3-drug synergistic interactions of small molecular inhibitors of hepatitis C virus replication.

Small molecular inhibitors of hepatitis C virus (HCV) replication provide remarkable potency, but the rapid selection of resistance mutations will require that these agents be used in combination for clinical treatment. Using a model HCV replicon system, we have extended prior in vitro studies of double combinations of candidate small molecular inhibitors to studies evaluating the simultaneous use of 3 agents. This was done in an effort to anticipate conditions that might ultimately be required clinically. We formally demonstrate synergistic antiviral activity with 3-drug combinations in this model, further supporting the concept of clinical investigations of combination therapy for HCV infection.