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A Bi-Monthly Publication of the Hepatitis Support Project

January 10 , 2007
Volume 4, Issue 1

Liz Highleyman

To download pdf version click here

In This Issue:

Hepatitis C

• Combination Anti-HCV Therapy

• Disease Severity Affects Treatment Outcomes

• Treatment of Patients with Advanced Fibrosis

• Therapy for Patients with Decompensated Cirrhosis

• Coinfection with Multiple Hepatitis Viruses

Combination Anti-HCV Therapy
Researchers are developing various small-molecule drug candidates that have direct activity against the hepatitis C virus (HCV), including telaprevir (VX-950), valopicitabine (NM283), and ITMN-191. As with antiretroviral agents for HIV, using such agents in combination should help prevent resistance by targeting multiple steps of the HCV lifecycle. In the December 20, 2006 electronic edition of the Journal of Virology, D.L. Wyles and colleagues presented data from an in vitro assessment of combinations of interferon and/or novel anti-HCV agents from several different classes. They found that combinations of HCV inhibitors with different mechanisms of action consistently demonstrated more synergy than compounds with similar mechanisms, leading the researchers to recommend that “combinations of inhibitors with different mechanisms of action should be prioritized for assessment in clinical trials for chronic hepatitis C virus infection.”

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Disease Severity Affects Treatment Outcomes
Research has shown that advanced fibrosis is associated with lower rates of sustained virological response (SVR) to interferon-based therapy. As reported in the December 2006 issue of Hepatology, G.T. Everson and colleagues assessed virological response to retreatment with pegylated interferon alfa-2a (Pegasys) plus ribavirin in 1046 prior nonresponders enrolled in the HALT-C trial, and its association with baseline Ishak fibrosis scores and platelet counts. They found that SVR rates decreased as fibrosis score increased, from a high of 23% in patients with stage 3-4 bridging fibrosis, to 10% in those with stage 5-6 cirrhosis. This pattern was independent of age, race/ethnicity, HCV genotype, HCV viral load, and type of previous therapy. “[D]isease severity is a major independent determinant of rate of SVR in patients with advanced chronic hepatitis C,” the researchers concluded. “New strategies are needed to optimize antiviral therapy in these ‘difficult-to-cure’ patients.”

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Treatment of Patients with Advanced Fibrosis
In the December 2006 Journal of Viral Hepatitis, A. Abergel and colleagues described a study comparing SVR rates in 203 chronic hepatitis C patients with severe fibrosis who were randomly assigned to receive 800 mg/day ribavirin plus pegylated interferon alfa-2b (PegIntron) at either the standard dose of 1.5 mcg/kg/week or a low dose of 0.75 mcg/kg/week. After 48 weeks, 45% of patients in the standard-dose PegIntron arm achieved SVR, compared with 37% in the low-dose arm. Among “difficult-to-treat” patients with HCV genotypes 1, 4, or 5, the SVR rates were 25% and 17%, respectively. Neither of these differences were statistically significant. Among patients with genotypes 2 or 3, the SVR rate was 73% regardless of PegIntron dose. Among patients with high HCV RNA levels, the high-dose SVR rate was 24%, compared with 9% in the low-dose arm. The researchers concluded that low-dose PegIntron is effective for genotype 2/3 patients, though optimal treatment duration remains to be determined. For genotype 1/4/5 patients, the standard dose appears more effective, but “side effects limit the efficacy of the treatment.”

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Therapy for Patients with Decompensated Cirrhosis
In addition to poorer response to therapy, hepatitis C treatment is considered contraindicated for individuals with decompensated cirrhosis due to the risk of serious adverse side effects. However, these patients have the greatest need for effective therapy in order to avoid liver transplantation or death. As reported in the February 2007 Journal of Hepatology, A. Iacobellis and colleagues from Italy studied long-term outcomes in 129 chronic hepatitis C patients hospitalized for decompensated cirrhosis; 66 elected to receive PegIntron plus ribavirin, while 63 chose to remain untreated (the current standard of care). Over 24 weeks, 27 patients tolerated therapy, 26 had their doses reduced due to toxicity, and 13 discontinued due to intolerance. End-of-treatment response rates were 83% for genotype 2/3 patients and 30% for genotype 1/4 patients; corresponding SVR rates were 44% and 7%. During therapy, treated patients were more likely to develop severe infections compared with untreated subjects. During a 30-month follow-up period after completion of therapy, the risk of decompensation events such as ascites, hepatic encephalopathy, and esophageal bleeding decreased significantly in treated patients. Survival rates were similar in treated and untreated patients, though treated patients who achieved SVR appeared to obtain a survival benefit. “In decompensated cirrhotics,” the researchers concluded, “HCV clearance by therapy is life-saving and reduces disease progression.”

In an accompanying editorial, M. Navas and X. Forns suggested that “the reduction in decompensation episodes may be the consequence of a decrease in necroinflammation (and even in liver fibrosis) in treated patients, which may ultimately lead to a reduction in portal pressure.” However, they noted that despite the decreased incidence of decompensation episodes, Child-Pugh scores worsened in treated patients who did not achieve SVR. “Although the [Iacobellis] study has a number of shortcomings,” they wrote, “the results strongly suggest that viral clearance slows disease progression and increases survival in HCV [patients with] decompensated cirrhosis.”

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Coinfection with Multiple Hepatitis Viruses
Due to overlapping risk factors, many individuals are infected with more than one type of viral hepatitis. L. Lin and colleagues presented an overview of coinfection with multiple hepatitis viruses in the December 2006 European Journal of Gastroenterology and Hepatology. The combined effects of coinfection are attributable not only to virus-virus and virus-cell interactions, but also to enhanced immune response. Hepatitis B virus (HBV) coinfection increases the risk that chronic hepatitis C patients will develop hepatocellular carcinoma. HCV infection impairs the body’s response to the hepatitis A and B vaccines, and treatment that suppresses HCV “endangers dually infected patients with reactivation of coinfected hepatitis B virus.” The researchers concluded that “[o]ptimized strategies and follow-up are thus necessary in the treatment of infection with multiple viruses.” They stressed the importance of testing for HBV and hepatitis delta virus (HDV) in patients who test positive for HCV antibodies but negative for HCV RNA, and testing for HCV RNA in patients who have undetectable HBV surface antigen, detectable HBV core antibodies, and low HBV DNA.

In a related study, reported in the December 2006 Journal of Hepatology, K. Deterding and colleagues from Germany reported data from a small study of 17 chronic hepatitis C patients with acute hepatitis A virus (HAV) infection. None of the HCV positive patients had a fulminant course of hepatitis A. HCV RNA was detected in 84% of patients with undetectable anti-HAV antibodies, compared with 65% of those with acute hepatitis A. After recovery from acute hepatitis A, 6 out of 9 patients (67%) experienced increased HCV replication. However, two subjects remained HCV RNA negative after clearance of HAV. “HAV superinfection is associated with decreased HCV RNA replication which may lead to recovery from HCV in some individuals,” the researchers concluded. They added that fulminant hepatitis A was not observed among chronic hepatitis C patients in this study, in contrast with some past research showing that coinfection with more than one hepatitis virus increases the risk of severe acute liver failure.

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