Efficacy of hepatitis C treatment may be enhanced by a longer interferon administration

The treatment of chronic hepatitis C with the combination of interferon alpha (IFNa) and ribavirin has been proved to be highly effective (1–3), although many patients still fail to achieve a sustained viral response. Much effort has been made to improve virological end points, and even before the publication of the combination trials, it was shown that shifting the duration of treatment from 6 to 12 months could improve responses (4). Before starting the combination therapy studies, some authors have addressed the question of duration and doses of IFN monotherapy, particularly long-lasting therapies and higher doses of medication at the beginning of treatment (5–7). In general, the results have shown that higher percentages of complete response were achieved, but sustained response was poor (7). The main problems with a schedule of 18 or 24 months of IFN were related to higher percentages of side effects and poor compliance (4). In order to overcome these difficulties, research efforts were conducted to access effectiveness of the pegylated form of IFN, which is a long-acting and more potent type of the same drug (8). Three large multicenter trials have been performed comparing peginterferon a to conventional IFNa alone or in combination with ribavirin (9–11). Overall, efficacy increased up to 61%. And for non-1 genotypes (particularly genotypes 2 and 3), the association of peginterferon a-2a and ribavirin can provide up to 80% of sustained response (10). Nevertheless, therapy still needs further improvements in difficult-to-treat patients, especially genotype 1. The reasons for the lack of a sustained response in genotype 1 patients, the most prevalent group, are only partly elucidated (12). Understanding the viral kinetics may be a clue to solve this issue. Indeed, the first phase of an initial sharp decline of the hepatitis C virus (HCV) RNA levels represents antiviral efficacy in terms of blocking viral production and secretion. The second more gradual decrease of viral load, called d, is interpreted as the clearance rate of the infected cells and it varies even among the responders group (13–15). This second phase has a large range of variations among patients and may represent differences in specific T-cell responses (16). It has been shown that viral, host characteristics and IFN-related factors play a role in determining the outcome of IFN-based therapy. Among the viral factors, genotype seems to be the most important predicting factor for IFN response. Cytokines (IL 10, IL 8, tumor necrosis factor alpha (TNFa), TNFa-R1, Fas/ FasL) and IFN a/b receptor levels, hepatic iron, age, gender and race are host factors that may affect the response rate (17). There is a hypothesis that the so-called slow responders could benefit from longer periods of IFN therapy (18). Another important issue is viral relapse after end-of-treatment complete response, particularly in genotype 1 patients. The current issue of Liver International includes an interesting report of Tarantino et al., who found a better sustained response rate in genotype 1 HCV patients. They were treated with low daily doses of IFNa for 12 extra months, after completing 6 or 12 months of conventional IFN standard combination therapy. The authors randomized only patients who achieved end-of-treatment response, which means that their approach was directed to prevent relapse. This single-center study followed 236 genotype 1 naive patients. The initial groups received 6MU of IFNa three times a week plus 1.0–1.2 g of daily ribavirin (according to body weight) for 6 or 12 months. One hundred and seventeen patients achieved end-of-treatment virological response and were then randomized Liver International 2003: 23: 410–412 Printed in Denmark. All rights reserved Copyright r Blackwell Munksgaard 2003