The paradox of highly effective sofosbuvir combo therapy despite slow viral decline
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.
