Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial

Summary

Background

Treatment of HBeAg-positive patients with chronic hepatitis B is not effective in most. A combination of immunomodulatory pegylated interferon alfa-2b and antiviral lamivudine might improve the rate of sustained response.

Methods

307 HBeAg-positive patients with chronic hepatitis B were assigned combination therapy (100 μg/week pegylated interferon alfa-2b and 100 mg/day lamivudine) or monotherapy (100 μg/week pegylated interferon alfa-2b and placebo) for 52 weeks. During weeks 32–52 the pegylated interferon dose was 50 μg/week in both treatment groups. The analyses were based on the modified intention-to-treat population after exclusion of 24 patients from one centre withdrawn for misconduct, ten who lost HBeAg before the study start, and seven who received no study medication. All included patients were followed up for 26 weeks after treatment.

Findings

49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the end of follow-up (p=0·91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; p=0·01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase. Response rates (HBeAg loss) varied by HBV genotype (p=0·01): A, 42 (47%) patients; B, ten (44%); C, 11 (28%); and D, 26 (25%).

Interpretation

Treatment with pegylated interferon alfa-2b is effective for HBeAg-positive chronic hepatitis B. Combination with lamivudine in the regimen used is not superior to monotherapy. HBV genotype is an important predictor of response to treatment.

Introduction

Patients successfully treated for chronic hepatitis B are less likely to develop cirrhosis, liver failure, and hepatocellular carcinoma than those who do not respond to treatment.1, 2 However, to date, treatment for chronic hepatitis B has been unsuccessful in the majority of patients. Of the few currently approved agents for treatment of chronic infection with hepatitis B virus (HBV), the most commonly used are interferon alfa and nucleoside or nucleotide analogues, such as lamivudine and adefovir dipivoxil.

In early studies, use of standard (non-pegylated) interferon alfa reportedly cleared HBeAg and HBV DNA in about a third of treated patients.3, 4 Subsequently, response rates of only 19% have been noted.⁵ HBeAg clearance induced by interferon alfa has been reported to be durable in 80–90% of patients, and the clearance is associated with a reduction in rates of hepatocellular carcinoma and death.1, 6, 7, 8

Inhibitors of DNA polymerase, of which lamivudine and adefovir dipivoxil are currently the most effective and most studied, achieve profound reductions in viral load.9, 10 However, sustained response after discontinuation of treatment is as yet unknown for adefovir dipivoxil and occurs in only 10–15% of patients treated with lamivudine.¹¹ Responses to lamivudine are significantly less durable than that those to interferon alfa.¹² Furthermore, the long-term efficacy of nucleoside analogues is compromised by the almost inevitable emergence of drug-resistant HBV mutants.¹³ Lamivudine resistance has been reported in 57% of patients after 3 years of treatment.¹⁴

There is increasing evidence that only a complete and vigorous HBV-specific immune response can achieve control and elimination of the virus, preventing disease progression.¹⁵ This evidence suggests that sustained response to HBV treatment requires induction of a host immune response, which can only be achieved with immunomodulatory therapy, such as interferon.

The introduction of pegylated interferons in the treatment of hepatitis C has led to greater treatment efficacy than is achieved with standard interferon,¹⁶ and a preliminary study has been done in the treatment of HBeAg-positive chronic hepatitis B.¹⁷ The better efficacy of pegylated interferons could be due to more constant concentrations in the serum than are achieved with standard interferon. These features are combined with a similar safety profile and simpler and more convenient dosing (once weekly) than with standard interferon (three times per week). The convenience of dosing is important because, across the therapeutic range, simpler dosing regimens improve adherence, which in turn increases treatment efficacy.¹⁸

To date, most studies of standard interferon combination regimens for the treatment of chronic HBV disease have investigated the efficacy of 16-week regimens.5, 19 However, longer regimens might result in higher rates of sustained response.²⁰ Our study is based on the rationale that combination of the immunomodulatory properties of interferon and the strong antiviral potency of lamivudine in a long-term treatment regimen might increase the rate of sustained response in chronic hepatitis B.