November 15, 2011
Silymarin, an extract of milk thistle (Carduus marianus), had no benefit on levels of the liver enzyme alanine aminotransferase (ALT) in people living with hepatitis C, according to a new study reported Tuesday, November 8, by researchers at the 62nd annual meeting of the American Association for the Study of Liver Diseases in San Francisco.
Originally a native of Southern Europe and Asia, the milk thistle plant is now found throughout the world. The medicinal parts of the plant are the ripe seeds—slymarin is a complex of milk thistle seed extracts—which have been used for centuries to help manage a variety of liver diseases.
Whether sylimarin has been proved scientifically to treat chronic hepatitis is debatable. Though it has established activity in test tube studies, notably in calming immune system cells that contribute to liver inflammation, studies involving humans taking the drug have produced mixed results. One reason is that that supplement hasn't been systematically studied in a specific population of people living with liver disease, notably chronic HCV infection.
The study, reported at AASLD by Michael Fried, MD, of the University of North Carolina at Chapel Hill and his colleagues, randomized three groups of people who had chronic hepatitis C and had tried interferon-based treatment in the past but were unable to cure their infection and had elevated ALT levels. For the study, they received one of two doses of Legalon-brand silymarin or placebo for 24 weeks.
To participate in the study, volunteers had to have ALT levels exceeding 65 international units per liter, or IU/L (normal is 45 IU/L); the average ALT level, upon entering the study, was 106 IU/L.
The Legalon doses employed in the study were 420 milligrams (mg) or 700 mg, to be taken three times daily. These doses, which are 4.5 to 7.5 times higher than the customary amount, were selected for the study based on the findings of an earlier Phase I study of the supplement.
The study’s primary goal was to get participants’ ALT levels below 45 IU/L, or to decrease the ALT level to below 65 IU/L, provided this was at least a 50 percent decline from pre-treatment measurements.
Four U.S. clinical centers enrolled a total of 154 people, of whom 90 percent completed the requisite 24 weeks of follow-up. Roughly 71 percent of the study volunteers were male, and on average they were 54 years old.
Unfortunately, average declines in ALT levels after 24 weeks of treatment did not differ significantly between the three groups. Six study volunteers—two receiving 420 mg Legalon, two receiving 700 mg Legalon and two receiving placebo—met one of the primary goals of the study.
Knowing that adherence can be a problem, particularly with a treatment requiring three-times-daily dosing, Fried’s group examined whether failure to take the Legalon as prescribed contributed to the lack of efficacy. Yet, more than 90 percent of the study volunteers met or exceeded an 80 percent adherence threshold, determined by counting the number of dose cups returned to the clinic sites. And when the analysis was restricted only to those who maintained at least 80 percent adherence, there were still no statistically significant differences between the three groups.
Fried noted, however, that Legalon treatment was well tolerated—side effects were similar in all three study groups.
“Although well tolerated,” Fried’s team concluded, “oral silymarin administered at higher-than-customary doses did not significantly alter biochemical markers of disease activity in patients with chronic hepatitis C who had failed prior treatment with interferon-based regimens.”
Source
November 15, 2011
CDC: More Deaths From HCV Infection Than HIV
Neil Canavan
November 14, 2011 (San Francisco, California) — Beginning in 2006, the number of deaths related to chronic hepatitis C virus (HCV) infection exceeded the number related to HIV, according to an analysis of mortality trends performed at the Centers for Disease Control and Prevention (CDC). Results of that analysis were reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
Scott Holmberg, MD, MPH, chief of the epidemiology and surveillance branch, division of viral hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, at the CDC in Atlanta, Georgia, observed that "the relatively young age of most HCV-infected persons who are now dying portends a large and increasing healthcare burden."
As Dr. Holmberg pointed out, 3.2 million people in the United States are living with chronic HCV, and roughly a million more are infected with hepatitis B virus (HBV). Of the total, two thirds were born between 1945 and 1964. Because of the generally slow progression of chronic hepatitis infection, "these people are just now entering the period of risk for developing HCV- and HBV-related comorbidity and mortality."
Chronic liver disease and cirrhosis were among the 15 leading causes of death in the United States in 2007, when there were 19,000 deaths from hepatocellular carcinoma — half of which were directly attributable to HCV infection.
Dr. Holmberg's team reviewed death certificates abstracted by the National Center for Health Statistics from 1999 to 2007. A death related to HBV, HCV, and/or HIV (assessed to compare mortality trends) was defined as any death with a report of the standard International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes: B16.0, B17.0, B18.0, and B18.1 for HBV; B17.1 and B18.2 for HCV; and B20 to B24 for HIV. Reflected in the codes are underlying and contributing causes of death.
"Our aim was to compare trends in deaths associated with HCV, HBV, and HIV infection, and to describe associations between select sociodemographic characteristics and comorbid conditions associated with hepatitis-related mortality, with particular focus on potentially preventable conditions," said Dr. Holmberg.
Demographic variables included patient age, sex, race, ethnicity, level of education, and marital status; comorbid conditions included HIV infection, alcohol-related conditions, and any antecedent liver disease.
The results of the analysis were striking. "Just counting the 21.8 million death certificates clearly shows the increasing incidence of HCV-related deaths — a significant rise at that," said Dr. Holmberg.
In contrast, data clearly show a stable rate for HBV-related deaths and a declining incidence of HIV-related deaths, which dropped below the death rate observed for HCV in 2006. Of note, the majority of HBV- and HCV-related deaths occurred in patients who were 45 to 64 years of age. "This epidemic is hitting middle-aged adults especially hard."
In 2007 — the last year of the analysis — there were 1815 HBV-related deaths recorded, with 59% occurring in middle-aged individuals. For HCV, of the 15,106 recorded deaths, 73% were in people 54 to 64 years of age.
"For both HCV and HBV, there was heavy representation in persons from racial and ethnic minorities," Dr. Holmberg reported.
Dr. Holmberg found that comorbidities associated with increased odds of HCV- and HBV-related mortality included chronic liver disease, coinfection with the other hepatitis virus, alcohol-related conditions, and HIV coinfection.
Dr. Holmberg acknowledged that death certificates are imperfect sources of information. "These things are often filled in by someone who is not the primary physician," he said. "However, looking at millions of deaths, the trends are clear. In fact, I would argue that this analysis greatly underestimates the relative impact of viral hepatitis."
Previous studies have shown that only 40% to 50% of HCV-infected individuals are identified as such prior to death, whereas 80% to 85% of patients infected with HIV have been diagnosed before succumbing to their illness, he pointed out.
Targeting the Boom
"If you consider the stability of the rates for hepatitis B and the declining death rates seen with HIV — those are most likely caused by improved awareness and advances in treatment of HIV," said AASLD president, T. Jake Liang, MD, tenured senior investigator and chief of the liver diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, in Bethesda, Maryland. For HCV, "mortality has actually increased, and has surpassed HIV."
Dr. Liang noted that the increase is striking particularly hard at baby boomers. "This is a population that we are very concerned about. We really need to be more aggressive in terms of trying to identify who they are and getting them into treatment."
Dr. Holmberg and Dr. Liang have disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 243. Presented November 8, 2011.
Source
November 14, 2011 (San Francisco, California) — Beginning in 2006, the number of deaths related to chronic hepatitis C virus (HCV) infection exceeded the number related to HIV, according to an analysis of mortality trends performed at the Centers for Disease Control and Prevention (CDC). Results of that analysis were reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
Scott Holmberg, MD, MPH, chief of the epidemiology and surveillance branch, division of viral hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, at the CDC in Atlanta, Georgia, observed that "the relatively young age of most HCV-infected persons who are now dying portends a large and increasing healthcare burden."
As Dr. Holmberg pointed out, 3.2 million people in the United States are living with chronic HCV, and roughly a million more are infected with hepatitis B virus (HBV). Of the total, two thirds were born between 1945 and 1964. Because of the generally slow progression of chronic hepatitis infection, "these people are just now entering the period of risk for developing HCV- and HBV-related comorbidity and mortality."
Chronic liver disease and cirrhosis were among the 15 leading causes of death in the United States in 2007, when there were 19,000 deaths from hepatocellular carcinoma — half of which were directly attributable to HCV infection.
Dr. Holmberg's team reviewed death certificates abstracted by the National Center for Health Statistics from 1999 to 2007. A death related to HBV, HCV, and/or HIV (assessed to compare mortality trends) was defined as any death with a report of the standard International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes: B16.0, B17.0, B18.0, and B18.1 for HBV; B17.1 and B18.2 for HCV; and B20 to B24 for HIV. Reflected in the codes are underlying and contributing causes of death.
"Our aim was to compare trends in deaths associated with HCV, HBV, and HIV infection, and to describe associations between select sociodemographic characteristics and comorbid conditions associated with hepatitis-related mortality, with particular focus on potentially preventable conditions," said Dr. Holmberg.
Demographic variables included patient age, sex, race, ethnicity, level of education, and marital status; comorbid conditions included HIV infection, alcohol-related conditions, and any antecedent liver disease.
The results of the analysis were striking. "Just counting the 21.8 million death certificates clearly shows the increasing incidence of HCV-related deaths — a significant rise at that," said Dr. Holmberg.
In contrast, data clearly show a stable rate for HBV-related deaths and a declining incidence of HIV-related deaths, which dropped below the death rate observed for HCV in 2006. Of note, the majority of HBV- and HCV-related deaths occurred in patients who were 45 to 64 years of age. "This epidemic is hitting middle-aged adults especially hard."
In 2007 — the last year of the analysis — there were 1815 HBV-related deaths recorded, with 59% occurring in middle-aged individuals. For HCV, of the 15,106 recorded deaths, 73% were in people 54 to 64 years of age.
"For both HCV and HBV, there was heavy representation in persons from racial and ethnic minorities," Dr. Holmberg reported.
Dr. Holmberg found that comorbidities associated with increased odds of HCV- and HBV-related mortality included chronic liver disease, coinfection with the other hepatitis virus, alcohol-related conditions, and HIV coinfection.
Dr. Holmberg acknowledged that death certificates are imperfect sources of information. "These things are often filled in by someone who is not the primary physician," he said. "However, looking at millions of deaths, the trends are clear. In fact, I would argue that this analysis greatly underestimates the relative impact of viral hepatitis."
Previous studies have shown that only 40% to 50% of HCV-infected individuals are identified as such prior to death, whereas 80% to 85% of patients infected with HIV have been diagnosed before succumbing to their illness, he pointed out.
Targeting the Boom
"If you consider the stability of the rates for hepatitis B and the declining death rates seen with HIV — those are most likely caused by improved awareness and advances in treatment of HIV," said AASLD president, T. Jake Liang, MD, tenured senior investigator and chief of the liver diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, in Bethesda, Maryland. For HCV, "mortality has actually increased, and has surpassed HIV."
Dr. Liang noted that the increase is striking particularly hard at baby boomers. "This is a population that we are very concerned about. We really need to be more aggressive in terms of trying to identify who they are and getting them into treatment."
Dr. Holmberg and Dr. Liang have disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 243. Presented November 8, 2011.
Source
New Once-daily HCV Drug Overcomes Poor Interferon Response
Neil Canavan
November 10, 2011 (San Francisco, California) — The new once-daily oral medication PSI-7977 (Pharmasset), in combination with the standard regimen of pegylated interferon and ribavirin for patients infected with hepatitis C virus (HCV), cut the time for complete viral clearance in half, compared with interferon and ribavirin alone. In addition, the investigational agent was 100% effective in patients with the interleukin (IL)28B T/T mutation that has been associated with a poor response to interferon. These findings, from the PROTON trial, were presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting.
PROTON was 1 of 2 phase 2 studies of this investigational compound reported here
PSI-7977 plus interferon/ribavirin shows "a rapid and complete suppression in 95% of patients," said PROTON lead investigator Eric Lawitz, MD, from Alamo Medical Research in San Antonio, Texas.
PSI-7977, a uridine nucleotide analog polymerase inhibitor that is administered once daily with or without food, has previously shown activity in a broad range of HCV patient genotypes. There have been no drug-related viral breakthroughs reported to date, demonstrating a high barrier to resistance.
PROTON was a double-blind placebo-controlled dose-ranging phase 2 study that enrolled 121 treatment-naïve patients with HCV genotype 1. Participants were 18 years or older, with an HCV RNA level of at least 50,000 IU/mL, a platelet count above 90,000/mm3, a hemoglobin level of at least 11 g/dL, and no evidence of cirrhosis.
Subjects were randomized in a 2:2:1 ratio to 1 of 3 treatment groups: 12 weeks of interferon/ribavirin plus PSI-7977 200 mg, PSI-7977 400 mg, or placebo. All patients then received 12 weeks of interferon/ribavirin, and those who had still not achieved a rapid viral response received another 24 weeks of interferon/ribavirin.
"Duration of therapy was response-guided," said Dr. Lawitz. "Those who achieved rapid viral response discontinued therapy at 24 weeks, and those who did not continued for a total of 48 weeks." The control group consisted of the interferon/ribavirin standard combination for 48 weeks.
At baseline, median age was 51 years, 15% self-identified as black and 10% as Hispanic, median HCV load was 6.6 log IU/mL, median body mass index was 28 kg/m2, roughly 95% had mild fibrosis (F0 to F2), and 41% of the cohort had the IL28B C/C genotype.
Results showed a dramatic improvement with the triple drug combination, compared with placebo.
"The rapid viral response for the 200 mg dose was 98%, with an end-of- treatment response at 24 weeks of 91%," reported Dr. Lawitz. The same response rate was seen with the 400 mg dose. In the placebo group, the rapid viral response was 19%, and end-of-treatment response was 50%. The reported sustained viral response at 12 weeks was 88% for the 200 mg group, 91% for the 400 mg group, and roughly 40% for the placebo group (an estimate because observation is ongoing).
Significantly, a subanalysis of patients with the difficult-to-treat IL28B T/T mutation (n = 13) showed that "all had a rapid response and all became HCV-negative by week 3," said Dr. Lawitz.
These cohorts went on to achieve a 100% sustained viral response.
There were several failures reported. In the 200 mg group, 3 patients experienced viral breakthrough during the 12 weeks of interferon/ribavirin treatment immediately after the discontinuation of PSI-7977, and 1 patient relapsed at the end of treatment. "In contrast, in the 400 mg arm, there were no breakthroughs, suggesting that the 400 mg dose achieved a deeper viral suppression," said Dr. Lawitz. "There was 1 failure prior to [a sustained viral response at 4 weeks], but this was not due to any S282T resistance mutation."
The adverse events reported in the PROTON trial were typical of those seen with interferon/ribavirin treatment, with the single exception of a modest increase in the incidence of insomnia in the PSI-7977 treatment groups. No serious hematologic events were reported, and no dose-related changes in event rates were observed.
Optimism for the Novel Drug, With Caveats
"Part of the problem of working with a new product is all the unanswered questions due to the size of early trials," said Mauricio Lisker-Melman, MD, director of the hepatology program at the University of Washington, St. Louis, Missouri. What are the potential adverse effects of this medication that will only emerge with a larger dataset? How do these data translate into the community setting?
"There is a significant group of patients in my practice who have cirrhosis that may be more prone to develop some of the side effects," said Dr. Lisker-Melman, noting that patients with cirrhosis were excluded from PROTON.
"We should be very careful, especially when we analyze effects on the bone marrow — anemia, thrombocytopenia, and other complications related to these new targeted inhibitors," Dr. Lisker-Melman cautioned. "That's why analyzing different subgroups of patients is so important."
Dr. Lisker-Melman is also concerned that the racial make-up of PROTON did not reflect what he and others see in the clinic; responses to HVC medications have been found to vary widely by race.
"Don't get me wrong — it's a great study, a great beginning. The sister study, ELECTRON, just presented here, suggested that we can even be successful without the use of interferon. That offers a lot of hope," he said.
With these data and the results from other drugs in development for HCV infection, Dr. Lisker-Melman predicts that an interferon-free HCV regimen is less than 5 years away.
Dr. Eric Lawitz reports relationships with Abbott Laboratories, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Meyers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck & Co, Novartis, Pharmasset, Roche, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, and Zymogenics. Dr. Mauricio Lisker-Melman has disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting: Abstract 225. Presented November 8, 2011.
Source
Also See: New HCV Drug Achieves 100% Cure Rate Without Interferon
November 10, 2011 (San Francisco, California) — The new once-daily oral medication PSI-7977 (Pharmasset), in combination with the standard regimen of pegylated interferon and ribavirin for patients infected with hepatitis C virus (HCV), cut the time for complete viral clearance in half, compared with interferon and ribavirin alone. In addition, the investigational agent was 100% effective in patients with the interleukin (IL)28B T/T mutation that has been associated with a poor response to interferon. These findings, from the PROTON trial, were presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting.
PROTON was 1 of 2 phase 2 studies of this investigational compound reported here
PSI-7977 plus interferon/ribavirin shows "a rapid and complete suppression in 95% of patients," said PROTON lead investigator Eric Lawitz, MD, from Alamo Medical Research in San Antonio, Texas.
PSI-7977, a uridine nucleotide analog polymerase inhibitor that is administered once daily with or without food, has previously shown activity in a broad range of HCV patient genotypes. There have been no drug-related viral breakthroughs reported to date, demonstrating a high barrier to resistance.
PROTON was a double-blind placebo-controlled dose-ranging phase 2 study that enrolled 121 treatment-naïve patients with HCV genotype 1. Participants were 18 years or older, with an HCV RNA level of at least 50,000 IU/mL, a platelet count above 90,000/mm3, a hemoglobin level of at least 11 g/dL, and no evidence of cirrhosis.
Subjects were randomized in a 2:2:1 ratio to 1 of 3 treatment groups: 12 weeks of interferon/ribavirin plus PSI-7977 200 mg, PSI-7977 400 mg, or placebo. All patients then received 12 weeks of interferon/ribavirin, and those who had still not achieved a rapid viral response received another 24 weeks of interferon/ribavirin.
"Duration of therapy was response-guided," said Dr. Lawitz. "Those who achieved rapid viral response discontinued therapy at 24 weeks, and those who did not continued for a total of 48 weeks." The control group consisted of the interferon/ribavirin standard combination for 48 weeks.
At baseline, median age was 51 years, 15% self-identified as black and 10% as Hispanic, median HCV load was 6.6 log IU/mL, median body mass index was 28 kg/m2, roughly 95% had mild fibrosis (F0 to F2), and 41% of the cohort had the IL28B C/C genotype.
Results showed a dramatic improvement with the triple drug combination, compared with placebo.
"The rapid viral response for the 200 mg dose was 98%, with an end-of- treatment response at 24 weeks of 91%," reported Dr. Lawitz. The same response rate was seen with the 400 mg dose. In the placebo group, the rapid viral response was 19%, and end-of-treatment response was 50%. The reported sustained viral response at 12 weeks was 88% for the 200 mg group, 91% for the 400 mg group, and roughly 40% for the placebo group (an estimate because observation is ongoing).
Significantly, a subanalysis of patients with the difficult-to-treat IL28B T/T mutation (n = 13) showed that "all had a rapid response and all became HCV-negative by week 3," said Dr. Lawitz.
These cohorts went on to achieve a 100% sustained viral response.
There were several failures reported. In the 200 mg group, 3 patients experienced viral breakthrough during the 12 weeks of interferon/ribavirin treatment immediately after the discontinuation of PSI-7977, and 1 patient relapsed at the end of treatment. "In contrast, in the 400 mg arm, there were no breakthroughs, suggesting that the 400 mg dose achieved a deeper viral suppression," said Dr. Lawitz. "There was 1 failure prior to [a sustained viral response at 4 weeks], but this was not due to any S282T resistance mutation."
The adverse events reported in the PROTON trial were typical of those seen with interferon/ribavirin treatment, with the single exception of a modest increase in the incidence of insomnia in the PSI-7977 treatment groups. No serious hematologic events were reported, and no dose-related changes in event rates were observed.
Optimism for the Novel Drug, With Caveats
"Part of the problem of working with a new product is all the unanswered questions due to the size of early trials," said Mauricio Lisker-Melman, MD, director of the hepatology program at the University of Washington, St. Louis, Missouri. What are the potential adverse effects of this medication that will only emerge with a larger dataset? How do these data translate into the community setting?
"There is a significant group of patients in my practice who have cirrhosis that may be more prone to develop some of the side effects," said Dr. Lisker-Melman, noting that patients with cirrhosis were excluded from PROTON.
"We should be very careful, especially when we analyze effects on the bone marrow — anemia, thrombocytopenia, and other complications related to these new targeted inhibitors," Dr. Lisker-Melman cautioned. "That's why analyzing different subgroups of patients is so important."
Dr. Lisker-Melman is also concerned that the racial make-up of PROTON did not reflect what he and others see in the clinic; responses to HVC medications have been found to vary widely by race.
"Don't get me wrong — it's a great study, a great beginning. The sister study, ELECTRON, just presented here, suggested that we can even be successful without the use of interferon. That offers a lot of hope," he said.
With these data and the results from other drugs in development for HCV infection, Dr. Lisker-Melman predicts that an interferon-free HCV regimen is less than 5 years away.
Dr. Eric Lawitz reports relationships with Abbott Laboratories, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Meyers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck & Co, Novartis, Pharmasset, Roche, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, and Zymogenics. Dr. Mauricio Lisker-Melman has disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting: Abstract 225. Presented November 8, 2011.
Source
Also See: New HCV Drug Achieves 100% Cure Rate Without Interferon
New HCV Drug Achieves 100% Cure Rate Without Interferon
Neil Canavan
November 9, 2011 (San Francisco, California) — An interferon-free regimen for the treatment of infection with hepatitis C virus (HCV) might soon be available, according to data from the ELECTRON trial, presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
In ELECTRON — 1 of 2 phase 2 studies of the investigational compound PSI-7977 (Pharmasset) reported here — an interferon-free regimen of PSI-7977 plus ribavirin achieved a 100% sustained viral response (SVR) at 12 weeks in all study subjects. The second study, PROTON, was also reported here.
"PSI-7977 has the potential to dramatically change the treatment paradigm for HCV," said lead study investigator Edward Gane, MD, from Auckland City Hospital in New Zealand.
PSI-7977 is a uridine nucleotide analog polymerase inhibitor that is administered once daily with or without food. It has demonstrated robust activity in patients infected with HCV genotype 1 when used in combination with pegylated-interferon and ribavirin after a 12-week course.
Activity with this agent used as a monotherapy has also been reported.
"The aim of the ELECTRON trial was to determine the shortest duration of interferon, if any, required to achieve SVR when PSI-7977 plus ribavirin are administered for 12 weeks," Dr. Gane explained.
ELECTRON investigators recruited 40 patients who were randomized to 1 of 4 treatment groups: PSI-7977 400 mg plus ribavirin for 12 weeks plus interferon for 0, 4, 8, or 12 weeks.
Patients were treatment-naïve, noncirrhotic, infected with HCV genotype 2 or 3, and stratified by interleukin (IL)28B single-nucleotide polymorphisms (SNP) and HCV RNA levels. Mean age was 47 years and mean baseline HCV RNA was 6.49 log10 IU/mL, with 42.5% exhibiting the CC genotype at the IL28B SNP.
"We selected a genotype 2/3 population because this represents a population that would be more easily rescued with interferon in the event of virologic breakthrough," Dr. Gane explained.
Results after treatment initiation were dramatic. "All patients achieved a rapid virologic response, with over 80% being nondetectable at 2 weeks," reported Dr. Gane.
All patients had undetectable HCV at 3 weeks; furthermore, all patients achieved end-of-treatment response. No cases of treatment resistance were observed.
"Even following cessation of interferon, or with no interferon, there were no virologic breakthroughs on treatment." Also encouraging was the fact that all patients in the study experienced a rapid normalization of alanine aminotransferase.
There were no serious adverse events, and the mild to moderate events observed were attributed to either interferon or ribavirin. Significant improvements in safety and tolerability were seen in the interferon-free treatment group. No safety signals for PSI-7977 were observed, and there were no treatment-related discontinuations.
Results of the 12-week analysis prompted study investigators to add an exploratory treatment group of open-label PSI-7977 monotherapy for 12 weeks (n = 10). "The response was the same as with combination treatment with ribavirin," said Dr. Gane. Although this study is ongoing, 6 of 10 patients have achieved SVR at 4 weeks.
"These data clearly demonstrate that PSI-7977 exhibits high potency and has a high barrier to resistance," Dr. Gane said, noting that the drug is being advanced in phase 3 investigations in all HCV genotypes.
Too Good to be True?
Michael Bernstein, MD, director of the hepatitis clinic at the Coney Island Hospital, Brooklyn, New York, has doubts about PSI-7977. "If you use it with ribavirin and no interferon, you get a 100% SVR; if you use it alone, you get a 100% SVR."
Dr. Bernstein accepts the efficacy of PSI-7977 for the moment, but is concerned that ELECTRON isn't powered to say much about the tolerability or resistance profiles of the drug.
"What we've found with most of these [polymerase inhibitors] is that if you use them by themselves, you get resistance; if you don't, they can be very difficult to tolerate," said Dr. Bernstein. "There was a drug being investigated at Mount Sinai — a polymerase inhibitor, NM286 — and those patients got severe diarrhea and could not tolerate it. According to the ELECTRON study, everything was perfect — no gastrointestinal issues, no apparent adverse events of any kind, and it worked 100% of the time without interferon, or ribavirin.... If it's true, it will be great. The holy grail is to try to rid HCV treatment regimens of interferon."
Although sincerely impressed, Dr. Bernstein, who has seen many drugs come and go, suspects that as larger phase 3 trials of PSI-7977 are conducted, polymerase-associated adverse events, tolerability issues, and treatment resistance patterns will emerge.
Dr. Gane reports advisory board relationships with Pharmasset, Gilead, Roche, Janssen-Cilag, and Boehringer-Ingelheim. Dr. Bernstein has disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting: Abstract 34. Presented November 6, 2011.
Source
November 9, 2011 (San Francisco, California) — An interferon-free regimen for the treatment of infection with hepatitis C virus (HCV) might soon be available, according to data from the ELECTRON trial, presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
In ELECTRON — 1 of 2 phase 2 studies of the investigational compound PSI-7977 (Pharmasset) reported here — an interferon-free regimen of PSI-7977 plus ribavirin achieved a 100% sustained viral response (SVR) at 12 weeks in all study subjects. The second study, PROTON, was also reported here.
"PSI-7977 has the potential to dramatically change the treatment paradigm for HCV," said lead study investigator Edward Gane, MD, from Auckland City Hospital in New Zealand.
PSI-7977 is a uridine nucleotide analog polymerase inhibitor that is administered once daily with or without food. It has demonstrated robust activity in patients infected with HCV genotype 1 when used in combination with pegylated-interferon and ribavirin after a 12-week course.
Activity with this agent used as a monotherapy has also been reported.
"The aim of the ELECTRON trial was to determine the shortest duration of interferon, if any, required to achieve SVR when PSI-7977 plus ribavirin are administered for 12 weeks," Dr. Gane explained.
ELECTRON investigators recruited 40 patients who were randomized to 1 of 4 treatment groups: PSI-7977 400 mg plus ribavirin for 12 weeks plus interferon for 0, 4, 8, or 12 weeks.
Patients were treatment-naïve, noncirrhotic, infected with HCV genotype 2 or 3, and stratified by interleukin (IL)28B single-nucleotide polymorphisms (SNP) and HCV RNA levels. Mean age was 47 years and mean baseline HCV RNA was 6.49 log10 IU/mL, with 42.5% exhibiting the CC genotype at the IL28B SNP.
"We selected a genotype 2/3 population because this represents a population that would be more easily rescued with interferon in the event of virologic breakthrough," Dr. Gane explained.
Results after treatment initiation were dramatic. "All patients achieved a rapid virologic response, with over 80% being nondetectable at 2 weeks," reported Dr. Gane.
All patients had undetectable HCV at 3 weeks; furthermore, all patients achieved end-of-treatment response. No cases of treatment resistance were observed.
"Even following cessation of interferon, or with no interferon, there were no virologic breakthroughs on treatment." Also encouraging was the fact that all patients in the study experienced a rapid normalization of alanine aminotransferase.
There were no serious adverse events, and the mild to moderate events observed were attributed to either interferon or ribavirin. Significant improvements in safety and tolerability were seen in the interferon-free treatment group. No safety signals for PSI-7977 were observed, and there were no treatment-related discontinuations.
Results of the 12-week analysis prompted study investigators to add an exploratory treatment group of open-label PSI-7977 monotherapy for 12 weeks (n = 10). "The response was the same as with combination treatment with ribavirin," said Dr. Gane. Although this study is ongoing, 6 of 10 patients have achieved SVR at 4 weeks.
"These data clearly demonstrate that PSI-7977 exhibits high potency and has a high barrier to resistance," Dr. Gane said, noting that the drug is being advanced in phase 3 investigations in all HCV genotypes.
Too Good to be True?
Michael Bernstein, MD, director of the hepatitis clinic at the Coney Island Hospital, Brooklyn, New York, has doubts about PSI-7977. "If you use it with ribavirin and no interferon, you get a 100% SVR; if you use it alone, you get a 100% SVR."
Dr. Bernstein accepts the efficacy of PSI-7977 for the moment, but is concerned that ELECTRON isn't powered to say much about the tolerability or resistance profiles of the drug.
"What we've found with most of these [polymerase inhibitors] is that if you use them by themselves, you get resistance; if you don't, they can be very difficult to tolerate," said Dr. Bernstein. "There was a drug being investigated at Mount Sinai — a polymerase inhibitor, NM286 — and those patients got severe diarrhea and could not tolerate it. According to the ELECTRON study, everything was perfect — no gastrointestinal issues, no apparent adverse events of any kind, and it worked 100% of the time without interferon, or ribavirin.... If it's true, it will be great. The holy grail is to try to rid HCV treatment regimens of interferon."
Although sincerely impressed, Dr. Bernstein, who has seen many drugs come and go, suspects that as larger phase 3 trials of PSI-7977 are conducted, polymerase-associated adverse events, tolerability issues, and treatment resistance patterns will emerge.
Dr. Gane reports advisory board relationships with Pharmasset, Gilead, Roche, Janssen-Cilag, and Boehringer-Ingelheim. Dr. Bernstein has disclosed no relevant financial relationships.
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting: Abstract 34. Presented November 6, 2011.
Source
AASLD: New HCV Drugs Draw Attention
By Michael Smith, North American Correspondent, MedPage Today
Published: November 10, 2011
SAN FRANCISCO -- After years with a standard two-drug therapy for the hepatitis C virus (HCV), new agents that act directly on the virus are making an appearance, with two already approved. And at the annual meeting of the American Association for the Study of Liver Diseases, details are being reported on many more in the pipeline.
In this exclusive InFocus segment, MedPage Today North American Correspondent Michael Smith sat down to discuss the new agents with Gary Davis, MD, of Baylor University Medical School in Dallas
AASLD: Antiviral Likely Too Costly for Initial HCV Tx
Published: November 11, 2011
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
SAN FRANCISCO -- First-line treatment with the direct-acting antiviral agent telaprevir appeared unlikely to be cost-effective for hepatitis C virus (HCV) infection in patients with the favorable CC IL28B polymorphism, according to a decision modeling analysis.
Telaprevir-based treatment resulted in a clinical benefit comparable to that of two different regimens of pegylated interferon alfa plus ribavirin, but use of the agent increased the estimated cost by 27% to 47% compared with the other two regimens.
The combination of pegylated interferon and ribavirin proved dominant versus telaprevir, and the dominance was driven by the cost difference, Ziad Gellad, MD, reported here at the American Association for the Study of Liver Diseases meeting.
"In treatment-naïve genotype 1 patients with the CC IL28B polymorphism, initial therapy with a telaprevir-based regimen is unlikely to be cost effective under current cost and efficacy conditions," said Gellad, of Duke University Medical Center in Durham, N.C.
"Comparative-effectiveness trials should consider protease inhibitor-free strategies as first-line therapy in individuals with the favorable IL28B genotype."
The IL28B polymorphism is the strongest pretreatment predictor of sustained virologic response in patients with HCV genotype 1. Personalized HCV treatment regimens based on pretreatment factors such as IL28B or on-treatment response may improve the efficacy and tolerability of treatment.
By way of background, Gellad noted that a majority of patients with the CC IL28B polymorphism respond to treatment with the combination of pegylated interferon alfa and ribavirin. Direct-acting antivirals, such as telaprevir, have proven effective for patients who do not respond to first-line pegylated interferon alfa-ribavirin therapy or who relapse after the standard treatment.
One potential benefit of tailored therapy is lower cost. Depending on the duration of treatment, dual therapy with pegylated interferon alfa and ribavirin can vary between $18,000 and $36,000. Adding telaprevir or boceprevir (Victrelis) to the other two drugs more than doubles the cost of therapy to a range of $48,000 to $85,000, Gellad continued.
The economic aspects of therapy raise the question of whether clinically effective treatment with a direct-acting antiviral would make sense from a cost-effectiveness perspective if used in treatment-naïve patients with the CC IL28B polymorphism.
To address the question, Gellad and colleagues developed a decision model that evaluated three treatment strategies:
• 48 weeks of treatment with pegylated interferon-alfa and ribavirin
• 24 weeks of pegylated interferon alfa-ribavirin in patients with rapid virologic response
• 12 weeks of telaprevir in combination with 24 or 48 weeks of pegylated interferon alfa-ribavirin
Key assumptions of the analysis were limited societal perspective, no coinfection with other viruses, no factors that accelerated liver-related death or prevented treatment, and retreatment with telaprevir for patients who did not respond to or relapsed with pegylated interferon-ribavirin therapy.
The investigators estimated lifetime treatment costs and quality-adjusted life-years (QALYs) for each strategy and performed multiple sensitivity analyses to evaluate the impact of changes to key assumptions incorporated in the model.
Using data from published clinical trials of pegylated interferon alfa-ribavirin therapy, the investigators assumed a sustained virologic response (SVR) of 66% for 48 weeks of dual therapy, increasing to 90.6% with retreatment. They assumed an SVR of 71% for patients who achieved rapid virologic response with dual therapy, increasing to 87.6% with retreatment.
Using published data for telaprevir therapy, Gellad and colleagues assumed an SVR of 89%.
The three treatment strategies resulted in QALY gains of 19.26 to 19.38 and did not differ significantly. The estimated cost for dual therapy with pegylated interferon alfa and ribavirin was $46,785 when a treatment duration of 24 weeks was assumed for patients achieving rapid virologic response. The cost increased to $54,931 when all patients continued treatment for 48 weeks with the dual-drug regimen.
Adding telaprevir to first-line pegylated interferon alfa-ribavirin therapy increased the cost to $68,788.
"The efficacy of all three strategies is similar," said Gellad. "Telaprevir is dominated by the pegylated interferon alfa-ribavirin strategy, and the preference for interferon-only strategies is driven by cost."
Sensitivity analysis did identify a few specific circumstances under which telaprevir-based treatment became cost-effective versus dual therapy:
• When the probability of an extended SVR exceeded 89% with telaprevir (versus a base-case assumption of 78% for dual therapy)
• When the probability of achieving SVR with telaprevir exceeded 80% in patients who had not achieved an SVR with dual therapy (versus a 67% base-case assumption)
• When the probability of SVR with dual therapy fell below 62% and retreatment with telaprevir was pursued (versus an 88% base-case assumption)
Commenting on the results during an AASLD press briefing, T. Jake Liang, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases, said the study emphasizes the advances that have occurred in using biomarkers to aid treatment decisions related to HCV infection.
"The CC IL28B polymorphism is probably the most important and best genetic marker we have identified to date for predicting response to therapy," said Liang, who also is president of AASLD.
"If you compare the three treatment groups, it is clear that response-directed treatment with pegylated interferon and ribavirin is the most cost-effective way to treat patients with the favorable genotype," he added.
Gellad disclosed relationships with Merck and with PENTAX Medical.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Gellad ZF, et al "The cost-effectiveness of a telaprevir-inclusive regimen as initial therapy for genotype 1 hepaticis C infection in individuals with the CC IL28B polymorphism" AASLD 2011; Abstract 118.
Source
AASLD: HCV Drug Effective in Patients Co-Infected With HIV
By Michael Smith, North American Correspondent, MedPage Today
Published: November 12, 2011
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
SAN FRANCISCO -- In patients with both HIV and hepatitis C virus, response rates to a direct-acting agent that targets the liver virus were high, a researcher said here.
In an interim analysis of a randomized controlled trial, treatment with the protease inhibitor telaprevir (Incivek), combined with standard therapy, led to 24-week response rates of 71%, according to Kenneth Sherman, MD, of the University of Cincinnati College of Medicine.
In contrast, 55% of patients getting standard treatment alone had undetectable hepatitis C virus after 24 weeks, Sherman reported at the annual meeting of the American Association for the Study of Liver Diseases.
The study is the second to report encouraging results in coinfected patients when standard therapy is combined with a direct-acting agent. In October, researchers reported that boceprevir (Victrelis), the other approved direct-acting agent, yielded a 24-week response rate of 70.5%.
Sherman told MedPage Today that it's important to remember that the findings are interim results from a phase II study. Still, "the response rates are excellent (and) there are no surprises in the adverse event profile."
Indeed, the 24-week sustained virologic response rate -- defined as undetectable hepatitis C after 24 weeks of treatment -- is similar to the rate seen when telaprevir used in patients who only have the liver virus, he said.
Importantly, the researchers saw no adverse effect on HIV control, he said.
The 60 patients were randomly assigned to receive 12 weeks of standard therapy with pegylated interferon-alfa and ribavirin, or to receive the same treatment with the addition of telaprevir. In either case, the initial 12 weeks was to be followed by a further 36 weeks on peginterferon and ribavirin alone.
The patients, all with the difficult to treat genotype 1 hepatitis C virus, were also stratified by their anti-HIV regimen into three groups:
• No therapy
• Efavirenz-based triple therapy
• -based triple therapy
Sherman said the 24-week responses were similar in all three groups, ranging from 86% to 67%.
The study allowed the use of efavirenz (Sustiva), although the dose of telaprevir had to be boosted to compensate, Sherman said. In contrast, patients in the boceprevir study could not use an efavirenz-based regimen during treatment with the drug.
Safety and tolerability was similar to what has been seen in mono-infected patients, Sherman said. Pruritus, headache, nausea, and rash were more commonly reported by telaprevir patients, while insomnia and weight loss were more frequent among those getting standard treatment alone.
The results are "almost a doppelganger" of the earlier trial report concerning boceprevir in coinfected patients, according to Raymond Chung, MD, of Massachusetts General Hospital in Boston, who was not involved in the study.
The responses reported by Sherman are "very encouraging," Chung told MedPage Today in a telephone interview. "There appears to be no adverse effect on HIV control, at least at the 24-week mark," he said.
While there has been concern about drug interactions, especially for patients taking efavirenz, Chung said most people providing HIV care may be preparing coinfection patients by switching their regimens in advance of hepatitis treatment.
"Remember, this is a short-term switch," he said.
While the results with telaprevir are interim, he said, "it wouldn't be straining to imagine" sustained virologic response rates of 55% in coinfected patients, taking relapses into account. "That would be a real advance," Chung said.
The study was sponsored by Vertex Pharmaceuticals. Sherman reported financial links with the company and with Bristol-Myers Squibb, Tibotec, Merck, Johnson & Johnson, Baxter, Regulus, GSK, SciClone, Boehringer Ingelheim, Merck/Schering Plough, Genentech/Roche, Gilead, and Anadys.
Chung reported financial links with Merck, Gilead, Pfizer, and Romark.
Primary source: Hepatology
Source reference:
Sherman KE, et al "Telaprevir combination with peginterferon alfa - 2a/ribavirin in HCV/HIV coinfected patients: 24-week treatment interim analysis" Hepatology 2011; Abstract LB-8.
Source
Published: November 12, 2011
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
SAN FRANCISCO -- In patients with both HIV and hepatitis C virus, response rates to a direct-acting agent that targets the liver virus were high, a researcher said here.
In an interim analysis of a randomized controlled trial, treatment with the protease inhibitor telaprevir (Incivek), combined with standard therapy, led to 24-week response rates of 71%, according to Kenneth Sherman, MD, of the University of Cincinnati College of Medicine.
In contrast, 55% of patients getting standard treatment alone had undetectable hepatitis C virus after 24 weeks, Sherman reported at the annual meeting of the American Association for the Study of Liver Diseases.
The study is the second to report encouraging results in coinfected patients when standard therapy is combined with a direct-acting agent. In October, researchers reported that boceprevir (Victrelis), the other approved direct-acting agent, yielded a 24-week response rate of 70.5%.
Sherman told MedPage Today that it's important to remember that the findings are interim results from a phase II study. Still, "the response rates are excellent (and) there are no surprises in the adverse event profile."
Indeed, the 24-week sustained virologic response rate -- defined as undetectable hepatitis C after 24 weeks of treatment -- is similar to the rate seen when telaprevir used in patients who only have the liver virus, he said.
Importantly, the researchers saw no adverse effect on HIV control, he said.
The 60 patients were randomly assigned to receive 12 weeks of standard therapy with pegylated interferon-alfa and ribavirin, or to receive the same treatment with the addition of telaprevir. In either case, the initial 12 weeks was to be followed by a further 36 weeks on peginterferon and ribavirin alone.
The patients, all with the difficult to treat genotype 1 hepatitis C virus, were also stratified by their anti-HIV regimen into three groups:
• No therapy
• Efavirenz-based triple therapy
• -based triple therapy
Sherman said the 24-week responses were similar in all three groups, ranging from 86% to 67%.
The study allowed the use of efavirenz (Sustiva), although the dose of telaprevir had to be boosted to compensate, Sherman said. In contrast, patients in the boceprevir study could not use an efavirenz-based regimen during treatment with the drug.
Safety and tolerability was similar to what has been seen in mono-infected patients, Sherman said. Pruritus, headache, nausea, and rash were more commonly reported by telaprevir patients, while insomnia and weight loss were more frequent among those getting standard treatment alone.
The results are "almost a doppelganger" of the earlier trial report concerning boceprevir in coinfected patients, according to Raymond Chung, MD, of Massachusetts General Hospital in Boston, who was not involved in the study.
The responses reported by Sherman are "very encouraging," Chung told MedPage Today in a telephone interview. "There appears to be no adverse effect on HIV control, at least at the 24-week mark," he said.
While there has been concern about drug interactions, especially for patients taking efavirenz, Chung said most people providing HIV care may be preparing coinfection patients by switching their regimens in advance of hepatitis treatment.
"Remember, this is a short-term switch," he said.
While the results with telaprevir are interim, he said, "it wouldn't be straining to imagine" sustained virologic response rates of 55% in coinfected patients, taking relapses into account. "That would be a real advance," Chung said.
The study was sponsored by Vertex Pharmaceuticals. Sherman reported financial links with the company and with Bristol-Myers Squibb, Tibotec, Merck, Johnson & Johnson, Baxter, Regulus, GSK, SciClone, Boehringer Ingelheim, Merck/Schering Plough, Genentech/Roche, Gilead, and Anadys.
Chung reported financial links with Merck, Gilead, Pfizer, and Romark.
Primary source: Hepatology
Source reference:
Sherman KE, et al "Telaprevir combination with peginterferon alfa - 2a/ribavirin in HCV/HIV coinfected patients: 24-week treatment interim analysis" Hepatology 2011; Abstract LB-8.
Source
Role of Hepatitis C Virus Genotype 3 in Liver Fibrosis Progression
From Journal of Viral Hepatitis
A Systematic Review and Meta-analysis
A. Probst; T. Dang; M. Bochud; M. Egger; F. Negro; P.-Y. Bochud
Posted: 11/14/2011; J Viral Hepat. 2011;18(11):749-755. © 2011 Blackwell Publishing
Abstract and Introduction
Abstract
The progression of liver fibrosis in chronic hepatitis C has long been considered to be independent from viral genotypes. However, recent studies suggest an association between Hepatitis C virus (HCV) genotype 3 and accelerated liver disease progression. We completed a systematic review and meta-analysis of studies evaluating the association between HCV genotypes and fibrosis progression. PubMed, Embase and ISI Web of Knowledge databases were searched for cohort, cross-sectional and case–control studies on treatment-naïve HCV-infected adults in which liver fibrosis progression rate (FPR) was assessed by the ratio of fibrosis stage in one single biopsy to the duration of infection (single-biopsy studies) or from the change in fibrosis stage between two biopsies (paired biopsies studies). A random effect model was used to derive FPR among different HCV genotypes. Eight single-biopsy studies (3182 patients, mean/median duration of infection ranging from 9 to 21 years) and eight paired biopsies studies (mean interval between biopsies 2–12 years) met the selection criteria. The odds ratio for the association of genotype 3 with accelerated fibrosis progression was 1.52 (95% CI 1.12–2.07, P = 0.007) in single-biopsy studies and 1.37 (95% CI 0.87–2.17, P = 0.17) in paired biopsy studies. In conclusion, viral genotype 3 was associated with faster fibrosis progression in single-biopsy studies. This observation may have important consequences on the clinical management of genotype 3-infected patients. The association was not significant in paired biopsies studies, although the latter may be limited by important indication bias, short observation time and small sample size.
Introduction
The hepatitis C virus (HCV) chronically infects ~170 millions of persons worldwide, which represents ~3% of the world's population.[1] The important morbidity and mortality associated with chronic hepatitis C result mainly from the development of liver fibrosis and its evolution towards cirrhosis and hepatocarcinoma.[2] The identification of factors affecting fibrosis progression is critical for the optimal management of infected patients.[3] Factors associated with rapid progression include demographic characteristics (such as older age at infection and male sex), host genetic factors, viral co-infections (with the hepatitis B [HBV] or the human immunodeficiency virus [HIV]), metabolic features (such as steatosis, insulin resistance or iron overload) and exposure to toxic agents (alcohol, tobacco or cannabis).[4] Risk factors identification for fibrosis progression was first based on fibrosis stage. However, this approach leads to significant bias, because disease duration varies widely across the population. This issue has been addressed, at least in part, by the estimation of fibrosis progression rate (FPR) based on the ratio of fibrosis stage to disease duration, which might better reflect the true fibrosis progression. Recent studies, using the latter method, suggested that some viral genotypes, such as genotype 3, are associated with more rapid fibrosis progression than other genotypes.[5–7] In this study, we systematically reviewed the published literature about the impact of HCV genotypes on the natural history of chronic hepatitis C and conducted a meta-analysis of the studies reporting a FPR per genotype. Our aim was to examine the impact of viral genotype 3 on fibrosis progression compared with other genotypes.
Material and Methods
Search Strategy
This meta-analysis was performed according to the PRISMA statement for reporting systematic reviews and meta-analyses.[8] Three electronic databases (PubMed, Embase and ISI Web of Knoweldge) were searched for published studies evaluating the fibrosis progression per genotype in chronic HCV before October 2009 (Table S1). Additionally, the investigators hand-searched the bibliographies of obtained articles and reviews; they did not contact any study authors for further information.
Eligible Studies
Cohort, cross-sectional and case–control published trials studying the fibrosis progression in HCV-infected patients were eligible. There was no restriction on language or publication date. Participants were chronically infected with HCV genotype 3, and controls were chronically infected with other genotypes.
Study Selection
Two investigators independently selected studies meeting the following criteria (Table S1): (i) chronic HCV infection; (ii) fibrosis scoring; (iii) no HCV treatment before biopsies; (iv) an estimated date of HCV infection; and (v) an estimated FPR per genotype. Studies on participants of <18 years of age, studies on orthotopic liver transplant recipients, studies without full text available and reviews were excluded. When more than one article was available from the same cohort, we included the article containing most complete information. Disagreements between the two investigators were solved by discussion.
Study Quality Assessment and Data Extraction
Quality criteria were reported for each study, including study design, case definition, liver biopsy quality, nonviral factors associated with fibrosis progression and method used to estimate the date of infection (Table S1). The two investigators independently extracted data for each study. The extracted data were then cross-checked by two other investigators for accuracy. FPR values were assessed together for all genotype non-3 patients. Patients with unknown genotype were not included.
Statistical Analysis
Eligible studies were separated in two groups: those calculating FPR as the ratio of the fibrosis score to the interval between an estimated date of infection and one pretreatment liver biopsy (defined as 'single-biopsy studies') and those calculating fibrosis progression between two pretreatment liver biopsies ('paired-biopsies studies'). For single-biopsy studies, an effect size (ES) was calculated for each individual study (detailed in Appendix).[9] ES of both continuous and dichotomous outcomes was pooled in the same meta-analysis using a random effect model.[10] ES was then transformed back to odds ratio (OR). For paired biopsies studies, the OR for comparison of genotype 3 vs others was calculated for each individual study. We performed a meta-analysis by pooling the OR using a random effect model. All statistical analyses were performed with Stata software (StataCorp, College Station, TX, USA), version 10.0.
Results
From the 3133 citations yielded by the electronic database search, 2936 were excluded for nonrelevance after title or abstract screenings (Fig. 1). Among 197 remaining full-text papers, 181 were excluded for nonrelevance, inappropriate review design, use of post-treatment biopsy, lack of estimated HCV infection duration, or lack of data on genotyping (no data on genotype 3) or FPR. The remaining 16 studies (eight single-biopsy and eight paired biopsy studies) were selected for the meta-analysis. For single-biopsy studies in which both continuous and dichotomous outcomes were available,[6,7] the continuous outcome was used.
Study Quality
The studies showed a relative homogeneity in terms of design and settings: 11 were retrospective cohort studies (Table 1), four were prospective cohort studies and one was a retrospective case–control study. All studies performed in tertiary hospitals or liver centres, and all published between 1997 and 2009 (Table 1). Seven studies gave a fibrosis score according to the METAVIR system,[24] while four used Ishak's modified histology activity index (HAI),[25] three used the Knodell's HAI,[26] one used Desmet's system[27] and one study gave Scheuer's grades[28] (scores summarized in Table S3). In most single-biopsy studies (N = 6), the date of infection was considered to be the first reported event at risk (blood transfusion, IV drug or nosocomial infection). In most studies, the association of viral genotype 3 with FPR was solely assessed in univariate models, with multivariate analyses performed in only three single-biopsy studies (Fig. S1).
Meta-analyses
The meta-analysis of single-biopsy studies showed a faster FPR in patients infected by genotype 3 compared with the others (overall pooled ES = 0.23, [95% CI 0.06–0.40], P = 0.007, OR = 1.52 [95% CI 1.12–2.07], Fig. 2). The I2 test result was 62.2% (P = 0.010). Similar results were obtained when studies including HIV-infected patients were removed, but the number of patients was smaller (N = 455) and the association was at the limit of significance (OR = 1.67, [95% CI 0.99–2.85], P = 0.056). The cumulative meta-analysis showed that the effect of genotype 3 on fibrosis progression became significant only in 2009 (Fig. 3). The meta-analysis of paired biopsies studies showed a trend towards faster progression for genotype 3 patients compared with the others (OR = 1.37, 95% CI 0.87–2.17, P = 0.17, Fig. 4). The I2 test was 0.0% (P = 0.455). The dichotomization process differed widely across studies, with a progression definition ranging from a worsening of fibrosis unit between two biopsies to a fixed higher fibrosis score value at the second biopsy (Table 2).
The association of viral genotype 3 with FPR may have important practical implications. It has been reported that the uptake of antiviral therapy for hepatitis C has been declining during recent years.[31] Apart from poor rate of diagnosis and lack of referral, two major factors may account for this trend: the widespread perception on the supposedly slow average progression rate of hepatitis C, coupled with the huge expectations surrounding novel, more effective direct antiviral agents (DAA), to be first marketed in 2011–2012. Genotype 3-infected patients should be aware of a potentially faster progression rate and may benefit from individualized counselling, with particular attention given to the controllable factors, such as alcohol consumption and overweight.[32] While therapy with peginterferon alpha and ribavirin usually achieves 70–80% of sustained viral response among patients infected with HCV genotype 3, certain subgroups of patients still have high relapse rates, such as those with elevated baseline viral load (>800 000 copies/mL,[33,34]) and advanced fibrosis.[32] Patients with chronic hepatitis C may be deferred from current treatment regimens just because more potent DAA will be licensed in the near future.[35] However, this 'warehousing' attitude may not be justified in infections with genotype 3, given that the serine protease inhibitors, such as telaprevir, have very limited activity against genotype 3.[36] DAAs with significant activity against genotype 3, such as the nucleoside RNA polymerase inhibitor R7128[37] or the cyclophilin-binding molecule Debio 025,[38] are far from completing clinical development. These considerations argue against the indiscriminate deferral from antiviral therapy in patients infected with genotype 3.
Multiple reasons may explain why paired biopsies studies did not show a significant effect of genotype 3. First, confounding by indication is likely to be a major problem in paired biopsies studies, as only selected patients undergo a second biopsy (e.g. those with multiple comorbidities and potentially rapidly evolving liver disease). Second, paired biopsies studies have a smaller sample size than single-biopsy studies. Out of eight studies, none included more than 30 genotype 3 patients, and four included <7 genotype 3 patients, resulting in low power to detect a given ES. Third, paired biopsies studies have a much smaller observation time than single-biopsy studies (~5 years between 2 biopsies compared with ~13 years from the infection date to the first biopsy, Fig. S3). This short duration may not be sufficient to detect genotype-specific differences in terms of FPRs. Fourth, paired biopsies studies have used arbitrary cut-offs for dichotomizing the outcome into progression vs nonprogression, for instance a worsening of the score by one or several units[13–15,17,18,20,23] or reaching a specific fibrosis stage at the second biopsy.[19] This method results in more information loss if one considers that the process of fibrosis is continuous. Finally, given that FPRs are not constant over time, paired biopsies studies may have included patients when the progression rate is the slowest (e.g. transition from Metavir scores F1–F2[30] or F2–F3[7]), making it even more difficult to detect genotype-specific differences (Fig. S2).
As in many systematic reviews, the limitation of this study results from the limitation of the original studies themselves. Those include the inability to precisely determine the date of infection, the variability in the assessment of fibrosis staging, the nonlinearity of fibrosis progression over time, the failure to account for multiple risk factors. However, several studies addressed these issues. In three studies, the role of viral genotype 3 in fibrosis progression was confirmed in multivariate analyses, accounting for different covariates such as age, alcohol consumption and steatosis.[5–7] In one of them, the authors suggested that cannabis use, which may be more prevalent among genotype 3-infected patient, may have been a confounding factor for the role of genotype 3. However, this study clearly identified cannabis use, genotype 3, age at infection, alcohol intake and steatosis all as independent risk factors for rapid fibrosis progression (>0.74 U/year) in a stepwise logistic regression model of 267 patients.[5] In another study, the association of genotype 3 with faster progression remained significant among patients infected by blood transfusion (for whom the date of infection is certain), among different age groups, or among different periods of infection, and when using different methods to assess the progression rate.[7]
Owing to our stringent selection criteria, the number of studies included in the meta-analysis is relatively small. Therefore, it was not possible to perform a meta-regression analysis and explore the role of potential confounders. We could not include a large confirmatory study (N = 327, N genotype 3 = 80), showing that patients infected with HCV genotype 3 had shorter time to infection than others, because it did not provide FPR rates.[39]
This study provides new insight into the natural history of HCV infection. The evidence for a role of genotype 3 in fibrosis progression may have important implications for the management of patients infected with this genotype.
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19.Fartoux L, Poujol-Robert A, Guéchot J, Wendum D, Poupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut 2005; 54(7): 1003–1008.
20.Perumalswami P, Kleiner DE, Lutchman G et al. Steatosis and progression of fibrosis in untreated patients with chronic hepatitis C infection. Hepatology 2006; 43(4): 780–787.
21.Richardson MM, Powell EE, Barrie HD, Clouston AD, Purdie DM, Jonsson JR. A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C. J Med Genet 2005; 42(7): e45.
22.Reiberger T, Ferlitsch A, Sieghart W et al. HIV-HCV co-infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension. J Viral Hepat 2010; 17(6): 400–409.
23.Kanzler S, Baumann M, Schirmacher P et al. Prediction of progressive liver fibrosis in hepatitis C infection by serum and tissue levels of transforming growth factor-beta. J Viral Hepat 2001; 8(6): 430–437.
24.Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology 1994; 20(1 Pt 1): 15–20.
25.Ishak K, Baptista A, Bianchi L et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22(6): 696–699.
26.Knodell RG, Ishak KG, Black WC et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1(5): 431– 435.
27.Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994; 19(6): 1513–1520.
28.Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 1991; 13(3): 372– 374.
29.Castera L, Hezode C, Roudot-Thoraval F et al. Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies. Gut 2003; 52(2): 288– 292.
30.Thein H, Yi Q, Dore G, Krahn M. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology 2008; 48(2): 418–431.
31.Volk ML, Tocco R, Saini S, Lok AS. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology 2009; 50(6): 1750–1755.
32.Zeuzem S. Forewarned is forearmed. J Hepatol 2009; 51(4): 626–627.
33.Shiffman ML, Suter F, Bacon BR et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357(2): 124–134.
34.Zeuzem S, Hultcrantz R, Bourliere M et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004; 40(6): 993– 999.
35.Hezode C, Forestier N, Dusheiko G et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360(18): 1839–1850.
36.Foster GR, Hezode C, Bronowicki J-P et al. Activity of telaprevir alone or in combination with peginterferon alfa-2A and ribavirin in treatment-naive genotype 2 and 3 hepatitis C patients: final results of study C209. J Hepatol 2010; 52(Suppl. 1): S27.
37.Gane EJ, Rodriguez-Torres M, Nelson DR, Jacobson IM, McHutchison JG, Jeffers L, Beard A. Antiviral activity of the HCV nucleoside polymerase inhibitor R7128 in HCV genotype 2 and 3 prior non-responders: results of R7128 1500mg BID with PEGIFN and ribavirin for 28 days. Hepatology 2008; 48(Suppl. 4): LB10.
38.Flisiak R, Horban A, Gallay P et al. The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology 2008; 47(3): 817– 826.
39.De Nicola S, Aghemo A, Rumi MG, Colombo M. HCV genotype 3: an independent predictor of fibrosis progression in chronic hepatitis C. J Hepatol 2009; 51(5): 964–966.
40.Chevallier M, Guerret S, Chossegros P, Gerard F, Grimaud JA. A histological semiquantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens: comparison with morphometric studies. Hepatology 1994; 20(2): 349–355.
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A Systematic Review and Meta-analysis
A. Probst; T. Dang; M. Bochud; M. Egger; F. Negro; P.-Y. Bochud
Posted: 11/14/2011; J Viral Hepat. 2011;18(11):749-755. © 2011 Blackwell Publishing
Abstract and Introduction
Abstract
The progression of liver fibrosis in chronic hepatitis C has long been considered to be independent from viral genotypes. However, recent studies suggest an association between Hepatitis C virus (HCV) genotype 3 and accelerated liver disease progression. We completed a systematic review and meta-analysis of studies evaluating the association between HCV genotypes and fibrosis progression. PubMed, Embase and ISI Web of Knowledge databases were searched for cohort, cross-sectional and case–control studies on treatment-naïve HCV-infected adults in which liver fibrosis progression rate (FPR) was assessed by the ratio of fibrosis stage in one single biopsy to the duration of infection (single-biopsy studies) or from the change in fibrosis stage between two biopsies (paired biopsies studies). A random effect model was used to derive FPR among different HCV genotypes. Eight single-biopsy studies (3182 patients, mean/median duration of infection ranging from 9 to 21 years) and eight paired biopsies studies (mean interval between biopsies 2–12 years) met the selection criteria. The odds ratio for the association of genotype 3 with accelerated fibrosis progression was 1.52 (95% CI 1.12–2.07, P = 0.007) in single-biopsy studies and 1.37 (95% CI 0.87–2.17, P = 0.17) in paired biopsy studies. In conclusion, viral genotype 3 was associated with faster fibrosis progression in single-biopsy studies. This observation may have important consequences on the clinical management of genotype 3-infected patients. The association was not significant in paired biopsies studies, although the latter may be limited by important indication bias, short observation time and small sample size.
Introduction
The hepatitis C virus (HCV) chronically infects ~170 millions of persons worldwide, which represents ~3% of the world's population.[1] The important morbidity and mortality associated with chronic hepatitis C result mainly from the development of liver fibrosis and its evolution towards cirrhosis and hepatocarcinoma.[2] The identification of factors affecting fibrosis progression is critical for the optimal management of infected patients.[3] Factors associated with rapid progression include demographic characteristics (such as older age at infection and male sex), host genetic factors, viral co-infections (with the hepatitis B [HBV] or the human immunodeficiency virus [HIV]), metabolic features (such as steatosis, insulin resistance or iron overload) and exposure to toxic agents (alcohol, tobacco or cannabis).[4] Risk factors identification for fibrosis progression was first based on fibrosis stage. However, this approach leads to significant bias, because disease duration varies widely across the population. This issue has been addressed, at least in part, by the estimation of fibrosis progression rate (FPR) based on the ratio of fibrosis stage to disease duration, which might better reflect the true fibrosis progression. Recent studies, using the latter method, suggested that some viral genotypes, such as genotype 3, are associated with more rapid fibrosis progression than other genotypes.[5–7] In this study, we systematically reviewed the published literature about the impact of HCV genotypes on the natural history of chronic hepatitis C and conducted a meta-analysis of the studies reporting a FPR per genotype. Our aim was to examine the impact of viral genotype 3 on fibrosis progression compared with other genotypes.
Material and Methods
Search Strategy
This meta-analysis was performed according to the PRISMA statement for reporting systematic reviews and meta-analyses.[8] Three electronic databases (PubMed, Embase and ISI Web of Knoweldge) were searched for published studies evaluating the fibrosis progression per genotype in chronic HCV before October 2009 (Table S1). Additionally, the investigators hand-searched the bibliographies of obtained articles and reviews; they did not contact any study authors for further information.
Eligible Studies
Cohort, cross-sectional and case–control published trials studying the fibrosis progression in HCV-infected patients were eligible. There was no restriction on language or publication date. Participants were chronically infected with HCV genotype 3, and controls were chronically infected with other genotypes.
Study Selection
Two investigators independently selected studies meeting the following criteria (Table S1): (i) chronic HCV infection; (ii) fibrosis scoring; (iii) no HCV treatment before biopsies; (iv) an estimated date of HCV infection; and (v) an estimated FPR per genotype. Studies on participants of <18 years of age, studies on orthotopic liver transplant recipients, studies without full text available and reviews were excluded. When more than one article was available from the same cohort, we included the article containing most complete information. Disagreements between the two investigators were solved by discussion.
Study Quality Assessment and Data Extraction
Quality criteria were reported for each study, including study design, case definition, liver biopsy quality, nonviral factors associated with fibrosis progression and method used to estimate the date of infection (Table S1). The two investigators independently extracted data for each study. The extracted data were then cross-checked by two other investigators for accuracy. FPR values were assessed together for all genotype non-3 patients. Patients with unknown genotype were not included.
Statistical Analysis
Eligible studies were separated in two groups: those calculating FPR as the ratio of the fibrosis score to the interval between an estimated date of infection and one pretreatment liver biopsy (defined as 'single-biopsy studies') and those calculating fibrosis progression between two pretreatment liver biopsies ('paired-biopsies studies'). For single-biopsy studies, an effect size (ES) was calculated for each individual study (detailed in Appendix).[9] ES of both continuous and dichotomous outcomes was pooled in the same meta-analysis using a random effect model.[10] ES was then transformed back to odds ratio (OR). For paired biopsies studies, the OR for comparison of genotype 3 vs others was calculated for each individual study. We performed a meta-analysis by pooling the OR using a random effect model. All statistical analyses were performed with Stata software (StataCorp, College Station, TX, USA), version 10.0.
Results
From the 3133 citations yielded by the electronic database search, 2936 were excluded for nonrelevance after title or abstract screenings (Fig. 1). Among 197 remaining full-text papers, 181 were excluded for nonrelevance, inappropriate review design, use of post-treatment biopsy, lack of estimated HCV infection duration, or lack of data on genotyping (no data on genotype 3) or FPR. The remaining 16 studies (eight single-biopsy and eight paired biopsy studies) were selected for the meta-analysis. For single-biopsy studies in which both continuous and dichotomous outcomes were available,[6,7] the continuous outcome was used.
Figure 1.
Flow diagram for study selection.
The characteristics of the studies are shown in Table 1. In most studies, the primary endpoint was to assess together the role of several risk factors on fibrosis progression in chronically HCV-infected patients (N = 7 [6,7,11–15]). No study focused specifically on the role of viral genotypes, but some addressed specific factors such as steatosis (N = 5 [16–20]), cannabis use (N = 1 [5]), host genetic variants (N = 1 [21]), immunosuppression level in HIV-infected patients (N = 1 [22]) or transforming growth factor β (N = 1 [23]).
Overall, 3860 patients were included in the meta-analyses, 3182 (range 71–1157) from single-biopsy studies and 678 (range 20–136) from paired biopsies studies (Table S2). Most patients included in the studies were men (62%), the most frequent ethnicity was Caucasian (95%, data available in five studies) and the mean age was 42 years. The most frequent routes of infection were intravenous drug use (41%) and blood transfusion (31%). Eight studies included only HCV mono-infected patients (N = 8), two included both HCV mono-infected and HCV/HIV co-infected patients (percentage of co-infection 7% and 22%), two included only co-infected patients, while four other studies did not give any information on co-infection. The mean duration of HCV infection in single-biopsy studies was 13 years (range 10–17, six studies; median 9 and 21 years in two other studies). The mean interval time between paired biopsies was 5.3 years (range 2.3–12, 5 studies; median 4.1, 4.2 and 6 years in three other studies).
Study Quality
The studies showed a relative homogeneity in terms of design and settings: 11 were retrospective cohort studies (Table 1), four were prospective cohort studies and one was a retrospective case–control study. All studies performed in tertiary hospitals or liver centres, and all published between 1997 and 2009 (Table 1). Seven studies gave a fibrosis score according to the METAVIR system,[24] while four used Ishak's modified histology activity index (HAI),[25] three used the Knodell's HAI,[26] one used Desmet's system[27] and one study gave Scheuer's grades[28] (scores summarized in Table S3). In most single-biopsy studies (N = 6), the date of infection was considered to be the first reported event at risk (blood transfusion, IV drug or nosocomial infection). In most studies, the association of viral genotype 3 with FPR was solely assessed in univariate models, with multivariate analyses performed in only three single-biopsy studies (Fig. S1).
Meta-analyses
The meta-analysis of single-biopsy studies showed a faster FPR in patients infected by genotype 3 compared with the others (overall pooled ES = 0.23, [95% CI 0.06–0.40], P = 0.007, OR = 1.52 [95% CI 1.12–2.07], Fig. 2). The I2 test result was 62.2% (P = 0.010). Similar results were obtained when studies including HIV-infected patients were removed, but the number of patients was smaller (N = 455) and the association was at the limit of significance (OR = 1.67, [95% CI 0.99–2.85], P = 0.056). The cumulative meta-analysis showed that the effect of genotype 3 on fibrosis progression became significant only in 2009 (Fig. 3). The meta-analysis of paired biopsies studies showed a trend towards faster progression for genotype 3 patients compared with the others (OR = 1.37, 95% CI 0.87–2.17, P = 0.17, Fig. 4). The I2 test was 0.0% (P = 0.455). The dichotomization process differed widely across studies, with a progression definition ranging from a worsening of fibrosis unit between two biopsies to a fixed higher fibrosis score value at the second biopsy (Table 2).
Figure 2.
Forest plot of fibrosis progression rates estimated from one biopsy, genotype 3 vs other genotypes. ES, effect size; OR, odds ratio; 95% CI, 95% confidence interval.
Figure 3.
Meta-cumulative analysis of studies estimating fibrosis progression rate based on an estimated date of infection, genotypes 3 vs non-3. ES, effect size; OR, odds ratio; 95% CI, 95% confidence interval.
Figure 4.
Forest plot of odds ratio of fibrosis progression between two liver biopsies, genotype 3 vs non-3. OR, odds ratio; 95% CI, 95% confidence interval.
Discussion
Viral factors have usually been considered to have limited influence on liver FPR in chronically infected HCV patients.[29] However, recent studies highlighted a possible association between viral genotypes and rapid fibrosis progression. By pooling results from several, often small-sized studies, this meta-analysis provides a comprehensive summary of the published literature on the topic as well as new insights into the natural history of chronic HCV infection. The pooled analyses of eight single-biopsy studies clearly confirmed a significantly faster progression for genotype 3 patients compared with the other genotypes. Among them, five showed a significantly faster fibrosis progression or a clear trend towards faster progression for genotype 3-infected patients compared with others.[5–7,16,22] The failure of some studies to detect a significant effect for viral genotype 3 probably results from their insufficient sample size (i.e. 342 cases and 684 controls are necessary for 80% power to detect an OR of 1.5 for viral genotype 3 on fibrosis progression, considering a 30% prevalence of this genotype). Despite a much smaller observation time, the pooled analysis of eight paired biopsies studies showed a trend towards faster progression for genotype 3-infected compared with genotype non-3-infected patients.
A previous study assessing stage-specific FPR using a Markov model suggested that viral genotype 1 (compared with other genotypes) may influence fibrosis progression, but the estimation was performed using a meta-regression.[30] It is known that such ecological associations may lead to incorrect estimates of the relation for individual patients.
The association of viral genotype 3 with FPR may have important practical implications. It has been reported that the uptake of antiviral therapy for hepatitis C has been declining during recent years.[31] Apart from poor rate of diagnosis and lack of referral, two major factors may account for this trend: the widespread perception on the supposedly slow average progression rate of hepatitis C, coupled with the huge expectations surrounding novel, more effective direct antiviral agents (DAA), to be first marketed in 2011–2012. Genotype 3-infected patients should be aware of a potentially faster progression rate and may benefit from individualized counselling, with particular attention given to the controllable factors, such as alcohol consumption and overweight.[32] While therapy with peginterferon alpha and ribavirin usually achieves 70–80% of sustained viral response among patients infected with HCV genotype 3, certain subgroups of patients still have high relapse rates, such as those with elevated baseline viral load (>800 000 copies/mL,[33,34]) and advanced fibrosis.[32] Patients with chronic hepatitis C may be deferred from current treatment regimens just because more potent DAA will be licensed in the near future.[35] However, this 'warehousing' attitude may not be justified in infections with genotype 3, given that the serine protease inhibitors, such as telaprevir, have very limited activity against genotype 3.[36] DAAs with significant activity against genotype 3, such as the nucleoside RNA polymerase inhibitor R7128[37] or the cyclophilin-binding molecule Debio 025,[38] are far from completing clinical development. These considerations argue against the indiscriminate deferral from antiviral therapy in patients infected with genotype 3.
Multiple reasons may explain why paired biopsies studies did not show a significant effect of genotype 3. First, confounding by indication is likely to be a major problem in paired biopsies studies, as only selected patients undergo a second biopsy (e.g. those with multiple comorbidities and potentially rapidly evolving liver disease). Second, paired biopsies studies have a smaller sample size than single-biopsy studies. Out of eight studies, none included more than 30 genotype 3 patients, and four included <7 genotype 3 patients, resulting in low power to detect a given ES. Third, paired biopsies studies have a much smaller observation time than single-biopsy studies (~5 years between 2 biopsies compared with ~13 years from the infection date to the first biopsy, Fig. S3). This short duration may not be sufficient to detect genotype-specific differences in terms of FPRs. Fourth, paired biopsies studies have used arbitrary cut-offs for dichotomizing the outcome into progression vs nonprogression, for instance a worsening of the score by one or several units[13–15,17,18,20,23] or reaching a specific fibrosis stage at the second biopsy.[19] This method results in more information loss if one considers that the process of fibrosis is continuous. Finally, given that FPRs are not constant over time, paired biopsies studies may have included patients when the progression rate is the slowest (e.g. transition from Metavir scores F1–F2[30] or F2–F3[7]), making it even more difficult to detect genotype-specific differences (Fig. S2).
As in many systematic reviews, the limitation of this study results from the limitation of the original studies themselves. Those include the inability to precisely determine the date of infection, the variability in the assessment of fibrosis staging, the nonlinearity of fibrosis progression over time, the failure to account for multiple risk factors. However, several studies addressed these issues. In three studies, the role of viral genotype 3 in fibrosis progression was confirmed in multivariate analyses, accounting for different covariates such as age, alcohol consumption and steatosis.[5–7] In one of them, the authors suggested that cannabis use, which may be more prevalent among genotype 3-infected patient, may have been a confounding factor for the role of genotype 3. However, this study clearly identified cannabis use, genotype 3, age at infection, alcohol intake and steatosis all as independent risk factors for rapid fibrosis progression (>0.74 U/year) in a stepwise logistic regression model of 267 patients.[5] In another study, the association of genotype 3 with faster progression remained significant among patients infected by blood transfusion (for whom the date of infection is certain), among different age groups, or among different periods of infection, and when using different methods to assess the progression rate.[7]
Owing to our stringent selection criteria, the number of studies included in the meta-analysis is relatively small. Therefore, it was not possible to perform a meta-regression analysis and explore the role of potential confounders. We could not include a large confirmatory study (N = 327, N genotype 3 = 80), showing that patients infected with HCV genotype 3 had shorter time to infection than others, because it did not provide FPR rates.[39]
This study provides new insight into the natural history of HCV infection. The evidence for a role of genotype 3 in fibrosis progression may have important implications for the management of patients infected with this genotype.
References
1.Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol 2006; 44(1 Suppl.): S6–S9.
2.Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001; 345(1): 41–52.
3.Massard J, Ratziu V, Thabut D et al. Natural history and predictors of disease severity in chronic hepatitis C. J Hepatol 2006; 44(1 Suppl.): S19–S24.
4.Missiha SB, Ostrowski M, Heathcote EJ. Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. Gastroenterology 2008; 134(6): 1699–1714.
5.Hezode C, Roudot-Thoraval F, Nguyen S et al. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 2005; 42(1): 63–71.
6.Hissar SS, Kumar M, Tyagi P et al. Natural history of hepatic fibrosis progression in chronic hepatitis C virus infection in India. J Gastroenterol Hepatol 2009; 24(4): 581–587.
7.Bochud PY, Cai T, Overbeck K et al. Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C. J Hepatol 2009; 51(4): 655–666.
8.Liberati A, Altman DG, Tetzlaff J et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009; 6(7): e1000100.
9.Hedges LV. Distribution theory for glass's estimator of effect size and related estimators. J Edu Stat 1981; 6(2): 107–128.
10.Chinn S. A simple method for converting an odds ratio to effect size for use in meta-analysis. Stat Med 2000; 19(22): 3127–3131.
11.Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349(9055): 825–832.
12.Martinez-Sierra C, Arizcorreta A, Dıaz F et al. Progression of chronic hepatitis C to liver fibrosis and cirrhosis in patients coinfected with hepatitis C virus and human immunodeficiency virus. Clin Infect Dis 2003; 36(4): 491–498.
13.Shev S, Dhillon AP, Lindh M et al. The importance of cofactors in the histologic progression of minimal and mild chronic hepatitis C. Liver 1997; 17(5): 215–223.
14.Zarski J, Mc Hutchison J, Bronowicki J et al. Rate of natural disease progression in patients with chronic hepatitis C. J Hepatol 2003; 38(3): 307–314.
15.Bonnard P, Lescure FX, Amiel C et al. Documented rapid course of hepatic fibrosis between two biopsies in patients coinfected by HIV and HCV despite high CD4 cell count. J Viral Hepat 2007; 14(11): 806–811.
16.Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001; 33(6): 1358–1364.
17.Cross TJ, Quaglia A, Hughes S, Joshi D, Harrison PM. The impact of hepatic steatosis on the natural history ofchronic hepatitisCinfection. J Viral Hepat 2009; 16(7): 492–499.
18.Westin J, Lagging L, Spak F et al. Moderate alcohol intake increases fibrosis progression in untreated patients with hepatitis C virus infection. J Viral Hepat 2002; 9(3): 235–241.
19.Fartoux L, Poujol-Robert A, Guéchot J, Wendum D, Poupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut 2005; 54(7): 1003–1008.
20.Perumalswami P, Kleiner DE, Lutchman G et al. Steatosis and progression of fibrosis in untreated patients with chronic hepatitis C infection. Hepatology 2006; 43(4): 780–787.
21.Richardson MM, Powell EE, Barrie HD, Clouston AD, Purdie DM, Jonsson JR. A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C. J Med Genet 2005; 42(7): e45.
22.Reiberger T, Ferlitsch A, Sieghart W et al. HIV-HCV co-infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension. J Viral Hepat 2010; 17(6): 400–409.
23.Kanzler S, Baumann M, Schirmacher P et al. Prediction of progressive liver fibrosis in hepatitis C infection by serum and tissue levels of transforming growth factor-beta. J Viral Hepat 2001; 8(6): 430–437.
24.Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology 1994; 20(1 Pt 1): 15–20.
25.Ishak K, Baptista A, Bianchi L et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22(6): 696–699.
26.Knodell RG, Ishak KG, Black WC et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1(5): 431– 435.
27.Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994; 19(6): 1513–1520.
28.Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 1991; 13(3): 372– 374.
29.Castera L, Hezode C, Roudot-Thoraval F et al. Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies. Gut 2003; 52(2): 288– 292.
30.Thein H, Yi Q, Dore G, Krahn M. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology 2008; 48(2): 418–431.
31.Volk ML, Tocco R, Saini S, Lok AS. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology 2009; 50(6): 1750–1755.
32.Zeuzem S. Forewarned is forearmed. J Hepatol 2009; 51(4): 626–627.
33.Shiffman ML, Suter F, Bacon BR et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357(2): 124–134.
34.Zeuzem S, Hultcrantz R, Bourliere M et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004; 40(6): 993– 999.
35.Hezode C, Forestier N, Dusheiko G et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360(18): 1839–1850.
36.Foster GR, Hezode C, Bronowicki J-P et al. Activity of telaprevir alone or in combination with peginterferon alfa-2A and ribavirin in treatment-naive genotype 2 and 3 hepatitis C patients: final results of study C209. J Hepatol 2010; 52(Suppl. 1): S27.
37.Gane EJ, Rodriguez-Torres M, Nelson DR, Jacobson IM, McHutchison JG, Jeffers L, Beard A. Antiviral activity of the HCV nucleoside polymerase inhibitor R7128 in HCV genotype 2 and 3 prior non-responders: results of R7128 1500mg BID with PEGIFN and ribavirin for 28 days. Hepatology 2008; 48(Suppl. 4): LB10.
38.Flisiak R, Horban A, Gallay P et al. The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology 2008; 47(3): 817– 826.
39.De Nicola S, Aghemo A, Rumi MG, Colombo M. HCV genotype 3: an independent predictor of fibrosis progression in chronic hepatitis C. J Hepatol 2009; 51(5): 964–966.
40.Chevallier M, Guerret S, Chossegros P, Gerard F, Grimaud JA. A histological semiquantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens: comparison with morphometric studies. Hepatology 1994; 20(2): 349–355.
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