Combination of Alpha-interferon with Lamivudine Reduces Viral Breakthrough During Long-term Therapy

Background And Aim: Viral breakthrough is frequently encountered during long-term lamivudine therapy, mostly associated with YMDD mutants. In this study, we investigated the effects of alpha-interferon (IFN-alpha) combined with lamivudine on the occurrence of viral breakthrough during long-term lamivudine therapy.

Methods: Eighty-three patients with biopsy-proven chronic hepatitis B were randomly allocated to a combination of lamivudine and IFN-alpha (LAM/IFN; n = 41) or lamivudine only (LAM; n = 42), and then followed up for >12 months. We calculated the cumulative rate of undetectable serum HBV-DNA and hepatitis B e antigen (HBeAg) loss, as well as the cumulative occurrence rate of viral breakthrough. We also evaluated the relationship between YMDD mutants and the occurrence of viral breakthrough.

Results: There was no difference in cumulative rates of undetectable serum HBV-DNA (100%vs 100% at 24 months, P = 0.13) and cumulative rates of serum HBeAg loss between the LAM/IFN group and the LAM group (49%, 61% and 67%vs 31%, 39% and 42%, respectively, at 12, 24 and 36 months; P = 0.07). The cumulative occurrence rate of viral breakthrough, however, was significantly lower in the LAM/IFN group compared with the LAM group (5%, 20% and 30%vs 10%, 55% and 58%, respectively, at 12, 24 and 36 months; P = 0.006). From the patients with viral breakthrough, YMDD mutants were detected in 82% (18 of 22) of the LAM group in contrast with 56% (five of nine) of the LAM/IFN group in their sera.

Conclusion: IFN-alpha combined with lamivudine may reduce viral breakthrough during long-term lamivudine therapy, probably by suppressing the appearance of YMDD mutants.