Journal of Hepatology 40 (2004) 1030–1031 www.elsevier.com/locate/jhep
Editorial
Interferon-a for hepatitis C: antiviral or immunotherapy? Helmut M. Diepolder* Medical Department II, University Hospital Munich—Grosshadern, Marchioninistr. 15, D-81377 Munich, Germany
See Article, pages 971 –978
About 15 –20% of patients with acute hepatitis C virus (HCV) infection achieve permanent viral clearance proving principally that HCV can be controlled by antiviral immune mechanisms. In the majority of patients, however, HCV is obviously able to escape the efficient antiviral immune responses and to establish chronic viral persistence. Several mechanisms have been implicated in the pathogenesis of chronic hepatitis C: first, HCV seems to interfere at several levels with the action of type I interferons [1 – 3]; second, viral variability may lead to escape from specific humoral and cellular immune responses, and third, a general impairment of HCV-specific CD4þ and CD8þ T cells occurs, which is yet incompletely understood [4,5]. Whereas some studies suggest a dysfunction of dendritic cells leading to poor antigen presentation [6], animal models of other chronic viral infections suggest a mechanism of T cell exhaustion in the presence of high viral load [7]. Treatment of chronic hepatitis C with pegylated interferon-a/ribavirin combination therapy leads to sustained viral clearance in about 50% of patients with genotype 1 infection and more than 80% of patients with genotype 2 or 3 infection. In vitro, interferon-a has pleiotropic effects which can be separated into two major groups, inhibition of viral replication and immunomodulatory effects, respectively. During treatment of HCV infection, modelling of viral kinetics suggests that both mechanisms play a role for successful viral clearance [8]. In a first phase, lasting 1 to 2 days, a rapid decline of viral load is observed, which has been attributed to direct antiviral effects of interferon-a. In the most recent models of HCV kinetics this is followed by a second phase with little change in the peripheral blood viral load, lasting for 2 to 28 days [9]. In a third phase, viral load declines again, although usually at a slower rate compared to the first phase. This phase is thought to reflect clearance of HCV infected hepatocytes, most likely by HCV-specific * Tel.: þ 49-89-70-95-0; fax: þ 49-89-70-00-95-40. E-mail address:
[email protected] (H.M. Diepolder).
cellular immune responses. Several studies have tried to define this assumed HCV-specific cellular immune responses during interferon-a treatment. Indeed, a significant increase in the HCV-specific CD4þ T cell response was found to occur frequently during antiviral treatment [10 –13]. In contrast, little changes have been detected in HCV-specific CD8þ T cell responses [12]. Some studies have also claimed an association between the recovery of HCV-specific CD4þ T cell responses and a sustained virological responses to treatment [10,13]. Since patients infected with genotype 2 and 3 consistently show higher sustained viral response rates, not surprisingly also a higher frequency of HCV-specific T cell responses can be found in this group [11]. From these studies, however, it has not become clear whether the recovery of the T cell response is due to suppression of viral replication or whether the HCVspecific T cells indeed contribute to viral clearance. In fact, recovery of virus specific CD4þ T cell responses during treatment with pure antiviral drugs has been reported in chronic hepatitis B [14] and HIV infection [15] and could be due to the reduced T cell suppressive effect of a high viral load in addition to the redistribution of specific CD4þ T cells from the site of inflammation back into the circulation [7]. This subject has been addressed in the paper from Hultgren et al. in this issue of the Journal who initially studied a cohort of 71 treatment naı¨ve patients with chronic hepatitis C and subsequently looked at 32 patients undergoing antiviral therapy [16]. Frequent immunological and virological measurements were performed during the first 12 weeks of therapy allowing a detailed analysis of both viral and immunological kinetics. First, the authors could show in the group of treatment naı¨ve patients that a HCVNS3 specific CD4þ T cell proliferative response is significantly more frequent in patients with genotype 3 infection. Next, during antiviral treatment, NS3-specific CD4þ T cell responses appeared more frequently in genotype 2 and 3 patients as compared to patients with
0168-8278/$30.00 q 2004 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. doi:10.1016/j.jhep.2004.04.002
H.M. Diepolder / Journal of Hepatology 40 (2004) 1030–1031
genotype 1 infection, and an earlier appearance of the T cell response correlated with faster kinetics of viral elimination. Finally, there was a trend ðP ¼ 0:07Þ for an association between the appearance of T cell responses and a sustained viral response. Interestingly, NS3 specific T cell responses occurred as early as on day 1 and in most patients within the first week after the start of treatment. This was after the initial one to two log drop in viral load (corresponding to phase 1) but well before viral clearance occurred. Accordingly, the authors conclude that during antiviral therapy NS3 specific CD4þ T cell responses are more frequently restored in patients with genotype 2 or 3 infection and that this immune response may contribute to a more rapid clearance of HCV RNA. Based on these findings, however, new questions arise: the frequent testing of T cell responses in this study came to the price of a limited analysis of the breadth of the cellular immune response. Future studies will certainly have to address the role of CD4þ T cell responses to other HCV antigens. In addition, the proliferation assay detects only a subset of HCV-specific CD4þ T cells, usually those with the ability to produce IL-2 and to proliferate, corresponding to the so-called central memory cells. Further differentiated effector cells (‘effector memory’), which may still produce interferon-g but no IL-2 and which can also have important antiviral activity, may be missed in the proliferation assay. Nevertheless, recent evidence suggests that IL-2 production by CD4þ T cells is a critical factor for the differentiation of cytotoxic T cells into antiviral effector cells [17], indicating that the proliferation assay measures a relevant function of CD4þ T cells in this scenario. Eventually, the frequent determinations of CD4þ T cell activity in the study of Hultgren et al. highlights another issue: CD4þ T cells responses during antiviral treatment of chronic hepatitis C are relatively weak and fluctuating compared to patients with acute self-limited disease and are usually not maintained. This is consistent with previous studies [10,12] and leads to the important question whether these responses could be further augmented by therapeutic vaccination, potentially leading to a higher rate of sustained virological responses. In conclusion, the study of Hultgren et al. suggests that interferon-a based therapies hit HCV at two different sites, first by overriding the relative interferon resistance of the virus and second by partially restoring antiviral cellular immune responses, exemplified in this study by the NS3specific CD4þ T cell response. HCV-specific CD4þ T cell responses seem to be more frequent in patients with genotype 2 or 3 infection, both before and during interferon-a treatment, which offers an attractive explanation for the significantly higher sustained virological response rates in these patients.
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