Nonresponse to Interferon in Chronic Hepatitis C: Title and subTitle BreakRe-treatment Redux

In the past decade, chronic hepatitis due to hepatitis C virus (HCV) infection has emerged as the predominant liver disease in the United States. While progression of chronic hepatitis C to cirrhosis may be slow, end-stage liver disease due to HCV-associated cirrhosis is now the single most common indication for liver transplantation, and HCV-associated cirrhosis is responsible for the increasing incidence of hepatocellular carcinoma in this country.¹ Direct costs of care for patients with progressive disease are high, treatment is expensive, and the national economic burden of hepatitis C has been projected to increase dramatically in the future.² Fortunately, progress in antiviral treatment has been steady and impressive.

Permanent serum HCV RNA clearance is the principal goal of antiviral treatment and now can be achieved in about 40% of patients treated with the current regimen of interferon alfa and ribavirin (combination therapy).³ A sustained virological response is defined by the absence of detectable circulating serum HCV RNA levels at the end of treatment and 6 months after withdrawal of treatment. More than 95% of these responders appear to be cured and remain HCV RNA–negative, have normal serum alanine aminotransferase concentrations, and show improved liver histological results with regression of hepatic fibrosis on long-term follow-up.^{4 - 5} Relapsing patients who are HCV RNA–negative at the end of interferon monotherapy but do not remain so during follow-up can be successfully re-treated with combination therapy or high-dose interferon alfacon-1 approximately 50% of the time.^{6 - 7} Despite this good news, many patients still have detectable serum HCV RNA levels by the end of treatment and are labeled as "virological nonresponders."

The mechanisms responsible for nonresponse are poorly understood.⁸ Resistance to interferon is common in patients with HCV genotypes 1 and 4, with high serum viral loads, with a large variety of HCV quasi species, in older patients, in African Americans, in men more than in women, in human immunodeficiency virus–coinfected individuals, in some patients with cirrhosis, and in some with extrahepatic disorders associated with HCV infection. Resistance has been related, at least in part, to the inhibitory actions of the nonstructural 5A (NS5A) and E2 HCV proteins on the antiviral protein induced by interferon double-stranded RNA-activated protein kinase.⁹ Further studies are needed to understand the mechanism of interferon resistance and to permit the design of therapeutic regimens that can bypass or overcome nonresponsiveness. In the interim, re-treatment of nonresponders with available antiviral agents has received increasing attention.

In this issue of THE JOURNAL, Cummings et al¹⁰ provide a meta-analysis of published, randomized trials of re-treatment of virological nonresponders to interferon monotherapy with combination therapy or interferon alone. Despite considerable heterogeneity in these trials, re-treatment with combination therapy is shown to be superior to re-treatment with interferon alone. The pooled risk difference of 16% for the use of interferon alfa-2a or alfa-2b with high-dose ribavirin, 1000 to 1200 mg, indicates that the number of patients needed to treat (the inverse of the pooled risk difference) to achieve a sustained virological response in 1 patient was 6.

An earlier meta-analysis by Cheng et al,¹¹ in which controlled, uncontrolled, and preliminary studies were included, found that combination therapy was less beneficial. In that analysis, the pooled risk difference was 8% and the number of patients needed to treat to obtain a sustained virological response in 1 patient was 13. The meta-analysis of Cummings et al also raises interesting points about optimal combination therapy regimens. The findings suggest that all interferons do not have the same antiviral activities, and that high doses of ribavirin are likely to be more effective than lower doses.

Several important questions about the management of nonresponders are left unanswered by the focus of this meta-analysis on the comparison of combination therapy with interferon monotherapy. Novel strategies, such as treatment with interleukin 10,¹² which seems promising, or the use of iron reduction by phlebotomy as an adjuvant to interferon therapy,¹³ which seems less promising, are not discussed. Similarly, Cummings et al do not address recent data suggesting that re-treatment using interferon monotherapy with high-dose interferon in nonresponders is far more likely to achieve a sustained response in patients who had a substantial decrease in serum HCV RNA levels during the initial course of therapy but did not respond with a clearance of serum HCV RNA levels.¹⁴ The authors could not have included the very recently published report that re-treatment of nonresponders to interferon monotherapy with triple antiviral therapy, consisting of interferon, ribavirin, and amantadine hydrochloride for 12 months, produced a sustained virological response rate of 48%, whereas in these patients, re-treatment with interferon and ribavirin resulted in a sustained virological response rate of just 5%.¹⁵ Additionally, because their analysis was limited to nonresponders to interferon monotherapy, Cummings et al did not address the re-treatment of nonresponders to initial combination therapy, a growing proportion of current nonresponders. Moreover, information about re-treatment of nonresponders with long-acting pegylated interferon (interferon conjugated with polyethylene glycol) with or without ribavirin is not yet available, and comparisons with current regimens could not be drawn.

Pegylated interferon appears to be more effective than interferon monotherapy¹⁶ and a possible equivalent to the combination of interferon plus ribavirin³ for previously untreated patients with chronic hepatitis C, including patients with HCV-associated cirrhosis.¹⁷ The regimen of pegylated interferon with ribavirin is likely to become the treatment of choice for untreated patients with chronic hepatitis C,¹⁸ and by analogy, it may be effective in patients who relapsed and were nonresponsive. Sustained virological response rates in excess of 85% are anticipated in previously untreated patients with genotypes 2 and 3 and in approximately 45% of patients with genotype 1.¹⁸ However, pegylated interferon and the combination of pegylated interferon and ribavirin are not yet approved by the Food and Drug Administration, and long-term safety data are not yet available. Studies of virological nonresponders are in progress.

The focus on sustained virological response as the goal of treatment in chronic hepatitis C may have been overemphasized and somewhat misplaced because it is the liver injury that determines clinical outcome. While virological response predicts histological response, it should be noted that virological nonresponsiveness is less predictive of histological outcome. In fact, histological improvement may occur without a complete virological response. Recent studies demonstrate that progression of hepatic fibrosis in nonresponders is slowed by treatment with interferon, and the regression of fibrosis may be enhanced.^{19 - 21}

These observations strongly suggest that combination therapy and even interferon monotherapy have antifibrotic activities independent of their antiviral effects. If this hypothesis is correct, current treatment stopping rules based on failure to clear serum HCV RNA levels at specific time points, that is, 12 or 24 weeks posttreatment, may be inappropriate, and in these virological nonresponders, long-term therapy may be beneficial in reducing the risk of developing cirrhosis, end-stage liver disease, and hepatocellular carcinoma. If this concept is valid and histological improvement is achieved, the term "nonresponder" may prove to be a misnomer. The antifibrotic and clinically beneficial activity of long-term treatment of virological nonresponders with significant hepatic fibrosis is being assessed in the National Institutes of Health–sponsored HALT-C (Hepatitis C Antiviral Long-term Treatment to prevent Cirrhosis) trial of maintenance therapy.²²

In the HALT-C trial, a large multicenter study, 1350 virological nonresponders to interferon monotherapy or combination therapy with advanced histological hepatic lesions will be treated with pegylated interferon plus ribavirin.¹⁸ Those who do have detectable serum HCV RNA levels after a 5-month treatment period will be eligible for randomization, and 1 month later, to an additional 42 months of continued treatment with a reduced dose of pegylated interferon alone. End points will be the development of cirrhosis in those patients with bridging fibrosis, the development of hepatic decompensation, the development of hepatocellular carcinoma, and mortality.

Future improvements in antiviral therapy for chronic hepatitis C infection, such as the introduction of pegylated interferon and its use with ribavirin, should reduce the likelihood of virological and histological nonresponse and the need for re-treatment regimens. Until then, the decision to re-treat virological nonresponders will remain difficult and its cost-effectiveness uncertain. If re-treatment is considered, the combination of interferon alfa-2b or alfa-2a plus ribavirin is favored for virological nonresponders to interferon monotherapy. Some clinicians may target re-treatment to patients with favorable genotypes (both 2 and 3), those with a partial virological response during the initial treatment, or those with histologically proven advanced fibrosis on liver biopsy specimen. Uncertainty will persist until highly effective treatments are available for all patients with chronic hepatitis C infection and the value of prolonged therapy in reversing disease, as determined by histological analysis, is unequivocally demonstrated in virological nonresponders.