Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice

Abstract

Background & aims: The current treatment regimen for chronic hepatitis C virus (HCV) infection is peg-interferon plus ribavirin combination therapy. The majority of developing therapeutic strategies also contain peg-interferon with or without ribavirin. However, interferon is expensive and sometimes intolerable for some patients because of severe side effects.

Methods: Using human hepatocyte chimeric mice, we examined whether a short term combination therapy with the HCV NS3-4A protease inhibitor telaprevir and the RNA polymerase inhibitor MK-0608 with or without interferon eradicates the HCV from infected mice. The effect of telaprevir and MK-0608 combination therapy was examined using subgenomic HCV replicon cells.

Results: Combination therapy with the two drugs enhanced inhibition of HCV replication compared with either drug alone. In in vivo experiments, early emergence of drug resistance was seen in mice treated with either telaprevir or MK-0608 alone. However, emergence was prevented by the combination of these drugs. Mice treated with a triple combination therapy of telaprevir, MK-0608, and interferon became negative for HCV RNA soon after commencement of the therapy, and HCV RNA was not detected in serum of these mice 12 weeks after cessation of the therapy. Furthermore, all mice treated with a high dose telaprevir and MK-0608 combination therapy for 4 weeks became negative for HCV RNA 1 week after the beginning of the therapy and remained negative after 18 weeks.

Conclusions: Eradication of HCV from mice with only 4 weeks of therapy without interferon points the way to future combination therapies for chronic hepatitis C patients.