Thi Huyen Tram Nguyen (1), Jeremie Guedj (1), Laetitia Canini (2,3), Anu Osinusi (4), Phillip S. Pang (4), John McHutchison (4), Henry Masur (5), Anita Kohli (6), Shyam Kottilil (7) & Alan S Perelson (2)
(1) IAME, UMR 1137, INSERM, F-75018 Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France; (2) Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM; (3) Epidemiology Research Group, University of Edinburgh, Edinburgh, Scotland, UK; (4) Gilead Sciences, Foster City, CA; (5) Critical Care Medicine Department, NIH Clinical Center, Bethesda, MD; (6) Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc. (formerly SAIC–Frederick, Inc.), Frederick National Laboratory for Cancer Research, Frederick, MD; (7) Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD
Objectives: The Synergy trial showed that high cure rates for HCV infection could be achieved after 12-week treatment with sofosbuvir (SOF) and ledipasvir (LDV), and after only 6 weeks if GS-9669 (a non-nucleoside polymerase inhibitor) or GS-9451 (a protease inhibitor) was added [1]. Here we used viral kinetic models to better understand the effect of each drug in this very rapid and effective cure of HCV.
Methods: We conducted a pooled analysis of the early viral kinetics in patients treated with SOF+ribavirin (RBV) [2], SOF+LDV and SOF+LDV+GS9669/GS9451. Viral kinetics were fitted using a multiscale model that can distinguish the effect of blocking vRNA replication, εα, from blocking viral assembly/secretion, εs [3].
Results: The viral load decline was initially much more rapid in all arms of Synergy than in patients treated with SOF+RBV. This was attributed in our model to a high effectiveness of LDV in blocking viral assembly/secretion (εs=99.7%). However by day 3, patients treated with SOF+RBV achieved largely comparable levels of virus as the patients in all arms of Synergy, demonstrating a high effectiveness of SOF in blocking vRNA production (εα=99.96%). Surprisingly, the total effectiveness in blocking vRNA production was significantly lower in patients receiving SOF+LDV±GS-9669 (εα=96.5%, P<10-10) and, to a lesser extent, SOF+RBV±GS-9451 (εα=98.5%, P<10-10). Eventually, the final phase of viral decline was largely similar in all groups, and similar to that observed with IFN-based therapies, in contradiction with the large SVR rates of 95% observed. To explain this discrepancy, we hypothesized that most of the virus observed at EOT was non-infectious. Using a model that accounts for this hypothesis, we quantified the amount of infectious virus over time in dual or triple therapy, and predict the outcome of shorter treatment durations, e.g., 4 weeks. The validity of this hypothesis is being evaluated in vitro using in an infectious system by comparing the proportion of infectious virus over time under different treatments.
Conclusions: The kinetics of viral decline in patients of the Synergy trial was remarkably slow in regard of the very rapid cure of HCV. This suggests that HCV RNA is not a reliable marker for predicting outcome of treatment containing SOF+LDV. Additional mechanisms of action that are not reflected in the observed viral load, such as production of non-infectious virus, may explain the high cure rates.
References:
[1] Kohli A, Osinusi A, Sims Z, et al. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet 2015.Kohli A, Osinusi A, Sims Z, et al. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet 2015.
[2] Osinusi A, Meissner EG, Lee Y-J, et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. J. Am. Med. Assoc. 2013;310:804–811.
[3] Guedj J, Dahari H, Rong L, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc. Natl. Acad. Sci. U. S. A. 2013;110:3991–3996.
Reference: PAGE 25 (2016) Abstr 5718 [www.page-meeting.org/?abstract=5718]
Poster: Oral: Drug/Disease Modelling