Results from a large international clinical study reported in this week's issue of The Lancet showed that peginterferon alfa-2b produced sustained responses in patients with chronic hepatitis B. The investigator-initiated study is the largest clinical trial to date with peginterferon alfa-2b therapy for chronic hepatitis B.
"Our study showed that patients with chronic hepatitis B responded to peginterferon alfa-2b, and achieved higher sustained response rates than is typically seen with any other antiviral treatment," said lead investigator Harry Janssen, M.D., Ph.D., from the Erasmus Medical Center in Rotterdam, The Netherlands, where the international study was coordinated. "Based on our findings with peginterferon alfa-2b, it is appropriate to consider this therapy as a first-line treatment for HBeAg-positive chronic hepatitis B," he said.
The findings of this study are important because chronic hepatitis B currently affects an estimated 400 million people worldwide, making it one of the most common infectious diseases and one of the 10 leading causes of death. Chronic hepatitis B is the single most common cause of liver cirrhosis and liver cancer. Current antiviral therapies, such as the nucleoside analogues lamivudine and adefovir, do not achieve a durable response and probably are not effective long-term treatment options due to the inevitable emergence of drug resistance.
Dr. Janssen also explained the importance of hepatitis B virus genotype as a predictor for response to peginterferon alfa-2b treatment. "Just like in chronic hepatitis C, the genotype of the hepatitis B virus (HBV) will tell us what the likelihood of response is. It will become our best tool towards individualized treatment for patients with HBeAg-positive chronic hepatitis B," he said.
The study, organized and sponsored by the Foundation for Liver Research (SLO), is the first to assess whether prolonged treatment with peginterferon alfa-2b, alone or in combination with lamivudine improves sustained treatment response in patients with HBeAg-positive chronic hepatitis B. HBeAg indicates that the virus is actively replicating and the infected person is highly infectious. In the study, more patients in the lamivudine combination group had a response to therapy at the end of treatment, but the response was not sustained during the follow-up period. There is growing evidence that only a complete and vigorous HBV-specific immune response is capable of achieving control and elimination of the virus, preventing disease progression.
"This suggests that induction of a host immune response is necessary for sustained response to hepatitis B treatment, which can only be reached by immunomodulatory therapy, such as peginterferon alfa-2b," Janssen said.
The study was a multicentre, randomized, double-blind controlled trial conducted at 42 centres in 15 countries (in Europe, East Asia and North America). The study compared the efficacy and safety of peginterferon alfa-2b (PegIntron (R), 100 ug/week through 32 weeks; 50 ug/week 33-52 weeks) with or without lamivudine (Zeffix (R)) in 307 patients positive for HBeAg (final modified intent-to-treat analysis n=266). Treatment outcomes were assessed at the end of treatment (EOT) (52 weeks) and again after a 26-week treatment-free follow-up period (78 weeks).
The primary endpoint was the percent of patients who achieved a sustained viral response (SVR) (undetectable levels of serum HBeAg) at the end of follow-up. Secondary endpoints were the reduction of HBV DNA levels below 200,000 copies/ml or below the level of detection (400 copies/ml); ALT normalization and HBsAg response.
SVR rates were comparable between the peginterferon alfa-2b monotherapy and combination therapy groups, 36% and 35%, respectively. HBV DNA levels at the end of follow-up were suppressed to below 200,000 copies/ml in 32% of patients in the combination therapy arm and 27% of patients in the monotherapy arm. Similarly, there was no difference at the end of follow-up in undetectable levels of HBV DNA, 9% and 7%, respectively; ALT normalization, 35% and 32%, respectively; or in HBsAg loss, 7% in both groups.
Importantly, there was a significant difference in sustained response rate according to HBV genotype (p=0.01), with HBV genotypes A (47%) and B (44%) more responsive to therapy than genotypes C (28%) and D (25%). There was no difference in HBeAg loss according to HBV genotype between the two treatment groups.
Safety and tolerability were similar for patients treated with peginterferon alfa-2b alone and those treated with lamivudine combination therapy. The side effect profile of peginterferon alfa-2b was similar to that seen with standard interferons and there were no new side effects that could be attributable to peginterferon alfa-2b. Overall, the incidence and severity of adverse events were comparable between the treatment groups. Common side effects included flu-like symptoms, headache, fatigue and local reaction at the injection site. There were serious adverse events in 12% of patients that were reversible after treatment stopped. At the end of treatment, 91% of patients remained on treatment and 69% remained on full-dose treatment.