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Gut 46:562-568 doi:10.1136/gut.46.4.562
  • Liver disease

Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial

Abstract

BACKGROUND, AIM, AND METHODS Alpha interferon is the generally approved therapy for HBe antigen positive patients with chronic hepatitis B, but its efficacy is limited. Lamivudine is a new oral nucleoside analogue which potently inhibits hepatitis B virus (HBV) DNA replication. To investigate the possibility of an additive effect of interferon-lamivudine combination therapy compared with interferon or lamivudine monotherapy, we conducted a randomised controlled trial in 230 predominantly Caucasian patients with hepatitis B e antigen (HBeAg) and HBV DNA positive chronic hepatitis B. Previously untreated patients were randomised to receive: combination therapy of lamivudine 100 mg daily with alpha interferon 10 million units three times weekly for 16 weeks after pretreatment with lamivudine for eight weeks (n=75); alpha interferon 10 million units three times weekly for 16 weeks (n=69); or lamivudine 100 mg daily for 52 weeks (n=82). The primary efficacy end point was the HBeAg seroconversion rate at week 52 (loss of HBeAg, development of antibodies to HBeAg and undetectable HBV DNA).

RESULTS The HBeAg seroconversion rate at week 52 was 29% for the combination therapy, 19% for interferon monotherapy, and 18% for lamivudine monotherapy (p=0.12 and p=0.10, respectively, for comparison of the combination therapy with interferon or lamivudine monotherapy). The HBeAg seroconversion rates at week 52 for the combination therapy and lamivudine monotherapy were significantly different in the per protocol analysis (36% (20/56) v 19% (13/70), respectively; p=0.02). The effect of combining lamivudine and interferon appeared to be most useful in patients with moderately elevated alanine aminotransferase levels at baseline. Adverse events with the combination therapy were similar to interferon monotherapy; patients receiving lamivudine monotherapy had significantly fewer adverse events.

CONCLUSIONS HBeAg seroconversion rates at one year were similar for lamivudine monotherapy (52 weeks) and standard alpha interferon therapy (16 weeks). The combination of lamivudine and interferon appeared to increase the HBeAg seroconversion rate, particularly in patients with moderately elevated baseline aminotransferase levels. The potential benefit of combining lamivudine and interferon should be investigated further in studies with different regimens of combination therapy.

Footnotes

  • An initial eight week pretreatment period with lamivudine was included in the combination arm design to reduce HBV DNA load before the combination treatment as low HBV DNA levels have been significantly associated with improved response to interferon.3 6

  • The original study design had a lamivudine monotherapy arm with a six month treatment duration for comparison with the combination and interferon treatment arms. However, emerging results from phase II studies11 indicated lamivudine therapy of longer than six months duration was required for significant HBeAg seroconversion. The protocol was consequently amended to extend the duration of the lamivudine monotherapy arm to 12 months.

  • Abbreviations used in this paper:
    HBV
    hepatitis B virus
    HBsAg
    hepatitis B surface antigen
    HBeAg
    hepatitis B e antigen
    ALT
    alanine aminotransferase
    ULN
    upper limit of normal