December 29, 2013

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original Article

Jeremie Guedj1,2, Jing Yu3, Micha Levi4,  Bin Li3, Steven Kern5, Nikolai V. Naoumov5, Alan S. Perelson2,*

DOI: 10.1002/hep.26989

Copyright © 2013 American Association for the Study of Liver Diseases

Publication History

Accepted manuscript online: 23 DEC 2013 03:36AM EST
Manuscript Accepted: 19 DEC 2013
Manuscript Revised: 18 OCT 2013
Manuscript Received: 13 JUL 2013

Abstract

Alisporivir (ALV) is a cyclophilin inhibitor with pan-genotypic activity against hepatitis C virus (HCV). Here we characterize the viral kinetics observed in 249 patients infected with HCV genotypes 2 or 3 and treated for six weeks with different doses of ALV with or without ribavirin (RBV). We use this model to predict the effects of treatment duration and different doses of ALV plus RBV on the sustained virologic response (SVR).

Continuous viral decline was observed in 214 (86%) patients that could be well described by the model. All doses led to a high level of antiviral effectiveness equal to 0.98, 0.96 and 0.90 in patients treated with 1000, 800 and 600 mg ALV once-daily, respectively. Patients that received RBV had a significantly faster rate of viral decline, which was attributed to an enhanced loss rate of infected cells, δ (mean δ=0.35 d-1 vs 0.21 d-1 in patients +/- RBV, respectively, P=0.0001). The remaining 35 patients (14%) had a suboptimal response with flat or increasing levels of HCV RNA after one week of treatment, which was associated with ALV monotherapy, high body weight and low RBV levels in patients that received ALV+RBV.

Assuming full compliance and the same proportion of suboptimal responders, the model predicted 71% and 79% SVR following ALV 400 mg with RBV 400 mg twice-daily for 24 and 36 weeks, respectively. The model predicted that response guided treatment could allow a reduction in the mean treatment duration to 25.3 weeks and attain a 78.6% SVR rate.

Conclusion: Alisporivir plus ribavirin may represent an effective interferon-free treatment that is predicted to achieve high SVR rates in patients with HCV genotype 2 or 3 infection. (Hepatology 2013;)

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