The HALT-C trial assessed whether patients with chronic hepatitis C who had not had a sustained virologic response after optimal therapy with peginterferon and ribavirin would benefit from peginterferon maintenance therapy at a lower and perhaps better-tolerated dose.12
The outcome measure in most trials of antiviral therapy for chronic hepatitis C has been a sustained virologic response (i.e., undetectable HCV RNA in the serum 6 months after the cessation of therapy5
), which has been shown to be associated with long-term improvement in disease.6
In this trial, among patients who had not had a sustained virologic response after previous therapy, the criteria for efficacy of therapy were the prevention of progression to cirrhosis (among patients with noncirrhotic fibrosis at baseline) and the prevention of clinical progression of disease. To test the efficacy of long-term maintenance therapy, we randomly assigned 1050 patients with advanced fibrosis who had not had a response to peginterferon and ribavirin to several years of treatment or no treatment.
When the trial began, peginterferon was not approved by the FDA, and many patients who had been treated with standard interferon had not received concomitant ribavirin. Therefore, to ensure that we were assessing maintenance therapy in a cohort of patients who had not had a sustained virologic response to optimal therapy, we required a lead-in phase of retreatment with a regimen of peginterferon and ribavirin that had been shown to be superior to standard interferon with ribavirin.19
This lead-in phase provided not only a well-pedigreed cohort of uniformly documented patients who had not had a response to treatment but also a thoroughly evaluated group of patients highly motivated for such a demanding, long-term trial.
Maintenance peginterferon therapy was associated with significant decreases in serum HCV RNA levels, serum alanine aminotransferase levels, and histologic necroinflammatory scores. Nevertheless, therapy was not associated with a reduction in clinical outcomes or in the progression of fibrosis. Progression of liver disease (the primary study outcome) occurred in 34.1% of the treatment group and 33.8% of the control group. Among patients with bridging fibrosis at baseline, cirrhosis developed by year 3.5 in similar percentages of treated and control patients (28.2% and 31.9%, respectively). The high rate of clinical outcomes among patients with noncirrhotic fibrosis at baseline was not predicted and is worthy of note. A possible explanation for this finding is that liver biopsy underestimates the presence of cirrhosis, as evidenced by the presence of varices in some patients classified as having noncirrhotic fibrosis. Nonetheless, it is clear that patients with chronic hepatitis C and bridging fibrosis detected on biopsy appear to be at substantial risk for clinical outcomes, including hepatocellular carcinoma. The finding of excess deaths at 3.5 years among treated patients with noncirrhotic fibrosis at baseline was unexpected and is not well explained by other findings (i.e., changes in laboratory-test results and the rate of development of cirrhosis). All patients in this study continue to be followed prospectively, and it is important to assess whether this difference in mortality between treated patients and control patients will persist.
Our findings contradict the results of several previous studies, but those studies either were not prospective, randomized trials or relied on end points other than clinical outcomes.9-11
Several reports have suggested that interferon-based therapy in patients with chronic hepatitis C, even with a course as brief as 6 months and even with no sustained virologic response, can reduce the frequency of hepatocellular carcinoma; however, these nonrandomized studies were based on retrospective analyses.10,11
In contrast, a recent small study involving 102 patients with hepatitis C and cirrhosis who had not had a response to previous therapy with peginterferon and ribavirin and who were randomly assigned to receive either standard interferon or no treatment for 24 months yielded results similar to those of our trial.20
Several reports have suggested that interferon-based therapy in patients with chronic hepatitis C may reduce the risk of hepatocellular carcinoma among those patients with a sustained virologic response.10,11
The HALT-C trial was a large-scale, randomized, controlled assessment of the effect of interferon on the incidence of hepatocellular carcinoma, and our findings show definitively that, even when maintained for several years, peginterferon therapy does not reduce the incidence of hepatocellular carcinoma in patients with advanced fibrosis and persistent viremia.
In the HALT-C trial, we used half the recommended dose of peginterferon alfa-2a (90 μg rather than 180 μg per week) because of concern about adverse events that may be associated with full-dose, long-term peginterferon therapy. Indeed, in this study, which was conducted among highly motivated patients, the starting peginterferon dose was maintained for the full 3.5 years in only 59% of patients. Higher doses of peginterferon might have been more effective in suppressing HCV replication and might have prevented disease progression. In addition, patients in the HALT-C trial did not receive long-term ribavirin with peginterferon, which might have been more potent than monotherapy in suppressing HCV RNA levels and improving clinical outcomes; however, the preliminary data suggesting that long-term antiviral therapy improves histologic results were generated in trials of interferon monotherapy. Furthermore, the rate of adverse events associated with maintenance therapy would almost certainly have been higher had ribavirin or full-dose peginterferon been included in the maintenance regimen.
Shiffman et al.9
found that among patients who did not have a viral response to interferon therapy but who had a histologic response after 6 months, extended treatment suppressed HCV RNA levels, with reductions in necroinflammation and fibrosis. Unfortunately, the degree of virologic suppression in the HALT-C trial did not result in a diminished rate of disease progression, although theoretically, maintenance therapy that is associated with more marked suppression of serum HCV RNA levels might be more effective. We conclude that long-term maintenance therapy with half-dose peginterferon is ineffective in preventing clinical and histologic disease progression and is not indicated in patients with hepatitis C–associated advanced fibrosis, with or without cirrhosis, who have not had a response to a standard course of peginterferon and ribavirin therapy.