HCV Genotype 3 May Be Associated with More Rapid Liver Fibrosis Progression in People with Chronic Hepatitis C

Infection with hepatitis C virus (HCV) genotype 3 may increase the risk of accelerated fibrosis progression compared with other viral genotypes, according to a Swiss study published in the October 2009 Journal of Hepatology. This rapid progression -- combined with good response to interferon and the fact that experimental oral anti-HCV agents are less effective against genotype 3 -- suggests that such patients should receive prompt interferon-based therapy.

It is well known that different HCV genotypes respond differently to interferon-based therapy for chronic hepatitis C, with genotypes 2 and 3 considered easiest to treat, and genotype 1 (and 4 in some studies) yielding the lowest sustained response rates. It is less clear whether HCV genotype plays a role in liver fibrosis severity, however, though genotype 3 has been linked to steatosis, or fat accumulation in the liver.

Investigators with the Swiss Hepatitis C Cohort Study assessed independent predictors for fibrosis progression among 1189 patients from the Swiss Hepatitis C Cohort database with at least 1 biopsy prior to starting interferon-based antiviral treatment and an assessable date of infection.

Stage-constant fibrosis progression rates were assessed using the ratio of Metavir fibrosis score (F0 through F4) to duration of infection. Accelerated fibrosis progression was defined as > 0.083 fibrosis units per year.

Results

	Independent risk factors for accelerated stage-constant fibrosis progression included:
	Male sex: odds ratio (OR) 1.60 (P < 0.001); Older age at the time of infection: OR 1.08 (P < 0.001); Greater histological activity: OR 2.03 (P < 0.001); HCV genotype 3: OR 1.89 (P < 0.001).
	Patients infected through blood transfusions and invasive medical procedures or needle sticks had slower fibrosis progression rates than those infected though sharing equipment for injection drug use.
	Maximum likelihood estimates of stage-specific progression rates (fibrosis units per year) for genotype 3 versus other genotypes were:
	F0 (absent) to F1 (mild): 0.126 for genotype 2 vs 0.091 for other genotypes; F1 to F2 (moderate): 0.099 vs 0.065, respectively; F2 to F3 (advanced): 0.077 vs 0.068, respectively; F3 to F4 (severe fibrosis or cirrhosis): 0.171 vs 0.112, respectively.

"This study shows a significant association of genotype 3 with accelerated fibrosis using both stage-constant and stage-specific estimates of fibrosis progression rates," the investigators concluded. "This observation may have important consequences for the management of patients infected with this genotype."

"What are the practical consequences if indeed fibrosis progression rates are faster in patients infected with HCV genotype 3?" asked Stefan Zeuzem from JW Goethe University Hospital in an accompanying editorial.

"First, comprehensive counseling of patients with respect to proven (alcohol consumption) or suspected concomitant factors (overweight, iron overload) is mandatory. Second, reluctance to defer or delay antiviral therapy may not be appropriate." This is especially the case given that genotype 3 has a high rate of sustained virological response to pegylated interferon plus ribavirin for 24 weeks (70% to 80% in most studies, compared with about 50% for genotype 1 patients treated for 48 weeks).

While some people with hepatitis C and their clinicians are awaiting new oral specifically targeted antiviral therapies (STAT-C), Zeuzem noted that the drugs furthest along in the development pipeline -- the HCV protease inhibitors telaprevir and boceprevir -- are most active against HCV genotypes 1-2 and less so against genotypes 3-4, while non-nucleoside HCV polymerase inhibitors are generally primarily active against genotype 1.

"Taken together, [the] combination of peginterferon alfa and ribavirin could remain the key treatment option for patients infected with HCV genotype 3 in the years to come," Zeuzem concluded. "If indeed fibrosis progression in patients infected with HCV genotype 3 is faster than in HCV-1 infected patients, waiting for new treatment options should be strongly discouraged in this patient population."

Department of Internal Medicine, CHUV, Lausanne; Institute of Microbiology, University of Lausanne, CHUV, Lausanne; Division of Clinical Pathology, University Hospitals, Geneva; Institute for Social and Preventive Medicine, CHUV, Lausanne; Division of Clinical Pharmacology, University Hospital, Bern; Division of Gastroenterology and Hepatology, University Hospital of Zurich; Division of Gastroenterology, Canton Hospital, St. Gallen; Division of Gastroenterology and Hepatology, University Hospital of Basel, Basel; Division of Gastroenterology and Hepatology, CHUV, Lausanne; Clinica Moncucco, Lugano,; Pourtalès Hospital, Neuchâtel; Division of Hospital Preventive Medicine, CHUV, Lausanne; Division of Gastroenterology and Hepatology, University Hospitals of Geneva, Geneva, Switzerland.

10/27/09

References

P Bochud, T Cai, K Overbeck, and others (Swiss Hepatitis C Cohort Study Group). Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C. Journal of Hepatology 51(4): 655-666. (Abstract).

S Zeuzem. Forewarned is forearmed. Journal of Hepatology 51(4): 626-627.
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