By Jillian L. Lokere

September 27, 2004 — Peginterferon alfa-2a was more effective than lamivudine for the treatment of HBeAg-negative chronic hepatitis B, and the combination provided no additional benefit in efficacy, according to a recent large international clinical trial. However, peginterferon was also associated with a higher rate of side effects, although fewer than 10% discontinued therapy due to safety concerns. And of interest, the combination appeared to suppress the development of lamivudine resistance.

Peginterferon alfa has recently been shown to be superior to lamivudine in those with chronic hepatitis postive for hepatitis B e antigen (HBeAg), but it had not been tested prevously for HBeAg-negative disease. Patrick Marcellin, MD, and colleagues randomized 537 patients to receive 48 weeks of treatment with peginterferon alfa-2a 180 µg once weekly (n = 177), peginterferon alfa-2a 180 µg once weekly plus lamivudine 100 mg once daily (n = 197), or lamivudine 100 mg once daily (n = 181). Patients were required to be negative for HBeAg and positive for anti-HBe antibody and hepatitis B surface antigen (HBsAg) for 6 months prior to the start of treatment, to have an HBV DNA level of more than 100,000 copies/mL, to have a serum alanine aminotransferase (ALT) level between 1 and 10 times the upper limit of normal, and to have evidence of chronic hepatitis on liver biopsy within the previous 2 years. Patients with HIV, HCV, or HDV coinfection, HBV treatment within 6 months of the start of the trial, or alcohol or drug abuse within a year of the start of the trial were excluded.

The primary efficacy endpoints after 24 weeks of follow-up were ALT normalization and HBV DNA levels below 20,000 copies/mL. Secondary efficacy measures included HBsAg loss, HBsAg seroconversion, and suppression of HBV DNA to below 400 copies/mL.

Peginterferon was significantly more effective than lamivudine, and the combination was no better than peginterferon alone. ALT normalization was seen 59% of those receiving peginterferon alone and 60% of those receiving peginterferon plus lamivudine, compared with 44% receiving lamivudine alone, a significant difference, A total of 43% of the peginterferon monotherapy group and 44% of the combination group achieved an HBV DNA level < 20,000 copies/mL, as opposed to only 29% of the lamivudine monotherapy group.

Peginterferon was also significantly superior in the secondary efficacy analysis, and similarly, there was no added benefit from the combination. HBV DNA fell to below 400 copies/mL in 19% of patients with peginterferon monotherapy, 20% with peginterferon plus lamivudine, and 7% with lamivudine monotherapy. Additionally, HBsAg loss occurred in 4% of patients receiving peginterferon monotherapy, 3% of those receiving peginterferon plus lamivudine, and none of those receiving lamivudine alone. HBsAg seroconversion occurred in 3% of the peginterferon alfa-2a monotherapy group, 2% of the combination group, and none of the lamivudine monotherapy group.

Interestingly, peginterferon seemed to suppress development of lamivudine resistance. A total of 18% of the lamivudine monotherapy group developed the YMDD mutation at 48 weeks of therapy, compared with only 1% in the combination group.

Frequent adverse events significantly more common in groups receiving peginterferon included pyrexia (55-59% vs 4%), fatigue (42% vs 18%), myalgia (27% vs 6%), and headache (19-24% vs 8%). However, only a few patients in the peginterferon groups (7% for the peginterferon monotherapy group, 4% for the combination group, 0 for the lamivudine group) discontinued therapy due to safety reasons.

The investigators concluded that, "Peginterferon alfa-2a offers significantly improved efficacy over lamivudine in the treatment of HBeAg-negative chronic hepatitis B."

Reference

Marcellin P, Lau GKK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351:1206-1217.