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RESEARCH PRODUCT

Optimal therapy in hepatitis C virus genotypes 2 and 3 patients

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Current guidelines recommend that patients with genotype 2 (G2) and 3 (G3) chronic hepatitis C be treated with pegylated interferon (PEG-IFN) plus low doses of ribavirin (800 mg/day) for 24 weeks, resulting in a sustained virological response (SVR) rate of approximately 80%. Considering these high response rates, several recent randomized trials have assessed whether shorter treatment (12–16 weeks) could be cost-effective in these patients. The results of these studies vary but suggest better responsiveness in G2 patients, and overall, do not strongly support reducing treatment to o 24 weeks in all patients. On the other hand, the presence of a rapid virological response (RVR) (defined as an undetectable hepatitis C virus-RNA at 4 weeks of treatment) was always reported to be the best positive predictor of achieving SVR in both G2 and G3 patients. These results suggest that in a subgroup of subjects with RVR (G24 G3, viral load o 400 000 IU, low fibrosis, no metabolic cofactors), shorter treatment is as effective as standard regimens, and that it can be proposed mainly if problems of poor tolerance or adherence are foreseen. It is possible that the SVR rate in non-RVR patients and nonresponder patients could also be improved by prolonging therapy, but this must be specifically investigated in other studies along with the role of IL28B polymorphisms. Standard of care for patients with G2 and G3 chronic hepatitis C In the late 1990s, trials of standard interferon (IFN) plus ribavirin (RBV) (1) showed that 24 weeks of treatment in patients with genotypes 2 (G2) and 3 (G3) chronic hepatitis C (CHC) resulted in the same sustained virological response (SVR) rate as 48 weeks of treatment (about 65%). Despite these results, the phase 3 trials by Manns (2) and Fried (3), resulting in the registration of pegylated interferons (PEG-IFN) a-2a and a-2b in combination with RBV for the treatment of CHC, only investigated 48 weeks of combination therapy in these patients. These studies reported an SVR rate of about 80% in these easy-to-treat patients, raising the important issue of potential ‘overtreatment’ in these cases. The study by Hadziyannis et al. (4) was an initial effort to rectify this error, despite its methodological limitations, such as the lack of stratification by genotype. They clearly demonstrated that SVR rates in G2 and G3 patients treated with PEG-IFN a-2a plus RBV at a flat dose of 800 mg/day for 24 weeks were similar to patients treated for 48 weeks with higher doses of RBV of 1 000/ 1 200 mg/day. Thus, based on these trials, in the 2009 American Association for the Study of Liver Diseases guidelines on the diagnosis, management and treatment of hepatitis C (5), the recommended standard of care (SOC) for patients with G2 and G3 CHC was PEG-IFN a-2b 1.5mg/kg/week or PEG-IFN a-2a 180mg/week, combined with low doses (800 mg/day) of RBV for 24 weeks.