Editorial Board: Emmet B. Keeffe, MD (Chair); M. Eric Gershwin, MD;

Ira S. Goldman, MD; John L. Gollan, MD, PhD; Kris V. Kowdley, MD;

Paul Martin, MD; Marion G. Peters, MD

HEPATOLOGY WATCH^®

APRIL 2004

CHRONIC HEPATITIS C VIRUS (HCV) INFECTION

Meta-analysis on the effect of peginterferon alfa-2a on liver histology. Calogero Camma and colleagues performed a meta-analysis of 3 randomized trials consisting of 1,013 previously untreated HCV patients to compare the effects of peginterferon with those of interferon (IFN) on liver histology. All patients had pre- and post-treatment liver biopsies, and the authors used a random-effects model to quantify the average effect of treatment on histology. Peginterferon was associated with a greater reduction in hepatic fibrosis than IFN therapy. The comparative reduction in fibrosis between peginterferon and IFN therapy was seen in patients who achieved a sustained virologic response (SVR) and in patients who had a relapse. No reduction in fibrosis was noted in nonresponders treated with either peginterferon or IFN. This study showed that peginterferon reduced fibrosis to a greater extent than IFN and that beneficial effects are closely related to the achievement of SVR. (Camma C, et al. Hepatology 2004;39:333-342)

Combination peginterferon and ribavirin therapy. Previous studies had demonstrated that the duration of treatment with conventional IFN alfa-2b and ribavirin can be reduced from 48 to 24 weeks without loss of efficacy in certain patients. In an effort to generate similar data for the combination of peginterferon and ribavirin, Stephanos Hadziyannis et al. conducted a double-blind trial in which 1,311 patients with chronic hepatitis C were randomized to receive peginterferon alfa-2a 180 mg/wk for either 24 or 48 weeks plus a low-dose (800 mg) or a standard weight-based dose (1,000 or 1,200 mg) of ribavirin daily. For patients infected with HCV genotype 1, 48 weeks of treatment was superior to 24 weeks, and standard-dose ribavirin was superior to low-dose ribavirin for the achievement of SVR (52% vs. 29-42%). In patients with HCV genotypes 2 and 3, the SVR rates were similar for each of the 4 treatment groups (79-84%). These data showed that patients with HCV genotype 1 require peginterferon alfa-2a treatment for 48 weeks with a standard dose of ribavirin, while patients with HCV genotypes 2 and 3 were adequately treated with peginterferon alfa-2a for 24 weeks with a low-dose ribavirin regimen. (Hadziyannis GJ, et al. Ann Intern Med 2004;140:346-355)

Review article: heterogenous virologic response rates to interferon-based therapy. The recent introduction of peginterferon has improved therapy such that more than half of HCV patients can now expect to achieve a SVR. Despite this success, less satisfactory results continue to be obtained in certain patient subpopulations. Stefan Zeuzem reviewed the data on IFN-based therapies among subgroups of patients with lower chances of achieving SVR. HCV-related factors predictive of a lower SVR include genotype 1 and high viral load. Patient-related factors include previous relapse or no response, cirrhosis, African American ethnicity, older age, contraindications to treatment, and obesity. (Zeuzem S. Ann Intern Med 2004;140:370-381)

SEVERE ACUTE RESPIRATORY SYNDROME (SARS)

SARS-associated viral hepatitis. Liver impairment has been reported in up to 60% of SARS patients. Tai-Nin Chau and associates from the Princess Margaret Hospital in Hong Kong report the clinical course and liver pathology in 3 SARS patients with liver impairment. All 3 patients had moderate to marked elevation of serum ALT levels, and underwent liver biopsy with analysis of tissue specimens by light and electron microscopy and immunohistochemistry. Although viral particles were not detected by electron microscopy, reverse transcriptase polymerase chain reaction (RT-PCR) was positive for SARS coronavirus in liver tissue from all 3 patients. All 3 liver biopsies demonstrated hepatocyte apoptosis, and a marked accumulation of cells in mitosis was observed in 2 patients. Other common pathologic features included ballooning of hepatocytes and mild to moderate lobular lymphocytic infiltration. These liver biopsy findings indicated that the liver impairment in these SARS patients was due to SARS-associated coronavirus infection rather than other factors such as drug toxicity, superimposed bacterial infection, or a systemic inflammatory response. The prominence of hepatic mitotic activity may have resulted from a coronavirus-induced disruption of the cell cycle. An accompanying editorial by Atal Humar et al. from the University of Toronto notes that this is the first report to associate direct hepatic coronavirus infection with liver pathologic features and puts these findings in perspective with preclinical and clinical SARS data. (Chau T-N, et al. Hepatology 2004;39:302-310 and Humar A, et al. Hepatology 2004;39:291-294)

LIVER TRANSPLANTATION

Response to IFN-based therapy in patients with recurrent HCV. Treatment for posttransplant recurrent hepatitis C with IFN-based therapy results in loss of detectable virus in up to 30% of patients; however, the durability of viral clearance and the associated histologic response in this setting is unknown. Manal Abdelmalek et al. studied whether viral loss in response to antiviral therapy is durable and associated with improvement in liver histology. All liver transplant recipients who received IFN-based treatment for recurrent hepatitis C at the University of Florida from 1991 to 2002 were included in the study. Of 119 transplant recipients treated with IFN or combination therapy, 29 lost detectable HCV RNA and remained virus negative for at least 6 months after discontinuing therapy. The study cohort included one patient treated with IFN monotherapy and 28 patients with combination IFN and ribavirin therapy. All patients remained HCV RNA negative during follow-up of up to 5 years. Liver histology assessed 2 years after treatment showed less inflammation compared with before treatment in 50% and showed no change in 38%. At 3 to 5 years, the fibrosis stage improved in 67%, remained unchanged in 13%, and worsened in 20%, and the grade of inflammation was also improved. The authors concluded that loss of HCV after treatment is durable and associated with improvement in hepatic inflammation and regression of fibrosis. (Abdelmalek M, et al. Liver Transplantation 2004;10:199-207)

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