Enhanced antiviral benefit of combination therapy with lamivudine and alpha interferon against WHV replication in chronic carrier woodchucks

Cell culture studies in our laboratory previously demonstrated synergistic antiviral activity for the combinations of lamivudine and a novel recombina nt hybrid human alpha BID interferon (rHu alpha B/D IFN) against hepatitis B virus (HBV) replication. Based on these results, a study was designed to determine if an enhanced antiviral effect with this drug combination could be demonstrated in vivo using the woodchuck hepatitis virus (WHV)/woodchuck experimental model of chronic HBV infection, Both antiviral agents have be en shown to be effective against WHV replication in WHV chronic carriers du ring previous studies by our laboratories. Two combination treatment regime ns were compared to matched monotherapies in a placebo-controlled trial. Th e first used simultaneous administration of rHu alpha B/D IFN and lamivudin e for 24 weeks, The other combination treatment regimen used a staggered do sing schedule of 12 weeks of administration of lamivudine alone, followed b y 12 weeks of simultaneous dosing with both drugs, followed by 12 weeks of therapy with rHu alpha B/D IFN alone, Both treatment regimens with combinat ions of lamivudine and rHu alpha B/D IFN were more effective at reducing WH V replication in chronically infected woodchucks than the corresponding mon otherapies. Both combination treatments produced antiviral effects that wer e at least equal to that expected for additive activity based on estimation s generated by Bliss Independence calculations. The staggered treatment reg imen reduced viraemia and intrahepatic WHV replication significantly more t han that expected for additive interactions, indicating synergistic antivir al effects. These studies demonstrate that combination therapy of chronic W HV infection has enhanced antiviral benefit over corresponding monotherapie s and indicate that combination treatment of chronic HBV infection can be s uperior to therapies using a single antiviral agent.