For the past decade, the standard of care for patients with chronic infection with genotype 1 hepatitis C virus (HCV) has been 48 weeks of pegylated interferon (Peg-IFN) alpha and ribavirin (RBV). Observed rates of sustained virologic response (SVR) with Peg-IFN and RBV therapy are 40%-52%. 1-4 However, the addition of the HCV nonstructural protein (NS)3 serine protease inhibitors, telaprevir or boceprevir, results in higher rates of SVR (67%-75%), leading to the recent approval of these two drugs in the United States and the European Union. 5-10 Because triple therapy can result in higher rates of rapid virologic response (RVR; HCV RNA < lower limit of quantification at week 4) in the range of 60%-70%, 5, 6, 9, 10 shortened treatment duration, from 48 to 24 weeks, is possible in a significant proportion of patients.
Several novel inhibitors of viral replication, including those targeting NS3 serine protease and NS5B RNA-dependent RNA polymerase, are in clinical development. 11 Although many of these direct-acting antiviral agents (DAAs) can cause rapid, substantial reductions in viral load (VL), their use as monotherapies has been limited by inadequate suppression of replication and/or the development of resistance. 12, 13 In the context of polymerase- or protease-inhibitor therapy, Peg-IFN and RBV have repeatedly demonstrated their importance in reducing VL and suppressing viral breakthrough. 14-16 In studies of regimens containing telaprevir or boceprevir, excluding RBV or using a reduced dose results in higher rates of viral breakthrough and relapse. 5, 7, 17
Several recent studies have explored the combining of two DAAs to enhance early antiviral activity and to theoretically minimize the development of resistance. In a study of treatment-naïve patients with HCV genotype 1, 14 days of combination therapy with the nucleoside analog, RG7128, and the NS3 protease inhibitor, danoprevir, resulted in 5-log10 IU/mL HCV RNA reductions from baseline. 18 More recently, the combination of the non-nucleoside NS5B polymerase inhibitor, VX-222, with telaprevir improved early antiviral response, but was associated with high rates of viral breakthrough. 19
Tegobuvir (GS-9190) is a novel, non-nucleoside inhibitor of NS5B polymerase. Studies to elucidate tegobuvir's mechanism of action are ongoing; however, current data indicate that the inhibitory effect may be exerted via an interaction with the β-hairpin in the NS5B thumb subdomain. 20 Tegobuvir and the NS3 protease inhibitor, GS-9256, each have demonstrated antiviral activity in HCV-infected patients. 21-23 Tegobuvir demonstrated median reductions in HCV RNA of 1.5 log10 IU/mL for individual patients with 8 days of monotherapy 21 and enhanced rates of RVR (HCV RNA <25 IU/mL at week 4), when combined with Peg-IFN and RBV. 22 At 200 mg twice-daily (BID) for 3 days, GS-9256 monotherapy demonstrated a median HCV RNA reduction of 2.7 log10 IU/mL. 22 Both tegobuvir and GS-9256 were well tolerated in these short-term monotherapy studies. We, therefore, evaluated the antiviral activity of tegobuvir and GS-9256 dual therapy, tegobuvir and GS-9256 plus RBV, and tegobuvir and GS-9256 plus Peg-IFN and RBV for 28 days. After 28 days of treatment, patients then continued treatment with Peg-IFN and RBV for 48 weeks.