDEAL study2, and we included a further 67 patients from another prospective treatment study3. Briefly, the IDEAL study compared the effectiveness of three treatment regimens involving PegIFN-alpha-2b or PegIFN-alpha-2a combined with RBV. It demonstrated similar efficacy of the two IFN preparations and a significantly lower efficacy in self-reported African-Americans compared with Americans of European ancestry (European-Americans). All patients included were treatment-naive Americans who were chronically infected with genotype 1 HCV. Patients received 48 weeks of treatment and 24 weeks of follow-up. A total of 1,671 individuals were genotyped using the Illumina Human610-quad BeadChip, and we then searched for determinants of treatment response as a primary endpoint. We defined successful treatment response and non-response according to standard definitions4, concentrating on sustained virological response (SVR), which is the absence of detectable virus at the end of follow-up evaluation (Supplementary Information I). We included 1,137 patients who satisfied stringent compliance criteria (Supplementary Information I) in the analyses of treatment response, and 1,475 patients in a separate analysis of baseline viral load.
We found that a polymorphism on chromosome 19, rs12979860, is strongly associated with SVR in all patient groups (Fig. 1), with the European-American population sample showing overwhelming genome-wide significance (P = 1.06 times 10-25). Combining the P values across the population groups, the variant shows association at 1.37 times 10-28. The polymorphism resides 3 kilobases (kb) upstream of the IL28B gene (Fig. 2), encoding IFN-lambda-3.
FIGURE 1. Percentage of SVR by genotypes of rs12979860.
In patients of European ancestry, the CC genotype is associated with a twofold (95% confidence interval 1.8–2.3) greater rate of SVR than the TT genotype (Fig. 1), with similar ratios in both the African-American (threefold, 95% confidence interval 1.9–4.7) and the Hispanic (twofold, 95% confidence interval 1.4–3.2) population groups. The magnitude of this association is compared in Table 1 with other host or viral factors known to influence SVR in patients infected with genotype 1 HCV, including baseline viral load, fibrosis and ethnicity4, 5. Not only does the IL28B polymorphism strongly influence response within each of the major population groups, it also appears to explain much of the difference in response between different population groups (European-Americans compared with African-Americans). We estimate that approximately half of the difference in SVR between populations can be accounted for by the difference in frequency of the C allele between African-Americans and individuals of European ancestry (Supplementary Information XI). Interestingly, it has also been well documented that East Asians have higher SVR rates than patients of European ancestry6, 7. By looking at a random multi-ethnic population sample with unknown hepatitis C status (Supplementary Information II), we observed a substantially higher frequency of the C allele in East Asians (Fig. 3). Collectively, the SVR rates across different population groups displayed a striking concordance with C-allele frequency (Fig. 3). Finally, it is also noteworthy that African-Americans with the CC genotype have a significantly higher rate of response (53.3%) than individuals of European ancestry who have the TT genotype (33.3%, P < 0.05), which emphasizes the greater importance of individual genotype compared with ethnicity in predicting treatment response8.
FIGURE 3. Rate of SVR and rs12979860 C-allele frequency in diverse ethnic groups.
The SVR rate in East Asians is adopted from Liu et al.7. Sample sizes for C-allele frequency: n = 61 (African-Americans); n = 271 (European-Americans); n = 16 (Hispanics); n = 107 (East Asians); sample sizes for SVR rate: n = 191 (African-Americans); n = 871 (European-Americans); n = 75 (Hispanics); n = 154 (East Asians).
Table 1. Comparison between the genetic and conventional clinical factors associating with SVR.
Odds ratios and 95% confidence intervals are generated from the logistic regression model.
*Corresponding relative risks for rs12979860: 2.0 (95% confidence interval 1.8–2.3) in European-Americans; 3.0 (95% confidence interval 1.9–4.7) in African-Americans; 2.1 (95% confidence interval 1.4–3.2) in Hispanics.
†In clinical practice it is customary to divide patients into high and low viral-load groups, reflecting a well-described threshold effect. The IDEAL trial used a threshold of 600,000 (ref. 2).
‡Fibrosis was scored by METAVIR stage on a baseline centrally evaluated liver biopsy2, 18.
We next tested whether this variant influences baseline (pre-treatment) viral load and found a significant association in all groups (Supplementary Information XIII). Interestingly, the C allele, associated with better treatment response, is also associated with higher baseline viral load (CC 6.35, n = 485; TC 6.33, n = 744; TT 6.16, n = 246; P = 1.21 times 10-10; viral loads given as log10 international units (IU) ml-1). Although this finding is counter-intuitive in that lower baseline viral loads predict a better response to treatment, it could relate to recent speculation about the role of IFN-stimulated genes in modulating response to PegIFN9, and it seems plausible that the IL28B polymorphism has a role in the regulation of intra-hepatic IFN-stimulated gene expression with consequences both for viral load and treatment response (Supplementary Information XIII). We also note that the polymorphism has no association with whether individuals are classified as having baseline viral loads above or below a commonly used threshold that predicts respectively worse or better treatment response (Supplementary Information XIII), indicating that the association of the polymorphism with clearance and viral load may be independent. In addition, we note that the C-allele frequency was significantly reduced in the chronically infected cohort compared with ethnically matched controls (0.63 versus 0.73, controlled for population structure, P < 2.5 times 10-6, Supplementary Information II and XVI), which suggests an association between the C allele and a higher rate of natural clearance of hepatitis C. We note, however, that determination of the precise effect of the C allele on clearance will require comparison between matched cohorts known to have and have not naturally cleared this viral infection.
We sequenced the IL28B gene in 96 individuals, and found two variants highly associated with rs12979860 (r2 > 0.85 for all comparisons in all populations): a G > C transition 37 base pairs (bp) upstream of the translation initiation codon (rs28416813), and a non-synonymous coding single nucleotide polymorphism (SNP) (rs8103142) encoding the amino-acid substitution Lys70Arg. These new variants were then genotyped in the full cohort. Owing to the high degree of correlation among the three SNPs, tests for independence among these variants, using all available patients, were not able to resolve which, if any, of these sites is uniquely responsible for the association with SVR. Additional HCV-infected cohorts may help to determine whether one of these SNPs, or any other SNP in the region, is causal for the association, as the pattern of association suggests the possibility of more than one functional variant in the region (Supplementary Information IX). Ultimately, identification and elucidation of the functional SNPs will depend on in-depth functional studies.
Given the significant effect of the IL28B polymorphism on treatment response, and its likely clinical relevance, it was considered important to compare the magnitude of different predictors of response for the patients studied here. We developed a logistic regression model that related clinical predictors to response rates (Supplementary Information XI). We noted that the regression model showed that the CC genotype is associated with a more substantial difference in rate of response than other known baseline predictors included in the model.
It seems likely therefore that advance knowledge of host genotype of patients infected with HCV could in the future become an important component of the clinical decision to initiate treatment with PegIFN and RBV. Many important clinical questions remain. The current data are specific to patients with genotype 1 infection. It will therefore be necessary to evaluate the role of host IL28B genotype and treatment response in other less common HCV genotypes. Novel small molecules, including HCV protease inhibitors, are currently being developed and may soon be used in combination with PegIFN and RBV for the treatment of genotype 1 HCV10; the role of the IL28B genotype in these novel treatment regimens should therefore be investigated.
In conclusion, we have identified a polymorphism 3 kb upstream of IL28B that is significantly associated with response to PegIFN and RBV for patients with chronic genotype 1 HCV infection. The polymorphism explains much of the difference in response between European-American and African-American patients. Given that the polymorphism appears to associate with natural clearance as well as treatment response, it seems likely that the gene product is involved in the innate control of HCV. Indeed, IFN-lambdas have demonstrated antiviral activity against genotype 1 HCV in vitro11 and in vivo12. The IFN-lambda proteins, encoded by the IL28A/B and IL29 genes, were first described in 2003 (refs 13, 14). These IFNs signal through a unique receptor but appear to share a common downstream signalling system with the type 1 IFNs, including IFN-alpha. These findings, and further study of the functional mechanism underlying the IL28B-response association, may help identify patients for whom therapy is likely to be successful, and highlight the IFN-lambda signalling axis as a potential target for novel antiviral drug development.
Methods Summary
Our primary association tests involved single-marker genotype trend tests performed in three independent groups (European-Americans, n = 871; African-Americans, n = 191; Hispanics, n = 75; Supplementary Information I), using logistic regression models for treatment response and linear regression for baseline viral load (Supplementary Information VI). Association tests were implemented in the PLINK software15, correcting for several clinical covariates, including baseline (pre-treatment) HCV viral load and severity of fibrosis. Then the association signals (P values) were combined using Stouffer's weighted Z-method16, correctly taking into account sample sizes, effect sizes and effect directions in each population. This combined P value was then reported as the main result, along with the P values in each ethnic group. A series of quality-control steps resulted in 565,759 polymorphisms for the association tests. We applied methods to assess copy number variants and tested the relation between copy number variants and SVR. To control for the possibility of spurious associations resulting from population stratification, we used a modified EIGENSTRAT17 method and corrected for population ancestry within each group. We assessed significance with a Bonferroni correction (Pcutoff = 4.4 times 10-8; see Supplementary Information VIII for details).
References
1. World Health Organization. Hepatitis C. left fencehttp://www.who.int/mediacentre/factsheets/fs164/en/right fence (2009)
2. McHutchison, J. G. et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N. Engl. J. Med. 361, 580–593 (2009)
3. Muir, A. J., Bornstein, J. D. & Killenberg, P. G. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N. Engl. J. Med. 350, 2265–2271 (2004)
4. Ghany, M. G., Strader, D. B., Thomas, D. L. & Seeff, L. B. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49, 1335–1374 (2009)
5. Shiffman, M. L. et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 126, 1015–1023; discussion 947 (2004)
6. Yan, K. K. et al. Treatment responses in Asians and Caucasians with chronic hepatitis C infection. World J. Gastroenterol. 14, 3416–3420 (2008)
7. Liu, C. H. et al. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial. Clin. Infect. Dis. 47, 1260–1269 (2008)
8. Wilson, J. F. et al. Population genetic structure of variable drug response. Nature Genet. 29, 265–269 (2001)
9. Sarasin-Filipowicz, M. et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc. Natl Acad. Sci. USA 105, 7034–7039 (2008)
10. McHutchison, J. G. et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N. Engl. J. Med. 360, 1827–1838 (2009) 11. Robek, M. D., Boyd, B. S. & Chisari, F. V. Lambda interferon inhibits hepatitis B and C virus replication. J. Virol. 79, 3851–3854 (2005)
12. Shiffman, M. L. et al. PEG-IFN-lambda: antiviral activity and safety profile in a 4-week phase 1b study in relapsed genotype 1 hepatitis C infection. J. Hepatol. 50 (suppl. 1), abstr. A643 s237 (2009)
13. Kotenko, S. V. et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nature Immunol. 4, 69–77 (2003)
14. Sheppard, P. et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nature Immunol. 4, 63–68 (2003)
15. Purcell, S. et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am. J. Hum. Genet. 81, 559–575 (2007)
16. Whitlock, M. C. Combining probability from independent tests: the weighted Z-method is superior to Fisher's approach. J. Evol. Biol. 18, 1368–1373 (2005)
17. Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nature Genet. 38, 904–909 (2006)
18. The French METAVIR Cooperative Study Group Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 20, 15–20 (1994)
19. Ge, D. et al. WGAViewer: software for genomic annotation of whole genome association studies. Genome Res. 18, 640–643 (2008)
Letter
Nature advance online publication 16 August 2009 | doi:10.1038/nature08309; Received 27 May 2009; Accepted 17 July 2009; Published online 16 August 2009
Dongliang Ge1, Jacques Fellay1, Alexander J. Thompson2, Jason S. Simon3, Kevin V. Shianna1, Thomas J. Urban1, Erin L. Heinzen1, Ping Qiu3, Arthur H. Bertelsen3, Andrew J. Muir2, Mark Sulkowski4, John G. McHutchison2 & David B. Goldstein1
1. Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, North Carolina 27708, USA
2. Duke Clinical Research Institute and Division of Gastroenterology, School of Medicine, Duke University, Durham, North Carolina 27705, USA
3. Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
4. Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
Correspondence to: David B. Goldstein1 Correspondence and requests for materials should be addressed to D.B.G. (Email: d.goldstein@duke.edu).
Abstract
Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America1. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or -alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 times 10-25) and African-Americans (P = 2.06 times 10-3). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.
To identify human genetic contributions to anti-HCV treatment response, we have performed a genome-wide association study of more than 1,600 individuals who were part of the IDEAL study2, and we included a further 67 patients from another prospective treatment study3. Briefly, the IDEAL study compared the effectiveness of three treatment regimens involving PegIFN-alpha-2b or PegIFN-alpha-2a combined with RBV. It demonstrated similar efficacy of the two IFN preparations and a significantly lower efficacy in self-reported African-Americans compared with Americans of European ancestry (European-Americans). All patients included were treatment-naive Americans who were chronically infected with genotype 1 HCV. Patients received 48 weeks of treatment and 24 weeks of follow-up. A total of 1,671 individuals were genotyped using the Illumina Human610-quad BeadChip, and we then searched for determinants of treatment response as a primary endpoint. We defined successful treatment response and non-response according to standard definitions4, concentrating on sustained virological response (SVR), which is the absence of detectable virus at the end of follow-up evaluation (Supplementary Information I). We included 1,137 patients who satisfied stringent compliance criteria (Supplementary Information I) in the analyses of treatment response, and 1,475 patients in a separate analysis of baseline viral load.
We found that a polymorphism on chromosome 19, rs12979860, is strongly associated with SVR in all patient groups (Fig. 1), with the European-American population sample showing overwhelming genome-wide significance (P = 1.06 times 10-25). Combining the P values across the population groups, the variant shows association at 1.37 times 10-28. The polymorphism resides 3 kilobases (kb) upstream of the IL28B gene (Fig. 2), encoding IFN-lambda-3.
FIGURE 1. Percentage of SVR by genotypes of rs12979860.
In patients of European ancestry, the CC genotype is associated with a twofold (95% confidence interval 1.8–2.3) greater rate of SVR than the TT genotype (Fig. 1), with similar ratios in both the African-American (threefold, 95% confidence interval 1.9–4.7) and the Hispanic (twofold, 95% confidence interval 1.4–3.2) population groups. The magnitude of this association is compared in Table 1 with other host or viral factors known to influence SVR in patients infected with genotype 1 HCV, including baseline viral load, fibrosis and ethnicity4, 5. Not only does the IL28B polymorphism strongly influence response within each of the major population groups, it also appears to explain much of the difference in response between different population groups (European-Americans compared with African-Americans). We estimate that approximately half of the difference in SVR between populations can be accounted for by the difference in frequency of the C allele between African-Americans and individuals of European ancestry (Supplementary Information XI). Interestingly, it has also been well documented that East Asians have higher SVR rates than patients of European ancestry6, 7. By looking at a random multi-ethnic population sample with unknown hepatitis C status (Supplementary Information II), we observed a substantially higher frequency of the C allele in East Asians (Fig. 3). Collectively, the SVR rates across different population groups displayed a striking concordance with C-allele frequency (Fig. 3). Finally, it is also noteworthy that African-Americans with the CC genotype have a significantly higher rate of response (53.3%) than individuals of European ancestry who have the TT genotype (33.3%, P < 0.05), which emphasizes the greater importance of individual genotype compared with ethnicity in predicting treatment response8.
FIGURE 3. Rate of SVR and rs12979860 C-allele frequency in diverse ethnic groups.
The SVR rate in East Asians is adopted from Liu et al.7. Sample sizes for C-allele frequency: n = 61 (African-Americans); n = 271 (European-Americans); n = 16 (Hispanics); n = 107 (East Asians); sample sizes for SVR rate: n = 191 (African-Americans); n = 871 (European-Americans); n = 75 (Hispanics); n = 154 (East Asians).
Table 1. Comparison between the genetic and conventional clinical factors associating with SVR.
Odds ratios and 95% confidence intervals are generated from the logistic regression model.
*Corresponding relative risks for rs12979860: 2.0 (95% confidence interval 1.8–2.3) in European-Americans; 3.0 (95% confidence interval 1.9–4.7) in African-Americans; 2.1 (95% confidence interval 1.4–3.2) in Hispanics.
†In clinical practice it is customary to divide patients into high and low viral-load groups, reflecting a well-described threshold effect. The IDEAL trial used a threshold of 600,000 (ref. 2).
‡Fibrosis was scored by METAVIR stage on a baseline centrally evaluated liver biopsy2, 18.
We next tested whether this variant influences baseline (pre-treatment) viral load and found a significant association in all groups (Supplementary Information XIII). Interestingly, the C allele, associated with better treatment response, is also associated with higher baseline viral load (CC 6.35, n = 485; TC 6.33, n = 744; TT 6.16, n = 246; P = 1.21 times 10-10; viral loads given as log10 international units (IU) ml-1). Although this finding is counter-intuitive in that lower baseline viral loads predict a better response to treatment, it could relate to recent speculation about the role of IFN-stimulated genes in modulating response to PegIFN9, and it seems plausible that the IL28B polymorphism has a role in the regulation of intra-hepatic IFN-stimulated gene expression with consequences both for viral load and treatment response (Supplementary Information XIII). We also note that the polymorphism has no association with whether individuals are classified as having baseline viral loads above or below a commonly used threshold that predicts respectively worse or better treatment response (Supplementary Information XIII), indicating that the association of the polymorphism with clearance and viral load may be independent. In addition, we note that the C-allele frequency was significantly reduced in the chronically infected cohort compared with ethnically matched controls (0.63 versus 0.73, controlled for population structure, P < 2.5 times 10-6, Supplementary Information II and XVI), which suggests an association between the C allele and a higher rate of natural clearance of hepatitis C. We note, however, that determination of the precise effect of the C allele on clearance will require comparison between matched cohorts known to have and have not naturally cleared this viral infection.
We sequenced the IL28B gene in 96 individuals, and found two variants highly associated with rs12979860 (r2 > 0.85 for all comparisons in all populations): a G > C transition 37 base pairs (bp) upstream of the translation initiation codon (rs28416813), and a non-synonymous coding single nucleotide polymorphism (SNP) (rs8103142) encoding the amino-acid substitution Lys70Arg. These new variants were then genotyped in the full cohort. Owing to the high degree of correlation among the three SNPs, tests for independence among these variants, using all available patients, were not able to resolve which, if any, of these sites is uniquely responsible for the association with SVR. Additional HCV-infected cohorts may help to determine whether one of these SNPs, or any other SNP in the region, is causal for the association, as the pattern of association suggests the possibility of more than one functional variant in the region (Supplementary Information IX). Ultimately, identification and elucidation of the functional SNPs will depend on in-depth functional studies.
Given the significant effect of the IL28B polymorphism on treatment response, and its likely clinical relevance, it was considered important to compare the magnitude of different predictors of response for the patients studied here. We developed a logistic regression model that related clinical predictors to response rates (Supplementary Information XI). We noted that the regression model showed that the CC genotype is associated with a more substantial difference in rate of response than other known baseline predictors included in the model.
It seems likely therefore that advance knowledge of host genotype of patients infected with HCV could in the future become an important component of the clinical decision to initiate treatment with PegIFN and RBV. Many important clinical questions remain. The current data are specific to patients with genotype 1 infection. It will therefore be necessary to evaluate the role of host IL28B genotype and treatment response in other less common HCV genotypes. Novel small molecules, including HCV protease inhibitors, are currently being developed and may soon be used in combination with PegIFN and RBV for the treatment of genotype 1 HCV10; the role of the IL28B genotype in these novel treatment regimens should therefore be investigated.
In conclusion, we have identified a polymorphism 3 kb upstream of IL28B that is significantly associated with response to PegIFN and RBV for patients with chronic genotype 1 HCV infection. The polymorphism explains much of the difference in response between European-American and African-American patients. Given that the polymorphism appears to associate with natural clearance as well as treatment response, it seems likely that the gene product is involved in the innate control of HCV. Indeed, IFN-lambdas have demonstrated antiviral activity against genotype 1 HCV in vitro11 and in vivo12. The IFN-lambda proteins, encoded by the IL28A/B and IL29 genes, were first described in 2003 (refs 13, 14). These IFNs signal through a unique receptor but appear to share a common downstream signalling system with the type 1 IFNs, including IFN-alpha. These findings, and further study of the functional mechanism underlying the IL28B-response association, may help identify patients for whom therapy is likely to be successful, and highlight the IFN-lambda signalling axis as a potential target for novel antiviral drug development.
Methods Summary
Our primary association tests involved single-marker genotype trend tests performed in three independent groups (European-Americans, n = 871; African-Americans, n = 191; Hispanics, n = 75; Supplementary Information I), using logistic regression models for treatment response and linear regression for baseline viral load (Supplementary Information VI). Association tests were implemented in the PLINK software15, correcting for several clinical covariates, including baseline (pre-treatment) HCV viral load and severity of fibrosis. Then the association signals (P values) were combined using Stouffer's weighted Z-method16, correctly taking into account sample sizes, effect sizes and effect directions in each population. This combined P value was then reported as the main result, along with the P values in each ethnic group. A series of quality-control steps resulted in 565,759 polymorphisms for the association tests. We applied methods to assess copy number variants and tested the relation between copy number variants and SVR. To control for the possibility of spurious associations resulting from population stratification, we used a modified EIGENSTRAT17 method and corrected for population ancestry within each group. We assessed significance with a Bonferroni correction (Pcutoff = 4.4 times 10-8; see Supplementary Information VIII for details).
References
1. World Health Organization. Hepatitis C. left fencehttp://www.who.int/mediacentre/factsheets/fs164/en/right fence (2009)
2. McHutchison, J. G. et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N. Engl. J. Med. 361, 580–593 (2009)
3. Muir, A. J., Bornstein, J. D. & Killenberg, P. G. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N. Engl. J. Med. 350, 2265–2271 (2004)
4. Ghany, M. G., Strader, D. B., Thomas, D. L. & Seeff, L. B. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49, 1335–1374 (2009)
5. Shiffman, M. L. et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 126, 1015–1023; discussion 947 (2004)
6. Yan, K. K. et al. Treatment responses in Asians and Caucasians with chronic hepatitis C infection. World J. Gastroenterol. 14, 3416–3420 (2008)
7. Liu, C. H. et al. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial. Clin. Infect. Dis. 47, 1260–1269 (2008)
8. Wilson, J. F. et al. Population genetic structure of variable drug response. Nature Genet. 29, 265–269 (2001)
9. Sarasin-Filipowicz, M. et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc. Natl Acad. Sci. USA 105, 7034–7039 (2008)
10. McHutchison, J. G. et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N. Engl. J. Med. 360, 1827–1838 (2009) 11. Robek, M. D., Boyd, B. S. & Chisari, F. V. Lambda interferon inhibits hepatitis B and C virus replication. J. Virol. 79, 3851–3854 (2005)
12. Shiffman, M. L. et al. PEG-IFN-lambda: antiviral activity and safety profile in a 4-week phase 1b study in relapsed genotype 1 hepatitis C infection. J. Hepatol. 50 (suppl. 1), abstr. A643 s237 (2009)
13. Kotenko, S. V. et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nature Immunol. 4, 69–77 (2003)
14. Sheppard, P. et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nature Immunol. 4, 63–68 (2003)
15. Purcell, S. et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am. J. Hum. Genet. 81, 559–575 (2007)
16. Whitlock, M. C. Combining probability from independent tests: the weighted Z-method is superior to Fisher's approach. J. Evol. Biol. 18, 1368–1373 (2005)
17. Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nature Genet. 38, 904–909 (2006)
18. The French METAVIR Cooperative Study Group Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 20, 15–20 (1994)
19. Ge, D. et al. WGAViewer: software for genomic annotation of whole genome association studies. Genome Res. 18, 640–643 (2008)
National AIDS Treatment Advocacy Project - NATAP
National AIDS Treatment Advocacy Project - NATAP - HIV - AIDS - hepatitis C/B
NATAP website recently was rated by online survey among 150 HIV doctors as one of top 2 sources of information on the internet among websites that provide HIV information, and this did not include the email distribution program, NATAP is the only non-profit website.
NATAP website recently was rated by online survey among 150 HIV doctors as one of top 2 sources of information on the internet among websites that provide HIV information, and this did not include the email distribution program, NATAP is the only non-profit website.
NIAID HIV and Emerging Infectious Diseases Program
NIAID HIV and Emerging Infectious Diseases Program
Study name: An Open Label Non-Randomized Trial to Assess Safety and Tolerability of Alb-interferon Alfa 2b Every Two Weeks with Ribavirin Among HIV/HCV Coinfected Individuals
Study number:
07-I-0001
Goal of Study:
The specific aims of this study include determining the safety and toxicity profiles, as well as the pharmacokinetics and effect on HCV viral kinetics, of Alb-interferon (ALB-IFN) when given to patients who are co-infected with HCV and HIV. ALB-IFN has been genetically fused to human serum albumin in order to increase its half-life and subsequently decrease the frequency of injections required to achieve the same therapeutic effect as current Interferon therapy. The study will also assess the potential efficacy of ALB-IFN with ribavirin (RBV). RBV is a medication, in pill form, which is already approved by the FDA to treat chronic Hep C infection.
Study Regimen:
ALB-IFN 900 mcg by subcutaneous injection every 2 weeks with daily RBV will be given to HIV/HCV co-infected individuals for 48 weeks. We will enroll a total of 25 patients. In addition, all patients will receive recommended doses of RBV (based on patient’s weight) throughout the 48-week treatment period. Patients will be monitored throughout the study for ALB-IFN levels, HCV and HIV viral loads and CD4 counts. They will undergo a pre-treatment and optional post-treatment liver biopsy.
Eligibility Criteria:
Age 18 years or older with documented HCV (Genotype 1) and HIV infection.
Liver biopsy results upon study entry consistent with chronic Hepatitis C.
Patients must have absolute CD4 count > 100
Female patients must not be pregnant or breastfeeding. Pregnancy test must be negative prior to starting the study medications. Male patients who have female pregnant partners are also excluded.
Patient needs to have a primary doctor who will assume care for their HIV and HCV infection.
Patient must not have any other documented cause of liver disease besides Hepatitis C.
Patient must abstain from alcohol use during the trial, not have any active substance abuse within the past 6 months and in the opinion of the investigator not be at risk for substance addiction relapse.
Patient must not have the following medical conditions: autoimmune disorders, severe psychiatric disorders that would interfere with treatment adherence, severe cardiac or pulmonary disease, esophageal varices, gastrointestinal malabsorption or chronic nausea/vomiting, chronic pancreatitis, thalassemia, sickle cell anemia, severe retinopathy, or active systemic infections other than HIV/HCV.
Patient must not be taking the following medications: didanosine (ddI), stavudine (d4T) high dose ritonavir (600 mg three times per day or more), amphetamines, barbiturates, cocaine, ganciclovir, isoniazid, opiates, pyrazinamide, rifabutin, rifampin/rifampicin, thalidomide and theophylline.
Patient must not have used long-term systemic steroids (prednisone dose > 10 mg/day) or immunosuppressive medications within six months of enrollment into the study.
Patient must not have used interferon or pegylated interferon in the past.
Other: HCV medications used in this study will be provided (Albumin-fused Interferon injections & oral Ribavirin).
For questions about participating in any of these clinical studies, contact:
Patient Recruitment and Public Liaison Office
Toll Free: 1-800-411-1222
TTY: 1-866-411-1010
Se habla español.
Office hours: 8 am to 8 pm, Eastern Time
Study name: An Open Label Non-Randomized Trial to Assess Safety and Tolerability of Alb-interferon Alfa 2b Every Two Weeks with Ribavirin Among HIV/HCV Coinfected Individuals
Study number:
07-I-0001
Goal of Study:
The specific aims of this study include determining the safety and toxicity profiles, as well as the pharmacokinetics and effect on HCV viral kinetics, of Alb-interferon (ALB-IFN) when given to patients who are co-infected with HCV and HIV. ALB-IFN has been genetically fused to human serum albumin in order to increase its half-life and subsequently decrease the frequency of injections required to achieve the same therapeutic effect as current Interferon therapy. The study will also assess the potential efficacy of ALB-IFN with ribavirin (RBV). RBV is a medication, in pill form, which is already approved by the FDA to treat chronic Hep C infection.
Study Regimen:
ALB-IFN 900 mcg by subcutaneous injection every 2 weeks with daily RBV will be given to HIV/HCV co-infected individuals for 48 weeks. We will enroll a total of 25 patients. In addition, all patients will receive recommended doses of RBV (based on patient’s weight) throughout the 48-week treatment period. Patients will be monitored throughout the study for ALB-IFN levels, HCV and HIV viral loads and CD4 counts. They will undergo a pre-treatment and optional post-treatment liver biopsy.
Eligibility Criteria:
Age 18 years or older with documented HCV (Genotype 1) and HIV infection.
Liver biopsy results upon study entry consistent with chronic Hepatitis C.
Patients must have absolute CD4 count > 100
Female patients must not be pregnant or breastfeeding. Pregnancy test must be negative prior to starting the study medications. Male patients who have female pregnant partners are also excluded.
Patient needs to have a primary doctor who will assume care for their HIV and HCV infection.
Patient must not have any other documented cause of liver disease besides Hepatitis C.
Patient must abstain from alcohol use during the trial, not have any active substance abuse within the past 6 months and in the opinion of the investigator not be at risk for substance addiction relapse.
Patient must not have the following medical conditions: autoimmune disorders, severe psychiatric disorders that would interfere with treatment adherence, severe cardiac or pulmonary disease, esophageal varices, gastrointestinal malabsorption or chronic nausea/vomiting, chronic pancreatitis, thalassemia, sickle cell anemia, severe retinopathy, or active systemic infections other than HIV/HCV.
Patient must not be taking the following medications: didanosine (ddI), stavudine (d4T) high dose ritonavir (600 mg three times per day or more), amphetamines, barbiturates, cocaine, ganciclovir, isoniazid, opiates, pyrazinamide, rifabutin, rifampin/rifampicin, thalidomide and theophylline.
Patient must not have used long-term systemic steroids (prednisone dose > 10 mg/day) or immunosuppressive medications within six months of enrollment into the study.
Patient must not have used interferon or pegylated interferon in the past.
Other: HCV medications used in this study will be provided (Albumin-fused Interferon injections & oral Ribavirin).
For questions about participating in any of these clinical studies, contact:
Patient Recruitment and Public Liaison Office
Toll Free: 1-800-411-1222
TTY: 1-866-411-1010
Se habla español.
Office hours: 8 am to 8 pm, Eastern Time
Early treatment improves outcomes in acute hepatitis C virus infection: a meta-analysis
Early treatment improves outcomes in acute hepatitis C virus infection: a meta-analysis
"SVR rates varied inversely with time from acute HCV diagnosis. SVR rates for treatment within 12 weeks was 82.5%. Response rates fell to 66.9% for treatment between 12 and 24 weeks, and decreased further to 62.5% for treatment beyond 24 weeks. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis. Based on these findings, we would advocate a 12 week period of observation for spontaneous clearance before treatment initiation. If no clearance has occurred by 12 weeks, treatment should be initiated......Further studies are necessary to clarify the optimal duration of therapy and the optimal treatment regimen."
Journal of Viral Hepatitis Early view Aug 16 2009
K. E. Corey 1,3 , J. Mendez-Navarro 1,4 , E. C. Gorospe 1 , H. Zheng 2,3 and R. T. Chung 1,3
1 Gastrointestinal Unit and 2 MGH Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA ; 3 Harvard Medical School, Boston, MA, USA ; and 4 National Medical Center 'Hospital Especialidades CMN Siglo XXI', IMSS, Mexico City, DF, Mexico
Correspondence to Raymond T. Chung, MD, Massachusetts General Hospital, Warren 1007, 55 Fruit Street, Boston, MA 02114, USA. E-mail: rtchung@partners.org
ABSTRACT
Summary. Acute hepatitis C virus infection is associated with high rates of spontaneous clearance and variable rates of treatment-induced clearance. The benefit of early treatment versus awaiting spontaneous clearance is unknown, as is the optimal timing of treatment.We performed a MEDLINE and EMBASE search for the time period 1950 to October 2008. All English language abstracts using the search terms acute hepatitis C, hepatitis C and acute and hepatitis C and acute disease or acute infection were reviewed. Bibliographies were reviewed.Twenty-two studies including 1075 patients met the inclusion criteria. The sustained virologic response (SVR) rate for treated patients was 78%, significantly higher than 55.1% in untreated patients (OR = 3.08, 95% CI: 1.8–4.8 P value <0.0001). Mean time from diagnosis to spontaneous clearance was 9.7 weeks (SD 6.5). SVR rates varied inversely with time from acute HCV diagnosis. SVR rates for treatment within 12 weeks was 82.5% (95% CI: 75.6–89.3), significantly better than the clearance rates in untreated patients (P < 0.001). Response rates fell to 66.9% for treatment between 12 and 24 weeks, and decreased further to 62.5% for treatment beyond 24 weeks. Rates of viral clearance in treated patients with acute hepatitis C virus infection were significantly higher than that in untreated patients. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis. Based on these findings, we would advocate a 12 week period of observation for spontaneous clearance before treatment initiation. If no clearance has occurred by 12 weeks, treatment should be initiated.
Article Text
Chronic hepatitis C virus infection infects more than 170 million people worldwide and more than 4 million Americans [1]. The incidence of new hepatitis C virus infections in the United States is estimated to be 100–200 cases per 100 000 people each year, with 28 000 new cases globally [2]. Unfortunately, 75–80% of patients who acquire hepatitis C virus are asymptomatic, delaying diagnosis and preventing early treatment [3]. However, symptomatic patients who present with acute hepatitis C virus may have higher rates of spontaneous clearance, with some studies noting spontaneous clearance rates as high as 66% [4–7]. Treatment studies of patients with symptomatic acute HCV have yielded varying rates of treatment-induced SVR from as low as 21% to as high as 98% [8–10]. Trials have been limited by small patient numbers, the lack of randomized controls, and variability in enrollment criteria, including the definition of acute hepatitis C virus infection and of sustained virologic response [11,12]. Additionally, in several of these studies, early treatment (12–35 days after diagnosis) was initiated [13,14]. Early initiation of treatment most likely includes a proportion of patients who would have spontaneously cleared HCV which may overestimate the treatment response.
Recommendations for the timing of treatment initiation vary widely from 35 days after diagnosis to 120 days, with some studies suggesting that earlier treatment is associated with higher rates of SVR [8,14–18]. With high rates of spontaneous clearance and varying rates of treatment-induced clearance in symptomatic patients with acute hepatitis C virus infection, it is unknown whether treatment in the acute phase is clearly superior to watchful waiting. Furthermore, if treatment is chosen, the optimal timing of initial therapy remains unknown. Premature initiation of treatment in the acute phase may subject patients who would otherwise spontaneously clear HCV to unnecessary and costly treatment. However, delay in treatment initiation may lower rates of treatment-induced clearance.
This meta-analysis sought to more definitively establish the rate of spontaneous and treatment- induced clearance in patients with acute hepatitis C virus infection, and further sought to evaluate whether treatment outcomes vary based on the timing of treatment initiation.
Discussion
Our study answers several persistent questions regarding management of acute hepatitis C virus infection. First, we found a significant rate of spontaneous clearance in over half of untreated patients (55.1%) clearing HCV without treatment, indicating that more than half of patients diagnosed with acute hepatitis C virus infection do not require treatment. Importantly, the mean time from diagnosis to clearance was 9.7 weeks and mean time from exposure to clearance was 13 weeks. These findings are consistent with other data suggesting that spontaneous clearance of acute HCV typically occurs within 12 weeks of diagnosis [19–21]. Gerlach et al. found that the majority of patients who achieved spontaneous clearance cleared virus within 12 weeks of diagnosis and none cleared after 17 weeks following diagnosis [19]. Thus, our findings bolster the recommendation that a 12 week observation period is adequate to allow for spontaneous clearance.
While our study found that there was a high rate of spontaneous clearance we also confirmed that treatment was significantly better than no treatment with an odds ratio of 3.08 (95% CI: 1.8–4.8). The superiority of treatment-induced SVR was driven by treatment initiated by the 12 week mark, with SVR rates higher the earlier treatment was initiated. Treatment initiated beyond 12 weeks is comparable to SVR rates for chronic hepatitis C virus infection.
Our study has several limitations. First, we were unable to garner data from the individual studies including the hepatitis C virus infection genotypes for individual patients and their individual virologic outcomes (only overall genotypes for the study) and exact treatment regimen and duration for individual responders versus nonresponders for each trial which are significant factors that may influence treatment outcomes. We did find that majority of our patients (77%) were treated with pegylated interferon monotherapy and our overall treatment response rate was 78%, suggesting that monotherapy may be adequate. However, we are unable to directly compare outcomes between pegylated interferon monotherapy and other regimens. We did find that mean treatment durations in the 12 Week Group were not significantly different between responders and nonresponders (15.9 vs 17.8 weeks). However, the wide standard deviations of 9.1 and 10.5 weeks reflect the variability in treatment durations, so we are thus unable to recommend an optimal duration to maximize treatment response while limiting treatment-induced adverse effects. Thus, while our study can provide treatment outcomes based on timing of treatment initiation, we cannot provide recommendations on the optimal duration of treatment or treatment regimen.
In conclusion, our meta-analysis found high rates of spontaneous clearance in patients with acute hepatitis C virus infection. In addition, we found superior rates of viral clearance in patients with acute hepatitis C virus infection who underwent early treatment when compared with patients who did not receive treatment. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis and the mean time to spontaneous clearance was 9.7 weeks. Thus, we would advocate for a 12 week period of watchful waiting before treatment initiation to allow for spontaneous clearance. This 12 week mark in untreated acute hepatitis C virus infection patients is analogous to the early virologic response (EVR) time point of treatment in chronic patients. We have therefore adopted the term 'acute EVR' to denote spontaneous clearance of acute infection by 12 weeks. A lack of viral clearance at the 12 week mark in acute untreated patients, as in treated chronic patients, reflects an inadequate response and warrants a change in management. Just as failure to achieve EVR would justify cessation of treatment in chronic patients, failure to achieve acute EVR in acute patients would warrant initiation of treatment. If at the 12 week mark patients have not achieved an acute EVR, remaining viremic, we would recommend prompt initiation of treatment to ensure patients the greatest chance for treatment-induced clearance. Further studies are necessary to clarify the optimal duration of therapy and the optimal treatment regimen.
Results
Study and patient characteristics
A total of 2262 abstracts were found and all were reviewed. Of these reviewed abstracts, 139 articles were retrieved and 22 met our inclusion criteria (Table 1).
Sixteen studies were treatment studies of acute hepatitis C virus infection; five studies were randomized trials, with or without control groups and 11 studies were prospective, open label treatment trials. Six studies were observational in nature only and offered no acute hepatitis C virus infection treatment.
These studies included 1075 patients with acute hepatitis C virus infection. The mean age of the patients was 36.4 years. Fifty-four percent of subjects were men. Genotype 1 predominated with 46.9% of subjects, 12.6% with genotype 2, 12% with genotype 3, 17.3% genotype 4 and 11.2% unknown (Table 2). The mean ALT at time of diagnosis was 471 IU/L. Risk factors included intravenous drug abuse (IVDA) in 26.8%, occupational exposure in 29.3%, medical procedures in 15%, transfusion in 10%, sexual contact in 8.3% and unknown in 9.7%.
Clearance rates higher in treated patients
Four hundred and seventy-three patients (44%) received no treatment for acute hepatitis C virus infection. These patients deferred treatment, had contraindications to therapy, or underwent viral clearance prior treatment initiation. The overall clearance rate for untreated patients was 55.1% (Fig. 1), indicating that more than half of patients diagnosed with acute hepatitis C virus infection achieved viral clearance without treatment. Additionally, the mean time from symptom onset and diagnosis of acute hepatitis C virus infection to spontaneous clearance was 9.7 weeks (SD 3.2) and the mean time from exposure to spontaneous clearance was 13 weeks (SD 8.1), indicating that the majority of clearance occurred within 3 months of diagnosis and 4 months of presumed exposure.
Six hundred and two patients (56%) received treatment for acute hepatitis C virus. The majority of patients (77%) received peginterferon monotherapy. Sixteen percent of patients received interferon monotherapy, 4% received peginterferon and ribavirin and 3% of patients received interferon and ribavirin. The average duration of treatment was 19.7 weeks (±12.5 weeks) (Table 3).
The overall SVR rate for all patients receiving treatment for acute hepatitis C virus infection was 78% (Fig. 2). This is significantly higher than the clearance rate (55.1%) in untreated patients (OR = 3.08, 95% CI: 1.8–4.8 P value <0.0001).
Early treatment associated with increased SVR rates
Next, we sought to determine whether the timing of treatment initiation influenced SVR rates. Patients were divided into three subgroups, those treated at or within 12 weeks of acute hepatitis C virus infection diagnosis, patients treated between 12 and 24 weeks after diagnosis and patients treated 24 weeks post-diagnosis. Four hundred and seventeen patients initiated treatment within 12 weeks of diagnosis (12 Week Group). One hundred and ten patients initiated treatment between 12 and 24 weeks of diagnosis (12–24 Week Group) and 46 patients received treatment 24 or more weeks after diagnosis (24 Week Group).
The rate of SVR varied inversely with time from acute HCV diagnosis. The sustained virologic response rates for patients with acute hepatitis C virus infection treated in the 12 Week Group was 82.5% (95% CI: 75.6–89.3) (Fig. 3), which was significantly better than the clearance rates in untreated patients (P < 0.001). Response rates fell to 66.9% (P = 0.24 compared with untreated) in the 12–24 Week Group (Fig. 4) and decreased further to 62.5% for patients in the 24 Week Group (P = 0.68 compared with untreated) (Fig. 5).
There was no statistically significant difference in the mean duration of treatment for responders and nonresponders within the 12 Week Group (17.8 vs 15.9 weeks, P = 0.68), within the 12–24 Week group (16.7 vs 16.4 weeks, P = 0.98) or within the 24 Week Group (29.9 vs 32.4 weeks, P = 0.84).
There was no statistically significant difference between treatment durations when comparing responders in the 12 Week Group to responders in the 12–24 Week Group, responders within the 12 Week Group to the 24 Week Group or between responders in the 12–24 Week Group and 24 Week Group. (P = 0.82, P = 0.15, P = 0.21, respectively). Nonresponders in the 24 Week Group underwent a longer duration of treatment (32.5 weeks) than nonresponders in the 12 Week Group or 12–24 Week Group (15.9 weeks, P = 0.033, 16.4 weeks, P = 0.057 respectively). Despite this significant increase in treatment duration, response rates remained lower in this group (Table 4).
Materials and methods
We performed a MEDLINE and EMBASE search for the period of 1950 to October 2008. All English language abstracts using the search terms 'acute hepatitis C', 'hepatitis C and acute' and 'hepatitis C and acute disease or acute infection' were reviewed. Bibliographies of retrieved papers were also reviewed for eligible articles.
For inclusion into the meta-analysis the articles were required to meet the following criteria: (i) Acute hepatitis C virus infection, defined by seroconversion of anti-hepatitis C antibody, negative antibody and positive HCV RNA or positive antibody, positive HCV RNA, elevated ALT with a history of recent HCV exposure, (ii) Ability to determine the patient's management (treatment versus observation), (iii) Ability to determine patient's outcome (viral clearance versus the development of chronic disease), (iv) Follow-up period of 6 months or more, (v) Absence of co-infection with hepatitis B or HIV, (vi)Ability to determine the timing from acute HCV diagnosis to treatment, (vii) Ability to determine the duration of HCV treatment, (viii) Absence of end stage renal disease. Only trials prospective in nature were included.
The majority of studies were rejected because of the lack of a clear definition of acute hepatitis C virus infection, the inability to determine time to treatment, or the inability to assess patient outcomes.
Data were extracted using a pre-specified data extraction sheet by two independent reviewers. Variables extracted included study type, year, definition of acute hepatitis C virus infection, number of patients treated, number of patients with sustained virologic response, number of patients with spontaneous clearance, distribution of genotype. Differences between reviewers were resolved by consensus.
We fit a Bayesian model to take into account the between-study variability and estimated the treatment effect based on 22 studies.
We used WinBUGS software to fit this model and draw inferences regarding the overall treatment rates as well as response rates among treated or control groups.
Categorical variables were analysed using the chi-square test, while continuous variables were evaluated using the Student's t-test. A two-sided P-value of <0.05 is considered statistically significant.
"SVR rates varied inversely with time from acute HCV diagnosis. SVR rates for treatment within 12 weeks was 82.5%. Response rates fell to 66.9% for treatment between 12 and 24 weeks, and decreased further to 62.5% for treatment beyond 24 weeks. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis. Based on these findings, we would advocate a 12 week period of observation for spontaneous clearance before treatment initiation. If no clearance has occurred by 12 weeks, treatment should be initiated......Further studies are necessary to clarify the optimal duration of therapy and the optimal treatment regimen."
Journal of Viral Hepatitis Early view Aug 16 2009
K. E. Corey 1,3 , J. Mendez-Navarro 1,4 , E. C. Gorospe 1 , H. Zheng 2,3 and R. T. Chung 1,3
1 Gastrointestinal Unit and 2 MGH Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA ; 3 Harvard Medical School, Boston, MA, USA ; and 4 National Medical Center 'Hospital Especialidades CMN Siglo XXI', IMSS, Mexico City, DF, Mexico
Correspondence to Raymond T. Chung, MD, Massachusetts General Hospital, Warren 1007, 55 Fruit Street, Boston, MA 02114, USA. E-mail: rtchung@partners.org
ABSTRACT
Summary. Acute hepatitis C virus infection is associated with high rates of spontaneous clearance and variable rates of treatment-induced clearance. The benefit of early treatment versus awaiting spontaneous clearance is unknown, as is the optimal timing of treatment.We performed a MEDLINE and EMBASE search for the time period 1950 to October 2008. All English language abstracts using the search terms acute hepatitis C, hepatitis C and acute and hepatitis C and acute disease or acute infection were reviewed. Bibliographies were reviewed.Twenty-two studies including 1075 patients met the inclusion criteria. The sustained virologic response (SVR) rate for treated patients was 78%, significantly higher than 55.1% in untreated patients (OR = 3.08, 95% CI: 1.8–4.8 P value <0.0001). Mean time from diagnosis to spontaneous clearance was 9.7 weeks (SD 6.5). SVR rates varied inversely with time from acute HCV diagnosis. SVR rates for treatment within 12 weeks was 82.5% (95% CI: 75.6–89.3), significantly better than the clearance rates in untreated patients (P < 0.001). Response rates fell to 66.9% for treatment between 12 and 24 weeks, and decreased further to 62.5% for treatment beyond 24 weeks. Rates of viral clearance in treated patients with acute hepatitis C virus infection were significantly higher than that in untreated patients. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis. Based on these findings, we would advocate a 12 week period of observation for spontaneous clearance before treatment initiation. If no clearance has occurred by 12 weeks, treatment should be initiated.
Article Text
Chronic hepatitis C virus infection infects more than 170 million people worldwide and more than 4 million Americans [1]. The incidence of new hepatitis C virus infections in the United States is estimated to be 100–200 cases per 100 000 people each year, with 28 000 new cases globally [2]. Unfortunately, 75–80% of patients who acquire hepatitis C virus are asymptomatic, delaying diagnosis and preventing early treatment [3]. However, symptomatic patients who present with acute hepatitis C virus may have higher rates of spontaneous clearance, with some studies noting spontaneous clearance rates as high as 66% [4–7]. Treatment studies of patients with symptomatic acute HCV have yielded varying rates of treatment-induced SVR from as low as 21% to as high as 98% [8–10]. Trials have been limited by small patient numbers, the lack of randomized controls, and variability in enrollment criteria, including the definition of acute hepatitis C virus infection and of sustained virologic response [11,12]. Additionally, in several of these studies, early treatment (12–35 days after diagnosis) was initiated [13,14]. Early initiation of treatment most likely includes a proportion of patients who would have spontaneously cleared HCV which may overestimate the treatment response.
Recommendations for the timing of treatment initiation vary widely from 35 days after diagnosis to 120 days, with some studies suggesting that earlier treatment is associated with higher rates of SVR [8,14–18]. With high rates of spontaneous clearance and varying rates of treatment-induced clearance in symptomatic patients with acute hepatitis C virus infection, it is unknown whether treatment in the acute phase is clearly superior to watchful waiting. Furthermore, if treatment is chosen, the optimal timing of initial therapy remains unknown. Premature initiation of treatment in the acute phase may subject patients who would otherwise spontaneously clear HCV to unnecessary and costly treatment. However, delay in treatment initiation may lower rates of treatment-induced clearance.
This meta-analysis sought to more definitively establish the rate of spontaneous and treatment- induced clearance in patients with acute hepatitis C virus infection, and further sought to evaluate whether treatment outcomes vary based on the timing of treatment initiation.
Discussion
Our study answers several persistent questions regarding management of acute hepatitis C virus infection. First, we found a significant rate of spontaneous clearance in over half of untreated patients (55.1%) clearing HCV without treatment, indicating that more than half of patients diagnosed with acute hepatitis C virus infection do not require treatment. Importantly, the mean time from diagnosis to clearance was 9.7 weeks and mean time from exposure to clearance was 13 weeks. These findings are consistent with other data suggesting that spontaneous clearance of acute HCV typically occurs within 12 weeks of diagnosis [19–21]. Gerlach et al. found that the majority of patients who achieved spontaneous clearance cleared virus within 12 weeks of diagnosis and none cleared after 17 weeks following diagnosis [19]. Thus, our findings bolster the recommendation that a 12 week observation period is adequate to allow for spontaneous clearance.
While our study found that there was a high rate of spontaneous clearance we also confirmed that treatment was significantly better than no treatment with an odds ratio of 3.08 (95% CI: 1.8–4.8). The superiority of treatment-induced SVR was driven by treatment initiated by the 12 week mark, with SVR rates higher the earlier treatment was initiated. Treatment initiated beyond 12 weeks is comparable to SVR rates for chronic hepatitis C virus infection.
Our study has several limitations. First, we were unable to garner data from the individual studies including the hepatitis C virus infection genotypes for individual patients and their individual virologic outcomes (only overall genotypes for the study) and exact treatment regimen and duration for individual responders versus nonresponders for each trial which are significant factors that may influence treatment outcomes. We did find that majority of our patients (77%) were treated with pegylated interferon monotherapy and our overall treatment response rate was 78%, suggesting that monotherapy may be adequate. However, we are unable to directly compare outcomes between pegylated interferon monotherapy and other regimens. We did find that mean treatment durations in the 12 Week Group were not significantly different between responders and nonresponders (15.9 vs 17.8 weeks). However, the wide standard deviations of 9.1 and 10.5 weeks reflect the variability in treatment durations, so we are thus unable to recommend an optimal duration to maximize treatment response while limiting treatment-induced adverse effects. Thus, while our study can provide treatment outcomes based on timing of treatment initiation, we cannot provide recommendations on the optimal duration of treatment or treatment regimen.
In conclusion, our meta-analysis found high rates of spontaneous clearance in patients with acute hepatitis C virus infection. In addition, we found superior rates of viral clearance in patients with acute hepatitis C virus infection who underwent early treatment when compared with patients who did not receive treatment. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis and the mean time to spontaneous clearance was 9.7 weeks. Thus, we would advocate for a 12 week period of watchful waiting before treatment initiation to allow for spontaneous clearance. This 12 week mark in untreated acute hepatitis C virus infection patients is analogous to the early virologic response (EVR) time point of treatment in chronic patients. We have therefore adopted the term 'acute EVR' to denote spontaneous clearance of acute infection by 12 weeks. A lack of viral clearance at the 12 week mark in acute untreated patients, as in treated chronic patients, reflects an inadequate response and warrants a change in management. Just as failure to achieve EVR would justify cessation of treatment in chronic patients, failure to achieve acute EVR in acute patients would warrant initiation of treatment. If at the 12 week mark patients have not achieved an acute EVR, remaining viremic, we would recommend prompt initiation of treatment to ensure patients the greatest chance for treatment-induced clearance. Further studies are necessary to clarify the optimal duration of therapy and the optimal treatment regimen.
Results
Study and patient characteristics
A total of 2262 abstracts were found and all were reviewed. Of these reviewed abstracts, 139 articles were retrieved and 22 met our inclusion criteria (Table 1).
Sixteen studies were treatment studies of acute hepatitis C virus infection; five studies were randomized trials, with or without control groups and 11 studies were prospective, open label treatment trials. Six studies were observational in nature only and offered no acute hepatitis C virus infection treatment.
These studies included 1075 patients with acute hepatitis C virus infection. The mean age of the patients was 36.4 years. Fifty-four percent of subjects were men. Genotype 1 predominated with 46.9% of subjects, 12.6% with genotype 2, 12% with genotype 3, 17.3% genotype 4 and 11.2% unknown (Table 2). The mean ALT at time of diagnosis was 471 IU/L. Risk factors included intravenous drug abuse (IVDA) in 26.8%, occupational exposure in 29.3%, medical procedures in 15%, transfusion in 10%, sexual contact in 8.3% and unknown in 9.7%.
Clearance rates higher in treated patients
Four hundred and seventy-three patients (44%) received no treatment for acute hepatitis C virus infection. These patients deferred treatment, had contraindications to therapy, or underwent viral clearance prior treatment initiation. The overall clearance rate for untreated patients was 55.1% (Fig. 1), indicating that more than half of patients diagnosed with acute hepatitis C virus infection achieved viral clearance without treatment. Additionally, the mean time from symptom onset and diagnosis of acute hepatitis C virus infection to spontaneous clearance was 9.7 weeks (SD 3.2) and the mean time from exposure to spontaneous clearance was 13 weeks (SD 8.1), indicating that the majority of clearance occurred within 3 months of diagnosis and 4 months of presumed exposure.
Six hundred and two patients (56%) received treatment for acute hepatitis C virus. The majority of patients (77%) received peginterferon monotherapy. Sixteen percent of patients received interferon monotherapy, 4% received peginterferon and ribavirin and 3% of patients received interferon and ribavirin. The average duration of treatment was 19.7 weeks (±12.5 weeks) (Table 3).
The overall SVR rate for all patients receiving treatment for acute hepatitis C virus infection was 78% (Fig. 2). This is significantly higher than the clearance rate (55.1%) in untreated patients (OR = 3.08, 95% CI: 1.8–4.8 P value <0.0001).
Early treatment associated with increased SVR rates
Next, we sought to determine whether the timing of treatment initiation influenced SVR rates. Patients were divided into three subgroups, those treated at or within 12 weeks of acute hepatitis C virus infection diagnosis, patients treated between 12 and 24 weeks after diagnosis and patients treated 24 weeks post-diagnosis. Four hundred and seventeen patients initiated treatment within 12 weeks of diagnosis (12 Week Group). One hundred and ten patients initiated treatment between 12 and 24 weeks of diagnosis (12–24 Week Group) and 46 patients received treatment 24 or more weeks after diagnosis (24 Week Group).
The rate of SVR varied inversely with time from acute HCV diagnosis. The sustained virologic response rates for patients with acute hepatitis C virus infection treated in the 12 Week Group was 82.5% (95% CI: 75.6–89.3) (Fig. 3), which was significantly better than the clearance rates in untreated patients (P < 0.001). Response rates fell to 66.9% (P = 0.24 compared with untreated) in the 12–24 Week Group (Fig. 4) and decreased further to 62.5% for patients in the 24 Week Group (P = 0.68 compared with untreated) (Fig. 5).
There was no statistically significant difference in the mean duration of treatment for responders and nonresponders within the 12 Week Group (17.8 vs 15.9 weeks, P = 0.68), within the 12–24 Week group (16.7 vs 16.4 weeks, P = 0.98) or within the 24 Week Group (29.9 vs 32.4 weeks, P = 0.84).
There was no statistically significant difference between treatment durations when comparing responders in the 12 Week Group to responders in the 12–24 Week Group, responders within the 12 Week Group to the 24 Week Group or between responders in the 12–24 Week Group and 24 Week Group. (P = 0.82, P = 0.15, P = 0.21, respectively). Nonresponders in the 24 Week Group underwent a longer duration of treatment (32.5 weeks) than nonresponders in the 12 Week Group or 12–24 Week Group (15.9 weeks, P = 0.033, 16.4 weeks, P = 0.057 respectively). Despite this significant increase in treatment duration, response rates remained lower in this group (Table 4).
Materials and methods
We performed a MEDLINE and EMBASE search for the period of 1950 to October 2008. All English language abstracts using the search terms 'acute hepatitis C', 'hepatitis C and acute' and 'hepatitis C and acute disease or acute infection' were reviewed. Bibliographies of retrieved papers were also reviewed for eligible articles.
For inclusion into the meta-analysis the articles were required to meet the following criteria: (i) Acute hepatitis C virus infection, defined by seroconversion of anti-hepatitis C antibody, negative antibody and positive HCV RNA or positive antibody, positive HCV RNA, elevated ALT with a history of recent HCV exposure, (ii) Ability to determine the patient's management (treatment versus observation), (iii) Ability to determine patient's outcome (viral clearance versus the development of chronic disease), (iv) Follow-up period of 6 months or more, (v) Absence of co-infection with hepatitis B or HIV, (vi)Ability to determine the timing from acute HCV diagnosis to treatment, (vii) Ability to determine the duration of HCV treatment, (viii) Absence of end stage renal disease. Only trials prospective in nature were included.
The majority of studies were rejected because of the lack of a clear definition of acute hepatitis C virus infection, the inability to determine time to treatment, or the inability to assess patient outcomes.
Data were extracted using a pre-specified data extraction sheet by two independent reviewers. Variables extracted included study type, year, definition of acute hepatitis C virus infection, number of patients treated, number of patients with sustained virologic response, number of patients with spontaneous clearance, distribution of genotype. Differences between reviewers were resolved by consensus.
We fit a Bayesian model to take into account the between-study variability and estimated the treatment effect based on 22 studies.
We used WinBUGS software to fit this model and draw inferences regarding the overall treatment rates as well as response rates among treated or control groups.
Categorical variables were analysed using the chi-square test, while continuous variables were evaluated using the Student's t-test. A two-sided P-value of <0.05 is considered statistically significant.
Quality of life considerations for patients with chronic hepatitis C
Quality of life considerations for patients with chronic hepatitis C: "SVR improves long-term prognosis & health-related quality of life - mental health, physical & general health/virality, emotional health"
from Jules: I can tell you from my personal experience, after successfully completing peg/RBV therapy about 6 years ago (I was the first peg coinfection cure), I never felt better. My cognitive skills, energy, fatigue started to improve shortly after achieving SVR and continued improving for several years, I had not felt better in years.
Journal of Viral Hepatitis Aug 2009
G. R. Foster
The Liver Unit, Clinical Academic Unit of Digestive Diseases, Barts and The London School of Medicine and Dentistry, Queen Marys University of London, London, UK
Correspondence to Graham R. Foster, Professor of Hepatology, The Liver Unit, Clinical Academic Unit of Digestive Diseases, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, 4 Newark Street, London E1 2AT, UK. E-mail: g.r.foster@qmul.ac.uk
In a study involving 205 HCV-infected men, testosterone levels were lower in HCV-positive patients than in age-matched controls, and the HCV patients with erectile dysfunction had significantly lower testosterone levels than those with normal sexual function.....The association between psychiatric disturbances and chronic HCV infection is also strong
"HCV infection reduces the HRQoL of most chronically infected patients. Fatigue, depression and cognitive impairment are among the most common complaints of patients, and all of these symptoms have the potential to impair patients' ability to function at work or in society. For the vast majority of patients, SVR improves not only long-term prognosis but also HRQoL. Yet SVR is frequently an elusive goal, often because of the adverse effects of currently available agents. Many patients also refuse to start treatment, probably due to concerns about adverse effects [45,51]. Without treatment, however, patients with chronic HCV infection will be unlikely to see any improvement in HRQoL. This calls for greater efforts to encourage patients to start and stay on antiviral treatment. Various novel agents, including telaprevir, boceprevir and longer-acting interferons such as albinterferon alfa-2b, appear to offer improved SVR rates and/or more convenient administration options compared with current therapies, potentially leading to improvements in HRQoL in patients with chronic hepatitis C."
"Various studies have shown that HRQoL improves after SVR has been achieved [14,15,17–19]. A recent study of HRQoL in 29 patients receiving PEG-IFN-α showed that the 13 patients who achieved SVR after 12 weeks of treatment had significantly improved mental health summary scores on the SF-36 [14]. A recent analysis of data from the Hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial showed that SVR significantly improved scores in the role physical, general health, vitality, and role emotional domains of the SF-36. All patients in this trial had been previous nonresponders to antiviral therapy."
fatigue, malaise, depression and cognitive impairment – all neuropsychiatric disorders – are among the most common complaints of patients with chronic hepatitis C and occur independently of liver disease or treatment status
The strongest evidence for HCV action within the central nervous system comes from studies indicating that neurocognitive deficits occur in 15–30% of patients with chronic HCV infection [21,24,25]. These deficits are typically assessed using computer-directed, timed assessments of a variety of higher neurological functions, such as pattern recognition. These deficits were once attributed to cirrhosis-associated hepatic encephalopathy: in a study from 2003 that compared HRQoL and neuropsychological function in healthy control subjects and 120 patients divided according to severity of liver disease, neurologic abnormalities were found only in patients with decompensated cirrhosis [26]. However, studies using more sensitive tests of attention and concentration as well as brain imaging and evoked potential analyses have demonstrated that mild impairment of cognition and neural response does occur in patients with chronic HCV infection in the absence of liver disease......A more recent imaging study has confirmed that HCV causes neurologic damage, possibly through immune activation of cerebral microglial cells, as occurs in HIV infection
Another extrahepatic manifestation of chronic HCV infection that reduces HRQoL is sexual dysfunction. More data are available for male than for female sexual dysfunction and HCV. In one small study that included women, 50% of the 22 female patients in the study reported sexual dysfunction, compared with 43% in the general population [30,31]. The most frequently reported problems were lack of sexual drive (55%) and difficulties with arousal (50%) and orgasm (59%) [30]. The prevalence of male sexual dysfunction in patients with chronic HCV infection may range as high as 47%, with erectile dysfunction rates of up to 39% [30,32,33]. Antiviral treatment, depression and gamma glutamyl transpeptidase (GGT) levels may each contribute to male sexual dysfunction [30,34]. However, HCV itself appears to play a causative role [32,33].
The cause-and-effect relationship between chronic HCV infection and neuropsychological symptoms may be impossible to decipher in a disease that so profoundly compromises quality of life: is the patient depressed because of viral activity within the central nervous system, or is depression secondary to functional impairments, social stigma or the inevitable concerns relating to long-term prognosis? By itself, the news of an HCV diagnosis can reduce patients' perceived quality of life [38–40], and host-related factors and supporting networks may play a crucial role. In a large, cross-sectional survey of unselected HCV-positive patients, low household income, diabetes and history of intravenous drug use was shown to be independent predictors of reduced HRQoL, while viral load, HCV RNA presence or absence, and history of treatment success or failure were not significantly correlated with reduced scores on the SF-36 or Hospital Anxiety Depression Scale (HADS) [12]. Ultimately, however, the relevant observation is that chronic HCV infection is strongly associated with both neuropsychiatric disturbances and reduced HRQoL, whatever the cause–effect relationship.
Author's Conclusions
Independently of liver disease, HCV infection reduces the HRQoL of most chronically infected patients. Fatigue, depression and cognitive impairment are among the most common complaints of patients, and all of these symptoms have the potential to impair patients' ability to function at work or in society. For the vast majority of patients, SVR improves not only long-term prognosis but also HRQoL. Yet SVR is frequently an elusive goal, often because of the adverse effects of currently available agents. Many patients also refuse to start treatment, probably due to concerns about adverse effects [45,51]. Without treatment, however, patients with chronic HCV infection will be unlikely to see any improvement in HRQoL. This calls for greater efforts to encourage patients to start and stay on antiviral treatment. Various novel agents, including telaprevir, boceprevir and longer-acting interferons such as albinterferon alfa-2b, appear to offer improved SVR rates and/or more convenient administration options compared with current therapies, potentially leading to improvements in HRQoL in patients with chronic hepatitis C.
ABSTRACT
Summary. Chronic infection with the hepatitis C virus (HCV) has a profound effect on health-related quality of life (HRQoL) – with fatigue, depression and neurocognitive deficits among the most common complaints. Neuropsychiatric symptoms have prompted research to determine whether the HCV acts within the central nervous system. Replicating virus has been found in central nervous tissues, and changes in neurotransmitter levels in the frontal white matter of patients with chronic hepatitis C are correlated with impaired attention and concentration. Other symptoms of chronic hepatitis C that decrease HRQoL include associated sexual dysfunction and depression. Treatment of chronic HCV infection may temporarily worsen HRQoL, and common adverse effects of currently available agents include fatigue, muscle aches, depression and cognitive deficits. The relationship between sustained viral response and improvement in HRQoL is nonetheless well accepted. Although treatment-related adverse effects may dissuade people from starting therapy and reduce compliance with associated reductions in sustained viral response, for the majority of patients viral clearance produces improvements in both HRQoL and long-term prognosis. Novel agents, with improved adverse effect profiles, may afford more patients the opportunity to achieve a sustained viral response.
Article Text
Even in the absence of liver disease, chronic infection with the hepatitis C virus (HCV) compromises health-related quality of life (HRQoL), with profound negative impacts on both physical and mental well being, similar to other chronic conditions. In a classic study to define normative data for the Short Form 36 (SF-36), which is the most commonly used HRQoL assessment tool, 2489 of 9332 survey respondents reported a long-standing illness. Across all eight physical and mental health domains of the SF-36, scores for the chronic disease cohort were approximately 10–20 points lower than scores for individuals without long-standing illness, indicating consistently impaired well being as a consequence of chronic ill health [1]. Patients with chronic HCV infection had median decreases of 9–20 points (weighted mean decrease: 7–16 points) in a recent meta-analysis of 15 studies using the SF-36 to assess the HRQoL of patients with chronic hepatitis C vs healthy controls [2].
Hepatitis C-related detriments in physical well being are thus comparable to those of other chronic diseases. However, in an international comparison of the effects of various chronic conditions on HRQoL, physical and general health scores were significantly decreased by 7–12 points for arthritis, chronic lung disease, congestive heart failure, diabetes and ischemic heart disease, whereas mental health detriments were smaller, in the range of 2–5 points [3]. In contrast, HCV infection also significantly impacts mental health, with decrements of 10–12 points in median mental health scores (mean decrease: 7–13 points) [2]. The negative effects on HRQoL derive from various disease, host and treatment-related factors in chronic HCV infection. Understanding the scales used to measure quality of life, the physical and neurologic impairments due to chronic HCV infection, and the beneficial and adverse effects of available treatments is important for understanding patients' concerns. These topics will be addressed in this review.
Measuring HRQoL in chronic hepatitis C
HRQoL, which comprises the physical, mental and social effects of a disease, is measured by assessing somatic symptoms; psychological status; social interactions; physical, cognitive, and psychosocial functioning; sense of well being; and emotional status [4]. Various generic and disease-specific scales are available to measure HRQoL in patients with chronic hepatitis C. These include the SF-36, Hepatitis Quality of Life Questionnaire (HQLQ), Chronic Liver Disease Questionnaire (CLDQ), the Liver Disease Quality Of Life Questionnaire (LD QOL) and the Liver Disease Symptom Index 2.0 (LDSI 2.0). These instruments evaluate HRQoL from the patient's perspective. In addition, utility measures – such as the Health Utilities Index (HUI), Short Form-6D (SF-6D) and the EuroQol-5D (EQ-5D) – permit calculation of quality-adjusted life years (QALY) for cost effectiveness and medical decision-making analyses [4]. These instruments contain time-consuming questionnaires and are more widely used in research than in the clinical setting.
Of the patient-oriented scales, the SF-36 is the preferred tool for HRQoL assessment in a wide range of different diseases, including chronic HCV infection. This generic instrument, which permits comparison of HRQoL status with other conditions, includes 36 items divided into eight domain scales, which contribute to either a physical or a mental health summary measure (Fig. 1). Each scale is scored from 1 to 100, with higher scores indicating better HRQoL [1,5]. 'Normal' scores typically vary by scale; for example, vitality scores for the general population may be closer to 50 than 100, while a role-physical score for a healthy individual should be well above 80. Standard deviations within scales also vary widely. For these reasons, an updated SF-36 with norm-based scoring was issued in 2000. In the SF-36 version 2 (v2), each scale is scored to have the same average (50) and the same standard deviation of 10 points [5].
In some HCV-specific assessments, such as the HQLQ, the SF-36 is supplemented with HCV-specific scales (e.g. HCV-associated distress and limitations) [6]. Such disease-specific questionnaires have the advantage of capturing data on disease-specific symptoms – but with the disadvantage that they cannot be used to compare the effects of different illnesses – whereas the SF-36 is a sensitive measure of HCV-associated reductions in HRQoL. The SF-36 vitality scale, which measures symptoms such as fatigue, energy level and lassitude, may be particularly relevant to patients with chronic hepatitis C [7]. A recent systematic review of 15 studies comparing HRQoL in HCV-infected patients vs healthy controls showed that HCV infection most profoundly impaired vitality, general health, physical function and social function. Of these, vitality was considered the most important scale to patients, and based on the results of the systematic review, the authors concluded that a change of 4.2 points on the SF-36 vitality scale has clinical significance [7].
Disease-related HRQoL issues
Numerous studies have demonstrated that HRQoL is reduced regardless of the severity of liver disease or psychiatric comorbidities [7–13]. Moreover, quality of life frequently improves after completion of antiviral treatment [1,14–19]. These observations suggest that HCV may exert a direct effect on HRQoL, although the mechanism is unknown. One possibility is that HCV may act within the central nervous system [20,21], since replicating virus has been found within nervous system tissues [22,23]. Moreover, fatigue, malaise, depression and cognitive impairment – all neuropsychiatric disorders – are among the most common complaints of patients with chronic hepatitis C and occur independently of liver disease or treatment status [8–11].
The strongest evidence for HCV action within the central nervous system comes from studies indicating that neurocognitive deficits occur in 15–30% of patients with chronic HCV infection [21,24,25]. These deficits are typically assessed using computer-directed, timed assessments of a variety of higher neurological functions, such as pattern recognition. These deficits were once attributed to cirrhosis-associated hepatic encephalopathy: in a study from 2003 that compared HRQoL and neuropsychological function in healthy control subjects and 120 patients divided according to severity of liver disease, neurologic abnormalities were found only in patients with decompensated cirrhosis [26]. However, studies using more sensitive tests of attention and concentration as well as brain imaging and evoked potential analyses have demonstrated that mild impairment of cognition and neural response does occur in patients with chronic HCV infection in the absence of liver disease [11,21,24].
Small but significant changes in P300 event-related potentials were demonstrated in a study of 100 untreated HCV-infected patients compared with healthy, matched controls. These changes were not related to viral activity, fatigue severity, or psychiatric comorbidities, nor were they more likely to occur in patients with cirrhosis vs those without [24]. In another study, which used a computer-based cognitive assessment battery to evaluate 27 HCV-positive patients and 16 patients with cleared HCV, concentration was impaired and working memory was slower in the infected patients irrespective of intravenous drug use, depression, fatigue or symptom severity [11]. A cerebral proton magnetic resonance spectroscopy (MRS) procedure conducted in 17 of the subjects showed that choline/creatine ratios in the basal ganglia and white matter were significantly higher than those of healthy controls (P = 0.04) [11]. Moreover, mean ratios in the basal ganglia were significantly higher in patients impaired on two or more tasks in the cognition battery than were ratios in patients without cognitive impairment (P = 0.036) or ratios in healthy controls (P = 0.007). A more recent imaging study has confirmed that HCV causes neurologic damage, possibly through immune activation of cerebral microglial cells, as occurs in HIV infection [21]. MRS was used to study 25 HCV-positive patients with histologically mild liver disease. Cognitive tests in 16 of these patients showed significant impairment in attention and working memory compared with healthy volunteers (P < 0.005) and with HCV-negative patients previously exposed to HCV (P = 0.03). Mean myo-inositol/creatine ratios in the frontal white matter were significantly higher in the HCV-positive patients than in healthy control subjects (P = 0.02). As shown in Fig. 2, these elevated ratios were significantly correlated with prolonged working memory reaction times (R = 0.72, P = 0.002) [21].
Whether neurocognitive deficits are reversible remains an open question. Studies of the cognitive effects of antiviral therapy have found that cognition typically worsens with interferon-α (IFN-α) treatment and subsequently improves to baseline levels upon completion or withdrawal of therapy [20,25]. However, no studies have examined whether cognition improves beyond baseline levels after patients with cognitive impairment have achieved viral clearance. Ongoing studies examining this important question are in progress.
Even as the body of evidence grows demonstrating that HCV affects the central nervous system, whether its negative impact on HRQoL derives from that effect remains a topic of debate. In the study evaluating patients with different degrees of liver disease, even patients with mild liver damage due to HCV had decrements in HRQoL compared with controls, confirming the negative effect of HCV on quality of life independently of liver disease. These authors concluded that neurocognitive dysfunction was not related to reduced HRQoL because physical summary scores on the SF-36 were not correlated with patients' cognition, although it is possible that the instruments used in this study were not sensitive enough to detect mild impairments in cognition, or too few patients were included in the study [26]. Moreover, the SF-36 does not include a cognitive function scale and thus cannot assess difficulties with memory, concentration and attention – all problems frequently reported by patients infected with HCV [11,27,28].
Other studies have also failed to find a link between cognitive deficits and reduced HRQoL. In a small study to determine whether the effects of HCV might contribute to learning difficulties in children, no significant differences were found in adaptive behavior, general intelligence, attention/concentration, expressive vocabulary or visual-spatial construction between HCV-positive and -negative patients aged 6–19 years [29]. In another study evaluating cognition with P300 event-related potentials, no association between subclinical cognitive brain dysfunction and reduced quality of life was found. Instead, fatigue severity and age were independent predictors of HRQoL impairments [13]. In this case, it is possible that the cognitive deficits were not severe enough to have a significant effect on quality of life. Taken together, these data suggest that patients with chronic HCV infection have small but significant effects on higher neurological functioning, but the impact of these changes on physical and mental well being is unclear and, presumably, relates to both the magnitude of the changes and the individuals personal 'coping' strategies that, in some patients, may mitigate the effects of infection.
Another extrahepatic manifestation of chronic HCV infection that reduces HRQoL is sexual dysfunction. More data are available for male than for female sexual dysfunction and HCV. In one small study that included women, 50% of the 22 female patients in the study reported sexual dysfunction, compared with 43% in the general population [30,31]. The most frequently reported problems were lack of sexual drive (55%) and difficulties with arousal (50%) and orgasm (59%) [30]. The prevalence of male sexual dysfunction in patients with chronic HCV infection may range as high as 47%, with erectile dysfunction rates of up to 39% [30,32,33]. Antiviral treatment, depression and gamma glutamyl transpeptidase (GGT) levels may each contribute to male sexual dysfunction [30,34]. However, HCV itself appears to play a causative role [32,33].
In a study involving 205 HCV-infected men, testosterone levels were lower in HCV-positive patients than in age-matched controls, and the HCV patients with erectile dysfunction had significantly lower testosterone levels than those with normal sexual function (P < 0.01). Neither hepatic failure nor IFN-α therapy were related to erectile dysfunction in this study [32]. Another study involving 112 HCV-positive and 239 HCV-negative men found that HCV-related sexual dysfunction occurs independently of depression and significantly impairs HRQoL. Among the men in this study who did not have depression, 47% of HCV-positive men had low scores on sexual satisfaction scales, compared with only 11% of HCV-negative men (P < 0.001). In addition, HCV-positive men with sexual dysfunction scored significantly worse on six of the eight scales of the SF-36 than HCV-positive men with no sexual problems [33].
The association between psychiatric disturbances and chronic HCV infection is also strong. Between one quarter and more than half of patients who are infected with HCV show signs of clinical depression and/or anxiety, which dramatically affect HRQoL [35,36]. In a study involving 271 patients with HCV starting therapy with pegylated interferon (PEG-IFN), baseline depression scale scores were strongly correlated with HRQoL impairments. In fact, when history of depression and baseline depressive symptoms was added to an HRQoL regression analysis, the association between depression and HRQoL detriments was so strong that correlations between HRQoL and BMI, viral load and cirrhosis (previously analysed separately from depression) lost statistical significance. Not surprisingly, increasing degrees of depression, as indicated by higher scores on the Center for Epidemiologic Studies Depression Scale (CES-D), were associated with significantly greater detriments in HRQoL (Fig. 3) [37].
The cause-and-effect relationship between chronic HCV infection and neuropsychological symptoms may be impossible to decipher in a disease that so profoundly compromises quality of life: is the patient depressed because of viral activity within the central nervous system, or is depression secondary to functional impairments, social stigma or the inevitable concerns relating to long-term prognosis? By itself, the news of an HCV diagnosis can reduce patients' perceived quality of life [38–40], and host-related factors and supporting networks may play a crucial role. In a large, cross-sectional survey of unselected HCV-positive patients, low household income, diabetes and history of intravenous drug use was shown to be independent predictors of reduced HRQoL, while viral load, HCV RNA presence or absence, and history of treatment success or failure were not significantly correlated with reduced scores on the SF-36 or Hospital Anxiety Depression Scale (HADS) [12]. Ultimately, however, the relevant observation is that chronic HCV infection is strongly associated with both neuropsychiatric disturbances and reduced HRQoL, whatever the cause–effect relationship.
Treatment-related HRQoL issues
The adverse event profiles of interferon-based treatments and ribavirin pose formidable barriers to achieving a sustained viral response (SVR) for many patients. Combination therapy with these agents is now the standard of care for patients with chronic HCV infection, but these agents carry a high incidence of fatigue, depression, insomnia, muscle aches and cognitive impairment. Inevitably these adverse effects are associated with decreased HRQoL [25,25,37,41,42]. As a result, rates of dose reduction or therapy discontinuation can be high. In a study that compared combination therapy with PEG-IFN-α2a and ribavirin with IFN-α2b plus ribavirin or with PEG-IFN-α2a alone, 34–42% of patients who discontinued combination therapy did so because of adverse events (insufficient response was the most frequently cited reason for discontinuations). Dose reductions were also common in this study; of patients receiving combination therapy, one out of 10 had the dose of interferon reduced and one out of five had the ribavirin dose reduced [43]. In a study of patient concerns, side effects and depression were cited by as many as 73% of antiviral therapy recipients as challenges to treatment adherence, and 15% of patients in this study had discontinued therapy [44]. A pooled analysis of 1441 patients randomized to either PEG-IFN-α-2a or IFN-α-2a showed that worsening fatigue (P < 0.001) and SF-36 physical (P < 0.01) and mental (P < 0.05) summary scores were significant predictors of treatment discontinuation, which occurred in 10% of the patients studied [41].
Patients often rate the impact of treatment side effects as worse than providers do. In a survey of 92 patients with chronic hepatitis C and 23 providers, patients' perceptions of future treatment side effects were worse than their perception of their current health – leading to an unwillingness to undergo therapy to stave off disease worsening later in life [45]. In another study of treated patients, 31% reported needing to scale back or quit employment, and another 20% reported deterioration of relationships with family and friends due to treatment-related adverse effects [46].
Does sustained viral response lead to improved HRQoL?
Various studies have shown that HRQoL improves after SVR has been achieved [14,15,17–19]. A recent study of HRQoL in 29 patients receiving PEG-IFN-α showed that the 13 patients who achieved SVR after 12 weeks of treatment had significantly improved mental health summary scores on the SF-36 [14]. A recent analysis of data from the Hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial showed that SVR significantly improved scores in the role physical, general health, vitality, and role emotional domains of the SF-36. All patients in this trial had been previous nonresponders to antiviral therapy. Of the 1144 who entered a 24-week lead-in phase involving PEG-IFN-α and ribavirin, 373 responded and underwent another 24 weeks of therapy (for a total of 48 weeks). HRQoL data were available for 258 patients who were surveyed at baseline and at week 72, 24 weeks after completing treatment. Of these, the 76 patients who relapsed had significantly worse HRQoL scores than those who achieved SVR [15].
Although the relationship between SVR and HRQoL improvement is well accepted, several issues must be considered. First, many studies are small in scale, so data may not be applicable to larger patient populations. Second, the majority of these studies are not prospective. Patients learned of their HCV status before taking the HRQoL questionnaire, which inevitably influences the results. It is reasonable to suppose that if a diagnosis of HCV reduces HRQoL by itself [38–40], learning of viral clearance may improve HRQoL scores. However, some evidence suggests this may not be the case. In one study designed so that patients learned of their viral status after taking the post-treatment HRQoL assessment, significant improvements in five of the eight SF-36 domains were observed in SVR patients compared with nonresponders [16]. Anecdotal evidence from the HALT-C trial also suggests that actual viral status has a stronger bearing on HRQoL than patient perception. Two patients in the HALT-C trial were late relapsers and believed themselves to be HCV-negative at the time they answered the 72-week SF-36 questionnaire. Consistent with their HCV-positive status, their HRQoL scores were low, similar to those of the other patients who did not achieve SVR in this study [15].
Occasionally, there are patients who have no detectable HCV RNA but who also do not have improved HRQoL. Some may be false-negative patients, like the two reported from the HALT-C study. Others may have residual chronic fatigue syndrome despite cleared virus, as occurs after eradication of hepatitis A and B viruses [47]. Another possibility is persistence of HCV in liver or other tissues, even when it is undetectable in serum. In a recent study demonstrating the durability of SVR, HCV RNA remained undetectable in serum or peripheral blood mononuclear cells (PBMCs) for a median of 3.3 years in patients who had no serum HCV RNA 6 months after treatment. Yet in 1.7% of the patients who had liver biopsies, HCV RNA was detected in hepatic tissues [48]. Other studies have documented persistent HCV infection in the liver and also in PBMCs long after SVR [49,50]. These provocative findings suggest that persistent virus may account for low HRQoL despite SVR in a small subset of patients.
from Jules: I can tell you from my personal experience, after successfully completing peg/RBV therapy about 6 years ago (I was the first peg coinfection cure), I never felt better. My cognitive skills, energy, fatigue started to improve shortly after achieving SVR and continued improving for several years, I had not felt better in years.
Journal of Viral Hepatitis Aug 2009
G. R. Foster
The Liver Unit, Clinical Academic Unit of Digestive Diseases, Barts and The London School of Medicine and Dentistry, Queen Marys University of London, London, UK
Correspondence to Graham R. Foster, Professor of Hepatology, The Liver Unit, Clinical Academic Unit of Digestive Diseases, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, 4 Newark Street, London E1 2AT, UK. E-mail: g.r.foster@qmul.ac.uk
In a study involving 205 HCV-infected men, testosterone levels were lower in HCV-positive patients than in age-matched controls, and the HCV patients with erectile dysfunction had significantly lower testosterone levels than those with normal sexual function.....The association between psychiatric disturbances and chronic HCV infection is also strong
"HCV infection reduces the HRQoL of most chronically infected patients. Fatigue, depression and cognitive impairment are among the most common complaints of patients, and all of these symptoms have the potential to impair patients' ability to function at work or in society. For the vast majority of patients, SVR improves not only long-term prognosis but also HRQoL. Yet SVR is frequently an elusive goal, often because of the adverse effects of currently available agents. Many patients also refuse to start treatment, probably due to concerns about adverse effects [45,51]. Without treatment, however, patients with chronic HCV infection will be unlikely to see any improvement in HRQoL. This calls for greater efforts to encourage patients to start and stay on antiviral treatment. Various novel agents, including telaprevir, boceprevir and longer-acting interferons such as albinterferon alfa-2b, appear to offer improved SVR rates and/or more convenient administration options compared with current therapies, potentially leading to improvements in HRQoL in patients with chronic hepatitis C."
"Various studies have shown that HRQoL improves after SVR has been achieved [14,15,17–19]. A recent study of HRQoL in 29 patients receiving PEG-IFN-α showed that the 13 patients who achieved SVR after 12 weeks of treatment had significantly improved mental health summary scores on the SF-36 [14]. A recent analysis of data from the Hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial showed that SVR significantly improved scores in the role physical, general health, vitality, and role emotional domains of the SF-36. All patients in this trial had been previous nonresponders to antiviral therapy."
fatigue, malaise, depression and cognitive impairment – all neuropsychiatric disorders – are among the most common complaints of patients with chronic hepatitis C and occur independently of liver disease or treatment status
The strongest evidence for HCV action within the central nervous system comes from studies indicating that neurocognitive deficits occur in 15–30% of patients with chronic HCV infection [21,24,25]. These deficits are typically assessed using computer-directed, timed assessments of a variety of higher neurological functions, such as pattern recognition. These deficits were once attributed to cirrhosis-associated hepatic encephalopathy: in a study from 2003 that compared HRQoL and neuropsychological function in healthy control subjects and 120 patients divided according to severity of liver disease, neurologic abnormalities were found only in patients with decompensated cirrhosis [26]. However, studies using more sensitive tests of attention and concentration as well as brain imaging and evoked potential analyses have demonstrated that mild impairment of cognition and neural response does occur in patients with chronic HCV infection in the absence of liver disease......A more recent imaging study has confirmed that HCV causes neurologic damage, possibly through immune activation of cerebral microglial cells, as occurs in HIV infection
Another extrahepatic manifestation of chronic HCV infection that reduces HRQoL is sexual dysfunction. More data are available for male than for female sexual dysfunction and HCV. In one small study that included women, 50% of the 22 female patients in the study reported sexual dysfunction, compared with 43% in the general population [30,31]. The most frequently reported problems were lack of sexual drive (55%) and difficulties with arousal (50%) and orgasm (59%) [30]. The prevalence of male sexual dysfunction in patients with chronic HCV infection may range as high as 47%, with erectile dysfunction rates of up to 39% [30,32,33]. Antiviral treatment, depression and gamma glutamyl transpeptidase (GGT) levels may each contribute to male sexual dysfunction [30,34]. However, HCV itself appears to play a causative role [32,33].
The cause-and-effect relationship between chronic HCV infection and neuropsychological symptoms may be impossible to decipher in a disease that so profoundly compromises quality of life: is the patient depressed because of viral activity within the central nervous system, or is depression secondary to functional impairments, social stigma or the inevitable concerns relating to long-term prognosis? By itself, the news of an HCV diagnosis can reduce patients' perceived quality of life [38–40], and host-related factors and supporting networks may play a crucial role. In a large, cross-sectional survey of unselected HCV-positive patients, low household income, diabetes and history of intravenous drug use was shown to be independent predictors of reduced HRQoL, while viral load, HCV RNA presence or absence, and history of treatment success or failure were not significantly correlated with reduced scores on the SF-36 or Hospital Anxiety Depression Scale (HADS) [12]. Ultimately, however, the relevant observation is that chronic HCV infection is strongly associated with both neuropsychiatric disturbances and reduced HRQoL, whatever the cause–effect relationship.
Author's Conclusions
Independently of liver disease, HCV infection reduces the HRQoL of most chronically infected patients. Fatigue, depression and cognitive impairment are among the most common complaints of patients, and all of these symptoms have the potential to impair patients' ability to function at work or in society. For the vast majority of patients, SVR improves not only long-term prognosis but also HRQoL. Yet SVR is frequently an elusive goal, often because of the adverse effects of currently available agents. Many patients also refuse to start treatment, probably due to concerns about adverse effects [45,51]. Without treatment, however, patients with chronic HCV infection will be unlikely to see any improvement in HRQoL. This calls for greater efforts to encourage patients to start and stay on antiviral treatment. Various novel agents, including telaprevir, boceprevir and longer-acting interferons such as albinterferon alfa-2b, appear to offer improved SVR rates and/or more convenient administration options compared with current therapies, potentially leading to improvements in HRQoL in patients with chronic hepatitis C.
ABSTRACT
Summary. Chronic infection with the hepatitis C virus (HCV) has a profound effect on health-related quality of life (HRQoL) – with fatigue, depression and neurocognitive deficits among the most common complaints. Neuropsychiatric symptoms have prompted research to determine whether the HCV acts within the central nervous system. Replicating virus has been found in central nervous tissues, and changes in neurotransmitter levels in the frontal white matter of patients with chronic hepatitis C are correlated with impaired attention and concentration. Other symptoms of chronic hepatitis C that decrease HRQoL include associated sexual dysfunction and depression. Treatment of chronic HCV infection may temporarily worsen HRQoL, and common adverse effects of currently available agents include fatigue, muscle aches, depression and cognitive deficits. The relationship between sustained viral response and improvement in HRQoL is nonetheless well accepted. Although treatment-related adverse effects may dissuade people from starting therapy and reduce compliance with associated reductions in sustained viral response, for the majority of patients viral clearance produces improvements in both HRQoL and long-term prognosis. Novel agents, with improved adverse effect profiles, may afford more patients the opportunity to achieve a sustained viral response.
Article Text
Even in the absence of liver disease, chronic infection with the hepatitis C virus (HCV) compromises health-related quality of life (HRQoL), with profound negative impacts on both physical and mental well being, similar to other chronic conditions. In a classic study to define normative data for the Short Form 36 (SF-36), which is the most commonly used HRQoL assessment tool, 2489 of 9332 survey respondents reported a long-standing illness. Across all eight physical and mental health domains of the SF-36, scores for the chronic disease cohort were approximately 10–20 points lower than scores for individuals without long-standing illness, indicating consistently impaired well being as a consequence of chronic ill health [1]. Patients with chronic HCV infection had median decreases of 9–20 points (weighted mean decrease: 7–16 points) in a recent meta-analysis of 15 studies using the SF-36 to assess the HRQoL of patients with chronic hepatitis C vs healthy controls [2].
Hepatitis C-related detriments in physical well being are thus comparable to those of other chronic diseases. However, in an international comparison of the effects of various chronic conditions on HRQoL, physical and general health scores were significantly decreased by 7–12 points for arthritis, chronic lung disease, congestive heart failure, diabetes and ischemic heart disease, whereas mental health detriments were smaller, in the range of 2–5 points [3]. In contrast, HCV infection also significantly impacts mental health, with decrements of 10–12 points in median mental health scores (mean decrease: 7–13 points) [2]. The negative effects on HRQoL derive from various disease, host and treatment-related factors in chronic HCV infection. Understanding the scales used to measure quality of life, the physical and neurologic impairments due to chronic HCV infection, and the beneficial and adverse effects of available treatments is important for understanding patients' concerns. These topics will be addressed in this review.
Measuring HRQoL in chronic hepatitis C
HRQoL, which comprises the physical, mental and social effects of a disease, is measured by assessing somatic symptoms; psychological status; social interactions; physical, cognitive, and psychosocial functioning; sense of well being; and emotional status [4]. Various generic and disease-specific scales are available to measure HRQoL in patients with chronic hepatitis C. These include the SF-36, Hepatitis Quality of Life Questionnaire (HQLQ), Chronic Liver Disease Questionnaire (CLDQ), the Liver Disease Quality Of Life Questionnaire (LD QOL) and the Liver Disease Symptom Index 2.0 (LDSI 2.0). These instruments evaluate HRQoL from the patient's perspective. In addition, utility measures – such as the Health Utilities Index (HUI), Short Form-6D (SF-6D) and the EuroQol-5D (EQ-5D) – permit calculation of quality-adjusted life years (QALY) for cost effectiveness and medical decision-making analyses [4]. These instruments contain time-consuming questionnaires and are more widely used in research than in the clinical setting.
Of the patient-oriented scales, the SF-36 is the preferred tool for HRQoL assessment in a wide range of different diseases, including chronic HCV infection. This generic instrument, which permits comparison of HRQoL status with other conditions, includes 36 items divided into eight domain scales, which contribute to either a physical or a mental health summary measure (Fig. 1). Each scale is scored from 1 to 100, with higher scores indicating better HRQoL [1,5]. 'Normal' scores typically vary by scale; for example, vitality scores for the general population may be closer to 50 than 100, while a role-physical score for a healthy individual should be well above 80. Standard deviations within scales also vary widely. For these reasons, an updated SF-36 with norm-based scoring was issued in 2000. In the SF-36 version 2 (v2), each scale is scored to have the same average (50) and the same standard deviation of 10 points [5].
In some HCV-specific assessments, such as the HQLQ, the SF-36 is supplemented with HCV-specific scales (e.g. HCV-associated distress and limitations) [6]. Such disease-specific questionnaires have the advantage of capturing data on disease-specific symptoms – but with the disadvantage that they cannot be used to compare the effects of different illnesses – whereas the SF-36 is a sensitive measure of HCV-associated reductions in HRQoL. The SF-36 vitality scale, which measures symptoms such as fatigue, energy level and lassitude, may be particularly relevant to patients with chronic hepatitis C [7]. A recent systematic review of 15 studies comparing HRQoL in HCV-infected patients vs healthy controls showed that HCV infection most profoundly impaired vitality, general health, physical function and social function. Of these, vitality was considered the most important scale to patients, and based on the results of the systematic review, the authors concluded that a change of 4.2 points on the SF-36 vitality scale has clinical significance [7].
Disease-related HRQoL issues
Numerous studies have demonstrated that HRQoL is reduced regardless of the severity of liver disease or psychiatric comorbidities [7–13]. Moreover, quality of life frequently improves after completion of antiviral treatment [1,14–19]. These observations suggest that HCV may exert a direct effect on HRQoL, although the mechanism is unknown. One possibility is that HCV may act within the central nervous system [20,21], since replicating virus has been found within nervous system tissues [22,23]. Moreover, fatigue, malaise, depression and cognitive impairment – all neuropsychiatric disorders – are among the most common complaints of patients with chronic hepatitis C and occur independently of liver disease or treatment status [8–11].
The strongest evidence for HCV action within the central nervous system comes from studies indicating that neurocognitive deficits occur in 15–30% of patients with chronic HCV infection [21,24,25]. These deficits are typically assessed using computer-directed, timed assessments of a variety of higher neurological functions, such as pattern recognition. These deficits were once attributed to cirrhosis-associated hepatic encephalopathy: in a study from 2003 that compared HRQoL and neuropsychological function in healthy control subjects and 120 patients divided according to severity of liver disease, neurologic abnormalities were found only in patients with decompensated cirrhosis [26]. However, studies using more sensitive tests of attention and concentration as well as brain imaging and evoked potential analyses have demonstrated that mild impairment of cognition and neural response does occur in patients with chronic HCV infection in the absence of liver disease [11,21,24].
Small but significant changes in P300 event-related potentials were demonstrated in a study of 100 untreated HCV-infected patients compared with healthy, matched controls. These changes were not related to viral activity, fatigue severity, or psychiatric comorbidities, nor were they more likely to occur in patients with cirrhosis vs those without [24]. In another study, which used a computer-based cognitive assessment battery to evaluate 27 HCV-positive patients and 16 patients with cleared HCV, concentration was impaired and working memory was slower in the infected patients irrespective of intravenous drug use, depression, fatigue or symptom severity [11]. A cerebral proton magnetic resonance spectroscopy (MRS) procedure conducted in 17 of the subjects showed that choline/creatine ratios in the basal ganglia and white matter were significantly higher than those of healthy controls (P = 0.04) [11]. Moreover, mean ratios in the basal ganglia were significantly higher in patients impaired on two or more tasks in the cognition battery than were ratios in patients without cognitive impairment (P = 0.036) or ratios in healthy controls (P = 0.007). A more recent imaging study has confirmed that HCV causes neurologic damage, possibly through immune activation of cerebral microglial cells, as occurs in HIV infection [21]. MRS was used to study 25 HCV-positive patients with histologically mild liver disease. Cognitive tests in 16 of these patients showed significant impairment in attention and working memory compared with healthy volunteers (P < 0.005) and with HCV-negative patients previously exposed to HCV (P = 0.03). Mean myo-inositol/creatine ratios in the frontal white matter were significantly higher in the HCV-positive patients than in healthy control subjects (P = 0.02). As shown in Fig. 2, these elevated ratios were significantly correlated with prolonged working memory reaction times (R = 0.72, P = 0.002) [21].
Whether neurocognitive deficits are reversible remains an open question. Studies of the cognitive effects of antiviral therapy have found that cognition typically worsens with interferon-α (IFN-α) treatment and subsequently improves to baseline levels upon completion or withdrawal of therapy [20,25]. However, no studies have examined whether cognition improves beyond baseline levels after patients with cognitive impairment have achieved viral clearance. Ongoing studies examining this important question are in progress.
Even as the body of evidence grows demonstrating that HCV affects the central nervous system, whether its negative impact on HRQoL derives from that effect remains a topic of debate. In the study evaluating patients with different degrees of liver disease, even patients with mild liver damage due to HCV had decrements in HRQoL compared with controls, confirming the negative effect of HCV on quality of life independently of liver disease. These authors concluded that neurocognitive dysfunction was not related to reduced HRQoL because physical summary scores on the SF-36 were not correlated with patients' cognition, although it is possible that the instruments used in this study were not sensitive enough to detect mild impairments in cognition, or too few patients were included in the study [26]. Moreover, the SF-36 does not include a cognitive function scale and thus cannot assess difficulties with memory, concentration and attention – all problems frequently reported by patients infected with HCV [11,27,28].
Other studies have also failed to find a link between cognitive deficits and reduced HRQoL. In a small study to determine whether the effects of HCV might contribute to learning difficulties in children, no significant differences were found in adaptive behavior, general intelligence, attention/concentration, expressive vocabulary or visual-spatial construction between HCV-positive and -negative patients aged 6–19 years [29]. In another study evaluating cognition with P300 event-related potentials, no association between subclinical cognitive brain dysfunction and reduced quality of life was found. Instead, fatigue severity and age were independent predictors of HRQoL impairments [13]. In this case, it is possible that the cognitive deficits were not severe enough to have a significant effect on quality of life. Taken together, these data suggest that patients with chronic HCV infection have small but significant effects on higher neurological functioning, but the impact of these changes on physical and mental well being is unclear and, presumably, relates to both the magnitude of the changes and the individuals personal 'coping' strategies that, in some patients, may mitigate the effects of infection.
Another extrahepatic manifestation of chronic HCV infection that reduces HRQoL is sexual dysfunction. More data are available for male than for female sexual dysfunction and HCV. In one small study that included women, 50% of the 22 female patients in the study reported sexual dysfunction, compared with 43% in the general population [30,31]. The most frequently reported problems were lack of sexual drive (55%) and difficulties with arousal (50%) and orgasm (59%) [30]. The prevalence of male sexual dysfunction in patients with chronic HCV infection may range as high as 47%, with erectile dysfunction rates of up to 39% [30,32,33]. Antiviral treatment, depression and gamma glutamyl transpeptidase (GGT) levels may each contribute to male sexual dysfunction [30,34]. However, HCV itself appears to play a causative role [32,33].
In a study involving 205 HCV-infected men, testosterone levels were lower in HCV-positive patients than in age-matched controls, and the HCV patients with erectile dysfunction had significantly lower testosterone levels than those with normal sexual function (P < 0.01). Neither hepatic failure nor IFN-α therapy were related to erectile dysfunction in this study [32]. Another study involving 112 HCV-positive and 239 HCV-negative men found that HCV-related sexual dysfunction occurs independently of depression and significantly impairs HRQoL. Among the men in this study who did not have depression, 47% of HCV-positive men had low scores on sexual satisfaction scales, compared with only 11% of HCV-negative men (P < 0.001). In addition, HCV-positive men with sexual dysfunction scored significantly worse on six of the eight scales of the SF-36 than HCV-positive men with no sexual problems [33].
The association between psychiatric disturbances and chronic HCV infection is also strong. Between one quarter and more than half of patients who are infected with HCV show signs of clinical depression and/or anxiety, which dramatically affect HRQoL [35,36]. In a study involving 271 patients with HCV starting therapy with pegylated interferon (PEG-IFN), baseline depression scale scores were strongly correlated with HRQoL impairments. In fact, when history of depression and baseline depressive symptoms was added to an HRQoL regression analysis, the association between depression and HRQoL detriments was so strong that correlations between HRQoL and BMI, viral load and cirrhosis (previously analysed separately from depression) lost statistical significance. Not surprisingly, increasing degrees of depression, as indicated by higher scores on the Center for Epidemiologic Studies Depression Scale (CES-D), were associated with significantly greater detriments in HRQoL (Fig. 3) [37].
The cause-and-effect relationship between chronic HCV infection and neuropsychological symptoms may be impossible to decipher in a disease that so profoundly compromises quality of life: is the patient depressed because of viral activity within the central nervous system, or is depression secondary to functional impairments, social stigma or the inevitable concerns relating to long-term prognosis? By itself, the news of an HCV diagnosis can reduce patients' perceived quality of life [38–40], and host-related factors and supporting networks may play a crucial role. In a large, cross-sectional survey of unselected HCV-positive patients, low household income, diabetes and history of intravenous drug use was shown to be independent predictors of reduced HRQoL, while viral load, HCV RNA presence or absence, and history of treatment success or failure were not significantly correlated with reduced scores on the SF-36 or Hospital Anxiety Depression Scale (HADS) [12]. Ultimately, however, the relevant observation is that chronic HCV infection is strongly associated with both neuropsychiatric disturbances and reduced HRQoL, whatever the cause–effect relationship.
Treatment-related HRQoL issues
The adverse event profiles of interferon-based treatments and ribavirin pose formidable barriers to achieving a sustained viral response (SVR) for many patients. Combination therapy with these agents is now the standard of care for patients with chronic HCV infection, but these agents carry a high incidence of fatigue, depression, insomnia, muscle aches and cognitive impairment. Inevitably these adverse effects are associated with decreased HRQoL [25,25,37,41,42]. As a result, rates of dose reduction or therapy discontinuation can be high. In a study that compared combination therapy with PEG-IFN-α2a and ribavirin with IFN-α2b plus ribavirin or with PEG-IFN-α2a alone, 34–42% of patients who discontinued combination therapy did so because of adverse events (insufficient response was the most frequently cited reason for discontinuations). Dose reductions were also common in this study; of patients receiving combination therapy, one out of 10 had the dose of interferon reduced and one out of five had the ribavirin dose reduced [43]. In a study of patient concerns, side effects and depression were cited by as many as 73% of antiviral therapy recipients as challenges to treatment adherence, and 15% of patients in this study had discontinued therapy [44]. A pooled analysis of 1441 patients randomized to either PEG-IFN-α-2a or IFN-α-2a showed that worsening fatigue (P < 0.001) and SF-36 physical (P < 0.01) and mental (P < 0.05) summary scores were significant predictors of treatment discontinuation, which occurred in 10% of the patients studied [41].
Patients often rate the impact of treatment side effects as worse than providers do. In a survey of 92 patients with chronic hepatitis C and 23 providers, patients' perceptions of future treatment side effects were worse than their perception of their current health – leading to an unwillingness to undergo therapy to stave off disease worsening later in life [45]. In another study of treated patients, 31% reported needing to scale back or quit employment, and another 20% reported deterioration of relationships with family and friends due to treatment-related adverse effects [46].
Does sustained viral response lead to improved HRQoL?
Various studies have shown that HRQoL improves after SVR has been achieved [14,15,17–19]. A recent study of HRQoL in 29 patients receiving PEG-IFN-α showed that the 13 patients who achieved SVR after 12 weeks of treatment had significantly improved mental health summary scores on the SF-36 [14]. A recent analysis of data from the Hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial showed that SVR significantly improved scores in the role physical, general health, vitality, and role emotional domains of the SF-36. All patients in this trial had been previous nonresponders to antiviral therapy. Of the 1144 who entered a 24-week lead-in phase involving PEG-IFN-α and ribavirin, 373 responded and underwent another 24 weeks of therapy (for a total of 48 weeks). HRQoL data were available for 258 patients who were surveyed at baseline and at week 72, 24 weeks after completing treatment. Of these, the 76 patients who relapsed had significantly worse HRQoL scores than those who achieved SVR [15].
Although the relationship between SVR and HRQoL improvement is well accepted, several issues must be considered. First, many studies are small in scale, so data may not be applicable to larger patient populations. Second, the majority of these studies are not prospective. Patients learned of their HCV status before taking the HRQoL questionnaire, which inevitably influences the results. It is reasonable to suppose that if a diagnosis of HCV reduces HRQoL by itself [38–40], learning of viral clearance may improve HRQoL scores. However, some evidence suggests this may not be the case. In one study designed so that patients learned of their viral status after taking the post-treatment HRQoL assessment, significant improvements in five of the eight SF-36 domains were observed in SVR patients compared with nonresponders [16]. Anecdotal evidence from the HALT-C trial also suggests that actual viral status has a stronger bearing on HRQoL than patient perception. Two patients in the HALT-C trial were late relapsers and believed themselves to be HCV-negative at the time they answered the 72-week SF-36 questionnaire. Consistent with their HCV-positive status, their HRQoL scores were low, similar to those of the other patients who did not achieve SVR in this study [15].
Occasionally, there are patients who have no detectable HCV RNA but who also do not have improved HRQoL. Some may be false-negative patients, like the two reported from the HALT-C study. Others may have residual chronic fatigue syndrome despite cleared virus, as occurs after eradication of hepatitis A and B viruses [47]. Another possibility is persistence of HCV in liver or other tissues, even when it is undetectable in serum. In a recent study demonstrating the durability of SVR, HCV RNA remained undetectable in serum or peripheral blood mononuclear cells (PBMCs) for a median of 3.3 years in patients who had no serum HCV RNA 6 months after treatment. Yet in 1.7% of the patients who had liver biopsies, HCV RNA was detected in hepatic tissues [48]. Other studies have documented persistent HCV infection in the liver and also in PBMCs long after SVR [49,50]. These provocative findings suggest that persistent virus may account for low HRQoL despite SVR in a small subset of patients.
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