September 15, 2013

Journal of Viral Hepatitis

Volume 20, Issue 10, pages 699–707, October 2013

Original Article

E. J. Lawitz1,*, M. Rodriguez-Torres2, J. Denning3, A. Mathias3, H. Mo3, B. Gao3, M. T. Cornpropst4, M. M. Berrey5, W. T. Symonds3

Article first published online: 31 MAR 2013

DOI: 10.1111/jvh.12091

© 2013 Blackwell Publishing Ltd

Abstract

Keywords: antiviral agents; direct-acting antiviral agents; nucleotide analogue; viral drug resistance

Summary

Sofosbuvir and GS-0938 are distinct nucleotide analogues with activity against hepatitis C virus (HCV) in vitro. We evaluated the antiviral activity and safety of sofosbuvir and GS-0938 alone and in combination in HCV genotype 1 patients. In this double-blind study, 40 treatment-naïve patients were randomly assigned to 4 treatment cohorts: (i) GS-0938 for 14 days, (ii) GS-0938 for 7 days followed by GS-0938 plus sofosbuvir for 7 days, (iii) sofosbuvir for 7 days followed by GS-0938 plus sofosbuvir for 7 days and (iv) GS-0938 plus sofosbuvir for 14 days. In each arm, 8 patients received active drug and 2 placebo. After 7 days of dosing, patients in all 4 dose groups experienced substantial reductions in HCV RNA, with median declines (Q1, Q3) of −4.50 (−4.66, −4.24) in Cohort 1, −4.55 (−4.97, −4.13) in Cohort 2, −4.65 (−4.78, −4.17) in Cohort 3 and −4.43 (−4.81, −4.13) in Cohort 4; patients receiving placebo had essentially no change in HCV RNA (+0.07 log10 IU/mL). Seven days after the end of treatment, the proportions of patients with HCV RNA <15 IU/mL were 4 (50%), 8 (100%), 7 (88%) and 5 (63%) for Cohorts 1–4, respectively, vs 0 for placebo. No viral breakthrough or resistance mutations were observed. No serious adverse events or Grade 3 or 4 adverse events were reported. Sofosbuvir and GS-0938—alone and in combination—were well tolerated and led to substantial reductions in viral load. Sofosbuvir is undergoing further investigation as a possible backbone of an all-oral regimen for chronic HCV.

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