Maintenance interferon for chronic hepatitis C: more issues than answers?

In this issue of HEPATOLOGY, Ikeda et al.1 describe use of long-term maintenance therapy with beta-interferon to prevent recurrent hepatocellular carcinoma (HCC) after surgical resection or alcohol ablation of primary HCC in patients with chronic hepatitis C virus (HCV). Twenty patients, 10 per group, were randomly assigned to either beta-interferon or no treatment after potentially curative surgery (n 5 16) or alcohol ablation (n 5 4). The two groups were well matched in terms of demographics, hepatitis serology, HCV-RNA positivity, and percent cirrhosis (85% overall). Although most were cirrhotic and some had significantly reduced serum albumin and platelet count, none had evidence of clinical decompensation. Nearly all HCCs were solitary (90% for both groups), all were less than 5 cm, 50% were less than 2 cm, none exhibited vascular invasion, and histology was moderately well differentiated. In general, treatment was well-tolerated, with few patients requiring dose reductions. However, one patient was discontinued from treatment for spontaneous retinal hemorrhage after 19 months of interferon. During follow-up, no patient in either group experienced clinical decompensation as manifest by ascites, encephalopathy, variceal hemorrhage, or spontaneous bacterial peritonitis. Although the number of patients in this trial is too small to draw definitive conclusions, the preliminary data are striking: only 1 of 10 interferon-treated patients developed detectable recurrence of hepatoma, whereas 7 of 10 untreated patients had detectable recurrence (P , .0004). The implication of this result is that maintenance interferon might be considered for patients undergoing curative treatment for HCC. The difference in outcome for interferon-treated and control patients followed for a relatively short period of time (median of 25 months) is so dramatic as to raise skepticism. Were the two groups truly matched at entry into the trial? Could the apparent beneficial effect of interferon simply reflect randomization of patients with a higher tumor burden or metastatic disease to the control arm? This kind of problem is inherent in small-scale trials.2 Why was the tumor recurrence rate so high in the untreated group (70% of patients with recurrent HCC within 2 years of follow-up)? The HCCs were small, solitary, lacked vascular invasion, and were moderately well differentiated, consistent with a favorable prognosis. The high recurrence in the untreated arm again suggests an unrecognized bias in the randomization process. What is the evidence that interferon, particularly beta-interferon, is truly chemotherapeutic in HCC? The investigators cite studies suggesting that alfa-interferon is antiproliferative.3,4 However, the clinical evidence suggests only modest or no efficacy of alfa-interferon in causing regression or controlling growth of HCC. Furthermore, to my knowledge there are no studies that have directly evaluated the antiproliferative or antineoplastic effects of beta-interferon in similar experimental models. Given the concerns regarding efficacy and the considerable potential for significant adverse effects of interferon therapy, one cannot currently recommend routine use of beta-interferon in prevention of HCC recurrence without confirmation of these initial observations in large, randomized, controlled trials. Although the study focused on the use of interferon in the prevention of HCC recurrence, a broader question arises: What is the role of long-term interferon in preventing clinical complications of cirrhosis caused by chronic hepatitis C? Sixty to 70% of patients treated with current antiviral regimens fail to respond and remain infected with hepatitis C. Mounting evidence indicates that these virologic nonresponders experience reduction in hepatic inflammation and inhibition of hepatic fibrosis.5-13 However, it is not known whether current antiviral regimens halt disease progression, prevent complications of cirrhosis, and reduce the risk of HCC. Progression of liver disease in patients with hepatitis C is linked to progressive fibrosis arising from ongoing hepatic inflammation,14-15 and HCC develops mainly in patients with underlying cirrhosis.16 Interaction between virus and host results in immune-mediated inflammation, which may be suppressed by specific interferons, interleukins, or related cytokines. For this reason, long-term maintenance therapy with interferon has been suggested as possible therapy to prevent disease progression and reduce risk of HCC. The recent decision by the National Institutes of Health (NIH) to conduct a multicenter treatment trial of virologic nonresponders with advanced stages of chronic hepatitis C (HALT-C Trial, Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial) highlights the importance of this clinical and therapeutic issue.17 One study of virologic nonresponders showed a reduction in fibrosis with long-term interferon maintenance therapy compared with no treatment.18 Liver biopsy was performed before and after a 6-month course of interferon. Patients who had histologic improvement on the biopsy done at 6 months Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NIH, National Institutes of Health; HALT-C, Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial. From the University of Colorado School of Medicine, Denver. Received June 16, 2000; accepted June 19, 2000. Address reprint requests to: Gregory T. Everson, M.D., Professor of Medicine, Director of Hepatology, Medical Director of Liver Transplantation, University of Colorado School of Medicine, 4200 East Ninth Ave, B-154, Denver, CO 80262. E-mail: greg. [email protected]; fax: 303-372-8868. Copyright © 2000 by the American Association for the Study of Liver Diseases. 0270-9139/00/3202-0038$3.00/0 doi:10.1053/jhep.2000.16216