Treatment of chronic HCV in advanced liver disease: Unmet challenges, reason for optimism☆

The treatment of chronic hepatitis C virus (HCV) infection in advanced, compensated liver disease has long been a difficult clinical challenge. Sustained virologic response rates and tolerability of anti-viral therapy have proven consistently lower in groups of patients with bridging fibrosis–cirrhosis than in those with earlier stage fibrotic liver disease. In previous trials of interferon, sustained virologic response rates in patients with bridging fibrosis or cirrhosis ranged from 5% to 15% with interferon monotherapy to approximately 45% with the combination of peginterferon alfa and ribavirin [1], [2], [3], [4], [5]. More recently, the hepatitis C anti-viral long-term treatment against cirrhosis trial (HALT-C) investigators demonstrated an inverse relationship between disease severity and virologic response in previous non-responders with advanced fibrosis–cirrhosis retreated with combination peginterferon and ribavirin. Sustained virus eradication rates ranged from 23% in patients with the mildest disease to only 9% in patients with more advanced histologic features [6].

Though elusive, sustained virologic response in patients with chronic hepatitis C and advanced liver disease remains a worthy goal. Several studies have demonstrated that in patients receiving treatment, particularly those who permanently eradicate their virus, not only can progression of fibrosis be slowed but cirrhosis reversed [5], [7], [8], [9]. What is more, evidence suggests that anti-viral therapy may decrease rates of liver-related complications and mortality [10], [11], [12], [13]. These studies, on the whole, have been retrospective, inclusive of small numbers of subjects. As such, it is difficult to know the true impact of therapy on important clinical endpoints such as survival, rates of liver transplantation and/or complications of end-stage liver disease. Large scale, prospective studies are thus needed in order to clarify the long-term benefits of interferon-based therapy in chronic HCV and advanced liver disease.

In this issue of the Journal, Di Marco and colleagues offer one of the few prospective evaluations of interferon-based therapy for patients with compensated, HCV-related cirrhosis [14]. Their stated aims were twofold: to examine the efficacy of interferon-based therapy and to assess the impact of anti-viral therapy on the natural history of the disease. One hundred and two patients with compensated cirrhosis and evidence of portal hypertension randomized to pegylated interferon alone or in combination with 800mg/day of ribavirin for 52 weeks were followed prospectively for a median of 38 months. By intention to treat, the rate of sustained virologic response in those groups of patients with genotype 1 and 2 or 3 infection was 12.5% and 67%, respectively. Combination therapy was numerically superior to monotherapy – 21.6% vs 9.8% – but, presumably due to the small number of patients analyzed, not statistically different. Previous exposure to interferon did not significantly affect the likelihood of achieving a sustained virologic response. Dose reductions were common; and, in 32% of patients, therapy was withdrawn due to cytopenias and/or other adverse events. At the conclusion of the follow-up period, disease deterioration was significantly less in patients achieving sustained virologic eradication – 6% vs 38% (p=0.03).

The fairly dismal sustained virologic response rate in patients with genotype 1 infection mirrors the results of other recent studies. In registration trials of peginterferon for HCV, patients with bridging fibrosis–cirrhosis but without evidence of portal hypertension attained rates of sustained viral eradication as high as 41% [2], [3], [4]. Subsequent studies of interferon-based therapy have been less sanguine in regard to advanced HCV-related liver disease, particularly when accompanied by portal hypertension. The sustained virologic response rate in Heathcote et al.’s study of pegylated interferon monotherapy for compensated HCV-cirrhosis, for example, was 12% for genotype 1 patients receiving 180mcg/wk of peginterferon alfa-2a [5]. In HALT-C, virologic cure in non-responders with otherwise similar pretreatment characteristics to the Di Marco cohort occurred in just 9% [6].

It bears emphasis that the dose of ribavirin (800mg/day) used by the Di Marco investigators, presumably to mitigate against dose-modifying anemia, was likely inadequate for their genotype 1-predominant study population. Dose-finding studies have shown that weight-based ribavirin (1000 or 1200mg/day based on body weight of less than or greater than 75kg, respectively) provides the optimal balance between safety and efficacy in patients with genotype 1 infection independent of stage of fibrosis [2], [7], [15]. Whether this extends to the setting of compensated portal hypertension is not definitively known. Future studies will hopefully clarify this issue. In the meantime, weight-based ribavirin dosing, notwithstanding potentially higher toxicity, represents the preferred choice in these often “difficult to cure” cases.

As one would expect, patients with genotype 2 or 3 infection in the Di Marco study fared considerably better in terms of virologic response though a small sample size precludes drawing firm conclusions about this subgroup. With this caveat in mind, rate of sustained virologic response in genotype 2 and 3 infected patients compared favorably with the advanced fibrosis–cirrhosis subgroup of the Hadziyannis registration trial of peginterferon [2]. In the study of peginterferon from Heathcote and co-workers, 51% of genotype 2 or 3 infected patients receiving full-dose peginterferon went on to attain a sustained virologic response [5]. Whereas low rates of cure in genotype 1 infected patients with advanced histology might give clinicians, and patients alike, pause before considering treatment, consistently higher viral response rates leave little such therapeutic dilemma in cases of genotype 2 and 3 infection irrespective of stage of fibrosis.

Frequent, if unquantified, dose reductions were reported in the Di Marco experience. In fact, one-third of subjects were forced to discontinue therapy within 24 weeks of initiation of therapy. Rates of discontinuance were similar between the mono- and combination therapy study arms. Though higher than in other studies [6], [16], these figures underline the consistently poorer tolerability of anti-viral therapy for HCV in patients with bridging fibrosis-advanced cirrhosis, a population that can least afford dose reductions. Indeed, in the overall study cohort, the rate of sustained response was approximately half that of patients who received 80% or more of the intended dose for at least 80% of the prescribed treatment period. It should be noted that hematologic growth factors were not used in this study. Though yet to be evaluated in properly controlled trials, evidence suggests that hematologic support to counteract cytopenias maintains higher drug treatment levels which, in turn, may lead to an increase in treatment response rates [17].

The second aim of the Di Marco study was to assess the impact of interferon-based therapy on the incidence of liver-related complications in patients with bridging fibrosis–cirrhosis (defined by an increase of ⩾2 points in Child–Pugh score, hepatic decompensation, development of hepatocellular carcinoma, liver transplantation or death). In those achieving a sustained virologic response, disease deterioration occurred in only 6% of patients over the duration of the study, an absolute risk reduction of 32% vis-a-vis non-responder patients. Furthermore, in neither responders nor non-responders was liver decompensation or development of liver cancer observed during therapy, thus potentially suggesting a benefit of suppression, independent of sustained viral eradication. Though improvements in the endpoints of disease decompensation/HCC/mortality have been shown before [10], [11], [12], [13], Di Marco and colleagues have given added purchase to the growing appreciation of anti-viral therapy and its potential ability to ameliorate the course of advanced disease due to hepatitis C infection.

While the Di Marco study presents further compelling evidence for the benefit of interferon-based therapy in individuals with advanced disease who go on to achieve viral clearance, as discussed earlier, this benefit unfortunately extends to a proportionally small number of patients. It becomes important then to stratify, to the extent that one is able, the best candidates for therapy according to likelihood of sustained response. The authors identify three independent variables that may assist clinicians in this regard. Already discussed and most important of the three is genotype. Pretreatment viral load and the presence or absence of virus at 12 weeks were other variables further predictive of sustained viral clearance. In the case of the latter, virus persistence at 12 weeks portended a 0% sustained response rate. Conversely, 35% of patients with viral clearance at 12 weeks and completing 52 weeks of therapy attained a virologic cure.

In summary, Di Marco and co-workers’ comparison of peginterferon with or without ribavirin for chronic hepatitis C in advanced liver disease makes an important contribution to our understanding of the efficacy and impact of anti-viral therapy in this typically “difficult to treat” patient population. One of only a few studies to focus on patients with advanced fibrosis–cirrhosis, it is the only study to have examined prospectively the role of combination therapy in this population. Like the Heathcote study of peginterferon monotherapy, across the board rates of viral clearance were much lower than that seen in interferon trials involving patients with less advanced disease. Adverse events were common; and, when resulting in dose reductions, the effect on sustained virologic response was often calamitous. Future studies will hopefully clarify the role for growth factors in ameliorating the impact of cytopenias. Numerically superior though statistically equivalent to interferon monotherapy, combination therapy with ribavirin should be used whenever possible to maximize the chance of achieving a sustained virologic response and its benefits. Why the importance of sustained virologic response? Compellingly, the Di Marco group report a 32% absolute risk reduction in the incidence of liver-related complications, HCC and death in patients achieving viral clearance. This finding underscores the significance of sustained viral eradication as a clinically relevant endpoint for treatment; and furthermore, justifies an attempt at therapy despite often long odds of cure. In the end, however, the Di Marco experience reinforces the inherent limitations of currently available treatments for chronic hepatitis C and advanced liver disease. Newer, more effective agents are needed to meaningfully impact on this ever-expanding population of patients.