Hepatology highlights: Viral hepatitis
Treatment-Induced vs. Spontaneous Clearance of Acute HCV Infection
Three studies, published in the June and July issues of HEPATOLOGY, examined hepatitis C virus (HCV)–specific immune responses during and after antiviral treatment of acute hepatitis C. Rahman et al. studied 7 acutely infected patients and found that all mounted HCV-specific T cell responses prior to therapy. However, after initiation of therapy, HCV-specific cellular immune responses waned in the 6 patients who achieved a sustained virological response. At a follow-up of 21–24 weeks, sustained treatment responders showed significantly weaker proliferative T cell responses than a control group of spontaneously recovered patients. Indeed, responses were comparable to those of patients persistently infected with HCV (Figure). This is a surprising finding, since cellular immune responses have been shown to persist for decades after spontaneous viral clearance. Indeed, the results suggest that treatment-induced viral clearance is different from spontaneous viral clearance. Is it possible that viral elimination was achieved by the direct antiviral effects of interferon (IFN)-α and that cellular immune responses are less important in this setting? Does rapid and complete suppression of viral antigens abrogate the development and maintenance of immunological memory? Would one have to search for HCV-specific T cells in the liver instead of the peripheral blood? Or are we looking at an IFN-α-mediated inhibition of T cell effector functions? Further studies and an extended follow-up will be required to address these questions. (See HEPATOLOGY 2004;40:87–97.)
A second study, by Wiegand et al., may provide some answers. These investigators report the long-term outcome of 31 patients successfully treated for acute hepatitis C. The good news is that viral elimination is complete and durable in these patients. Interestingly, at their latest follow-up (i.e., 52-224 weeks after completion of therapy), these authors found that while antibody and CD4+ T cell responses had vanished in the majority of patients, robust CD8+ T cell responses were detectable in 4 out of 5 patients analyzed in detail. Thus, although the number of patients examined with respect to CD8+ T cell responses is small, it is possible that some cellular immune responses recover after longer follow-up. (See HEPATOLOGY 2004;40:98–107.)
A third study, by Kamal et al., provides quite a different view. These investigators prospectively followed 40 patients with acute hepatitis C treated with pegylated IFN-α with or without ribavirin. In contrast to the other two studies, a clear increase in the frequency and strength of HCV-specific CD4+ T cell responses was observed in these patients both during therapy and at follow-up (i.e., 48 weeks following cessation of therapy). (See HEPATOLOGY 2004;39:1721–1731.)
How do we explain these different results? A clear explanation is not forthcoming. Subtle differences in the timing and schedule of treatment, the viral genotype, and the techniques used to monitor T cell responses may, among other factors, explain the differences. In any case, further investigation of these issues may not only contribute to optimal care of patients with acute hepatitis C, but may shed light on basic aspects of immunological memory and the pathogenesis of hepatitis C.
Outcome of HCV Infection: Does Timing and Homing Make the Difference?
Not tired of studies on acute hepatitis C? Here's another elegant one. Previous studies in acutely HCV-infected chimpanzees have clearly shown that innate and adaptive immune responses contribute significantly to viral clearance and liver disease. However, these studies have been limited by small numbers of animals, the fact that some chimpanzees were previously exposed or immunized, and the heterogeneity of the inocula used. Major et al. have now analyzed 10 naïve chimpanzees that were inoculated with virus or RNA encoding the same clonal HCV sequence. Four animals cleared the virus and 6 developed chronic infection. As has been shown previously, all animals displayed an intrahepatic induction of IFN-α/β-related genes during the first 2 weeks of infection, irrespective of the outcome of infection. This correlated with the first significant slowing of virus accumulation, suggesting that early partial control of viral replication may be achieved by type I IFNs. Eight to 10 weeks after infection, liver disease and intrahepatic induction of IFN-γ were observed in all animals. This coincided with decreases of viral titers by at least 2 log10, and this effect was observed in all animals. Importantly, however, it occurred approximately 2 weeks later in the chronic group (Figure). In addition, the inability of the immune response to sustain viral clearance was associated with reduced intrahepatic CD3 mRNA, reflecting a reduced accumulation of presumably HCV-specific T cells at the site of disease. Thus, the most important finding of this study is that the difference between clearance and persistence of HCV may be governed by the timing of the host immune response and the accumulation of the right cells at the right place. But the big questions remain: What causes these differences? Can we influence them? Can the virus influence them? Looking more closely at viral evolution may yield additional insight into the complex mechanisms of viral persistence. (See HEPATOLOGY 2004;39:1709–1720.)
Expanding the Spectrum of Noninvasive Predictors of Fibrosis in Chronic Hepatitis C
The extent of hepatic fibrosis is directly related to the risk of developing complications of chronic hepatitis C and is a key factor in the decision to treat. Therefore, liver biopsy is usually recommended before treatment. However, it is associated with discomfort, rare but potentially serious complications, cost, and sampling variability if the size of the biopsy is not large enough. Therefore, several groups have recently described noninvasive predictors of fibrosis. Sud et al. revisited this issue and included clinical and metabolic parameters into their analysis. By multiple logistic regression, 5 out of 35 parameters analyzed were found to be independent predictors of significant (stages F2-F4) fibrosis: age, aspartate aminotransferase, total cholesterol level, insulin resistance as calculated from fasting plasma insulin and glucose levels, and past alcohol intake. A fibrosis probability index (FPI) incorporating these variables accurately predicted mild fibrosis in a liver clinic–based validation cohort. The authors calculated that application of this index would have made liver biopsy unnecessary in 44% to 48% of the patients with mild fibrosis and would not have missed any of the subjects with stage 3 or 4 fibrosis. The important aspect of this study is the inclusion of insulin resistance and past alcohol intake into the predictive index. Validation of the FPI in other centers with other cohorts of patients will be essential and important. As the authors correctly point out, the optimal index may turn out to be different in different settings and may evolve with time. The jury is out on how well this will translate into clinical practice and if we are going to routinely measure fasting insulin levels in our patients. (See HEPATOLOGY 2004;39:1239–1247.)
The ABC of HLA in HCV
McKiernan et al. report on a human leukocyte antigen (HLA) class I association study in an Irish cohort of women who had been infected with HCV from a single source of anti-D immunoglobulin in 1977. Of 227 subjects tested, 141 had chronic infection and 86 had successfully cleared the virus. The class I alleles A*03, B*27, and Cw*01 were more often detectable in patients who were able to clear the virus (39.5%, 14%, and 9.3%, respectively) compared to those with chronic infection (19.1%, 2.1%, and 1.4%, respectively, P ≤ .005). By contrast, B*08 occurred more often in chronically infected patients (39.7% vs. 19.8%, P = .002). Multiple logistic regression analysis revealed that B*27 had the strongest association with viral clearance. These results demonstrate for the first time a significant association between HCV clearance and certain class I HLA alleles, as has already been described for class II alleles. It will be interesting so see if this association, observed in a very special and homogenous cohort, will be confirmed in other patients. Most importantly, investigation of the functional significance of this association and of the CD8+ T cell epitopes presented by HLA-B27 may reveal new correlates of protection against hepatitis C. (See HEPATOLOGY 2004;40:108–114.)
A New Nucleoside Analogue Against HBV: New Answers, New Questions
Marcellin et al. report the results of a phase II dose finding study of clevudine (L-FMAU), a new pyrimidine nucleoside analogue, in patients with chronic hepatitis B. Thirty-two patients were treated with 10, 50, 100, or 200 mg clevudine once daily for 28 days. A profound, −2.5 to −3.0 log10 reduction of hepatitis B virus (HBV) DNA was observed at all doses. Interestingly, viral suppression was associated with a transient alanine aminotransferase increase in some patients, particularly at the 100 mg dose, suppression was unusually prolonged in most patients (−1.2 to −2.7 log10 at 6 months postdosing) and resulted in HBe antigen loss and anti–HBe seroconversion in an unexpectedly high number of 6 and 3 out of 27 patients, respectively (Figure). A similarly prolonged suppression of viral replication has previously been observed in woodchuck hepatitis virus–infected animals treated with clevudine. The mechanisms remain speculative. Is it possible that this particular nucleoside analogue may have immunomodulatory or other additional effects? What is the mechanism of the transient alanine aminotransferase increases observed in some patients? These are some of the new questions raised by this novel nucleoside analogue. (See HEPATOLOGY 2004;40:140–148.)