Combination of Entecavir or Tenofovir with Pegylated Interferon-alpha for Long-Term Reduction in Hepatitis B Surface Antigen Levels: Simultaneous, Sequential, or Add-on Combination Therapy

Seroclearance of hepatitis B surface antigen (HBsAg) ("functional cure") is the optimal endpoint of antiviral therapy for chronic hepatitis B virus (HBV) infection. Currently available anti-HBV therapy includes nucleoside/nucleotide analogs (NAs) and peginterferon-alpha (Peg-IFN alpha). Combination of NAs and Peg-IFN alpha, each with different mechanisms of action, is an attractive approach for treating chronic HBV infection. In earlier studies, compared with monotherapy using IFN alpha, combination therapy showed greater on-treatment HBV DNA suppression but no difference in the sustained response. However, responses to the combination of non-pegylated IFN alpha with lamivudine or adefovir were not assessed based on HBsAg quantification but were defined by normal alanine aminotransferase levels, testing negative for hepatitis B e-antigen, and low HBV DNA load over a short term. Here, we reviewed previous reports regarding the effects of combination therapy of entecavir or tenofovir with Peg-IFN alpha, focusing on long-term reduction in HBsAg levels. Regimens of combination therapy were classified into "simultaneous" combination ("de novo" strategy); "sequential" combination, which involved starting with one therapy followed by the other ("switch-to" strategy); "add-on" combination, which involved adding Peg-IFN alpha to an ongoing NAs. Some studies have shown promising results, but there is no robust evidence that combination therapy is superior to monotherapy. Large studies are needed to assess the safety and efficacy of combination therapies to increase the rates of HBsAg seroclearance over the long term.