Chronic hepatitis C: Interferon retreatment of relapsers. A meta-analysis of individual patient data

Abstract

Relapse after interferon (IFN) therapy for chronic hepatitis C virus (HCV) infection occurs in 50% of patients after the initial response. The benefit of retreatment with IFN alone has not been assessed in large controlled studies. To assess the effectiveness and the tolerability of IFN retreatment and to identify the optimal second course regimen, we performed a meta-analysis of individual patient's data on a set of 549 patients (mean age 43.8 years; 12.2 SD, men: 65%) who had an end-of-treatment biochemical response to a first IFN course and then relapsed. Retreatment was started within 24 months after the end of the first course. In chronic hepatitis C, the goal of treatment, defined as complete sustained response (SR) (normal alanine transaminase levels and undetectable serum hepatitis C virus-RNA (HCV-RNA) levels 6 to 12 months after therapy) is achieved in less than 20% of patients with standard interferon (IFN)-alfa schedule. 1 Although a complete end-of-treatment response (ETR) is obtained in about 50% of patients, half of them will relapse with a reappearance of viremia and liver necroinflammation soon after stopping therapy. Therefore, relapse remains a major issue in the long-term management of the disease. Several studies of retreatment with IFN alone in patients who had an ETR but subsequently relapsed after stopping IFN have been published. The results of these studies are inconclusive or conflicting because of the relatively small samples and the difficulty of generalizing patients owing to the differences in patient characteristics, study design, regimens, and types of IFN administered. Although the conclusions of the National Institutes of Health Consensus Development Conference for the retreatment of relapse of chronic hepatitis C have recently been published, 22 important questions still remain unanswered. Is monotherapy retreatment useful in relapsers? Are there any differences in the effectiveness of IFN retreatment between cirrhotic and noncirrhotic patients, between different HCV genotypes and, finally, between different second course regimens?To increase the statistical power and to resolve uncertainty we propose a meta-analysis of the individual patient' s data (MIPD), drawing from 1 Japanese center and 15 European centers. The aims of this MIPD were (1) to assess the efficacy and tolerability of IFN retreatment in obtaining a complete SR in relapsers; (2) to evaluate which retreatment schedule should be used and, finally, (3) to identify possible predictors of complete SR. Our aims seem particularly important at a time when combination therapy (IFN plus ribavirin) is being confirmed as an effective treatment for relapsers. MATERIALS AND METHODSThe study was planned within the European Concerted Action on Viral Hepatitis (EUROHEP). Twenty-four centers throughout the world, all with reported experience in this field, were invited to participate: 15 centers in Europe and 1 center in Japan agreed to make data available. Individual patient data from previously published and unpublished stud...

Hepatitis C Virus Resistance to Antiviral Therapy

“…79,81,82 In such cases, we observed significant qualitative HCV quasispecies changes after the first course of IFN. 79 The selected HCV variants were not intrinsically resistant to IFN-␣, because they were definitively cleared after the second course of IFN.…”

Retreatment with interferon plus ribavirin of chronic hepatitis C non-responders to interferon monotherapy: a meta-analysis of individual patient data

“…On the basis of experience gathered from naive patients and from preliminary evidence on retreated patients, 20 we selected as candidate predictors of biochemical and virological SR, age, sex, platelet counts, ALT and γ-glutamyltransferase levels, baseline liver histology, HCV genotype, HCV-RNA levels before retreatment, and amount of IFN received during the first and second cycles. All analyses used a two sided p=0.05 significance level and were conducted with the PROC LOGIS-TIC subroutine in SAS (SAS Institute, Inc., Cary, North Carolina, USA).…”

Treatment of chronic hepatitis C: Improved combination therapy

“…Retreatment with the same dose or duration of IFN is rarely effective, but past experience suggests that higher doses, longer duration of therapy, or the addition of more effective agents can induce sustained response in a subset of cases [52][53][54][55]. Although it is not unreasonable to expect that relapsers to IFN monotherapy or standard IFN combination therapy would have a reasonably high chance of response to peginterferon combination therapy, there is currently insufficient data.…”