Optimizing PEG-interferon and ribavirin combination therapy for patients infected with HCV-2 or HCV-3: is the puzzle completed?

Abstract

Therapy for chronic hepatitis C has greatly improved over the last decade, the major advance having undoubtedly been the shift from interferon monotherapy to interferon plus ribavirin combination therapy. Indeed, the addition of oral ribavirin to alfa interferon (IFN) in the late 1990s’ led to a 3 to 4-fold increase in sustained virological response (SVR) rates in patients infected by HCV-1 and to a 2 to 3-fold increase for those with HCV-2 or 3 [1–3]. This improvement was mainly due to a marked reduction in relapse rates seen after therapy withdrawal [4]. These pivotal studies also clearly indicated that SVR with IFN plus ribavirin combination therapy was significantly improved (almost doubled) in patients infected with HCV-1 when treatment was given for 48 weeks compared to 24 weeks. On the contrary, SVR rates were almost identical with the two regimens in patients infected with other genotypes (mainly HCV-2 and HCV-3) (Table 1). On the basis of these results, the Consensus Conference organized in 1999 by the European Association for the Study of the Liver (EASL) strongly recommended IFN plus ribavirin combination therapy as the new standard of therapy for patients with chronic hepatitis C, with the indication to treat HCV-1 infected cases for 12 months and HCV-2 and HCV-3 infected patients for 6 months [5]. Levels of pre-treatment viraemia were also recognized as an important variable affecting response to combination therapy but the data available in patients infected with HCV-2 and HCV-3 were not considered sufficient to recommend a different schedule of treatment according to baseline HCV-RNA levels. More recently, therapy of chronic hepatitis C has evolved further following the introduction of the pegylated forms of IFNa2a and of IFNa2b (PEG-IFNalphas). Both these new formulations of the two most frequently used recombinant interferons were initially evaluated as monotherapy, and clear evidence was obtained of their significantly higher antiviral efficacy compared to the old standard IFN, mainly due to improved pharmacokinetics [6,7]. The immediate next step was to compare the PEG-IFNalphas and standard IFN in combination with ribavirin. The results of two pivotal studies conducted with PEG-IFNa2b and with PEG-IFNa2a combined with ribavirin in comparison with standard IFN plus ribavirin demonstrated significantly higher rates of SVR with both types of PEG-IFNalphas when all HCV genotypes were considered together [8,9]. In both studies the benefit of using PEG-IFNalpha was significant for HCV-1 infected patients while the results with patients infected with HCV-2 or HCV-3 were not so clear cut. In these cases, there was no advantage in terms of SVR with PEG-IFNa2b plus ribavirin compared to standard IFNa2b plus ribavirin [8], considering that the percentage achieving SVR with the latter schedule was in this study higher than that reported in previous trials (Table 1). On the other hand, the difference was significant when PEG-IFNa2a plus ribavirin was compared with standard IFNa2b plus ribavirin [9]. Unfortunately, in both studies the PEG-IFNalphas and ribavirin were given to all patients for 48 weeks, independent of the HCV genotype and of pretreatment viral load. As a consequence, there was no information on the efficacy of PEG-IFN plus ribavirin combination therapy when given to patients with HCV-2 or HCV-3 for 6 months, that is for the duration that had been recommended at that time for standard IFN plus ribavirin combination therapy. Thus, optimal schedule for PEG-IFNbased therapy could not be defined for genotypes 2 and 3. On a strictly evidence based recommendation, PEG-IFN plus ribavirin had to be given for 12 months to patients with HCV-2 and HCV-3. But the efficacy of standard IFN plus ribavirin given for 48 weeks had been shown to be only marginally more effective than when given for 24 weeks. Journal of Hepatology 40 (2004) 1032–1035 www.elsevier.com/locate/jhep