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Abstract and Introduction
Abstract
The drugs currently licensed for the treatment of hepatitis C are Peg-Interferon (PEG-IFN) and ribavirin. In recent years, the recommendation to treat hepatitis C virus genotype 2- and 3-infected patients with a fixed 800 mg/day dose of ribavirin in combination with PEG-IFN and for just 24 weeks has been challenged by the concept of tailoring the length of therapy according to on-treatment viral response. Therefore, the objective of the present review was to highlight the different designs of the studies on short treatment duration and the role of wk4-R as a predictor of sustained virological response after an abbreviated course of treatment. The secondary aim was to verify whether we had enough evidence to support the implementation of a short treatment course in subsets of patients with genotype 2 and 3 infection. We will also focus on how drug dosing may have influenced the outcome of treatment. To clarify reasons for discrepant results in the studies so far published, the recently discovered genetic variant near the interleukin 28B gene will be presented and its predictive role will be discussed. Finally, we will face the debated issue of whether the subset of patients with genotype 2 or 3 requires an extended treatment duration.
Introduction
The approved therapeutic regimen for patients with hepatitis C virus (HCV) genotype 2 and 3 infection includes Peg-Interferon (PEG-IFN) and ribavirin at a fixed 800 mg/day dose for 24 weeks. However, several modifications of this regimen have been directed at an increasing tolerability and compliance and reducing costs. To define which kind of patients with genotype 2 and 3 can be treated for <24 weeks, we should bear in mind that the aim of an individualized short course of treatment is to avoid unnecessary side effects in patients with a very high expectancy of response after a standard 24-week course. Therefore, the essential condition for a successful short-course treatment is to attain, after 12–16 weeks, rates of sustained virological response (SVR) not inferior to those attained with the standard 24 weeks. The current literature has so far provided a number of studies with heterogeneous characteristics that support the efficacy of short treatment in patients with undetectable HCV RNA after 4 weeks of treatment [wk4-R or rapid virological response (RVR)] and three studies, one of them very large, named Accelerate, in which patients were randomized to a short course, independently of wk4-R. The Accelerate study enrolled a large number of patients of different ethnicity and showed that the efficacy of treatment may be compromised when patients are treated for <24 weeks as the relapse is unacceptably high. Although it has been shown that the occurrence of relapse after short therapy did not impact negatively on the outcome of a repeat 24-week course, the challenge we are facing now is to better refine features of patients with a lower likelihood of relapse after a short course of treatment. In our protocol, evaluating so far 496 individuals who were treated with PEG-IFN α2b (1.5 μg/kg) and weight-based ribavirin for 12 weeks after RVR, 96% attained an end-of-treatment response, but 14% relapsed after the end of treatment. This rate of relapse, lower than the rate reported in the Accelerate, can also be considered unacceptable when compared with the 2–7% rates observed after 24 weeks of treatment. The question, therefore, is: how to reduce the number of patients with HCV genotype 2 and 3 who experience a relapse after a short course and need to be retreated?
Pooled analysis and meta-analysis combining data derived from different trials have also attempted to clarify the controversial aspects of this issue, but this debated question is not definitely answered. Indeed, several differences in the existing trials not only in the design of the studies but also in the regimen of treatment and in the characteristics of the patients enrolled have raised the debate on the suitability of adopting a short treatment in current clinical practice.
The aim of the present review was to evaluate if there was enough evidence to support a personalized treatment in patients with genotype 2 and 3.
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