CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

efficacy analysis (N=26 mono-infected; N=1 co-infected). HCV RNA was determined using the Roche COBAS TaqMan RT-PCR assay; lower limit of quantification (LLOQ) =25 IU/ml. SVR 12 rates were analyzed according to the first week HCV RNA 〈 LLOQ was attained. Results: Mono- and co-infected patient groups were well matched for IL28B non-CC GT (78% [1607/2053] mono-infected; 81% [51/63] co-infected) and proportion with cirrhosis (19% [384/2053] mono-infected; 19% [12/63] co-infected). More co-infected than mono-infected patients were black (24% [15/63] vs 6% [123/2053], respectively). Most patients achieved HCV RNA 〈 LLOQ by week 2, regardless of mono- or co-infection (1652/2027 [81%] mono-infected, 57/62 [92%] co-infected); stratifying this by cirrhosis state yielded 283/374 (76%) for cirrhotic and 1369/1653 (83%) for non-cirrhotic mono-infected patients and 11/12 (92%) for cirrhotic and 46/50 (92%) for non-cirrhotic co-infected patients. By week 4, the 5 remaining co-infected patients who were not suppressed at week 2 had HCV RNA < LLOQ. Two out of three co-infected patients who achieved HCV RNA 〈 LLOQ at week 2 and did not achieve SVR 12 had documented HCV re-infection. Similar to mono-infected patients, SVR 12 rates (despite documented re-infection) in co-infected patients were high (89-100%), regardless of time of initial HCV viral suppression (Figure). The overall safety profile was similar for mono- and co-infected patients.

*Virologic failures occurring in 2 patients appear to have resulted from reinfection based on analyses of baseline and virologic failure samples Conclusions: Both HCV mono- and HCV/HIV-1 co-infected patients achieved rapid HCV viral suppression with 3D+/-RBV treatment. SVR 12 first virologic response. 148 The Paradox of Highly Effective Sofosbuvir Combo Therapy Despite Slow Viral Decline Thi HuyenTram Nguyen 1 ; Jérémie Guedj 1 ; Laetitia Canini 2 ; Anu Osinusi 5 ; Phillip S. Pang 5 ; John McHutchison 5 ; Henry Masur 6 ; Anita Kohli 3 ; Shyam Kottilil 4 ; Alan S Perelson 2 1 IAME, UMR 1137, Inserm, F-75018 Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France, Paris, France; 2 Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, US; 3 Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, US; 4 Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD, US; 5 Gilead Sciences, Inc, Foster City, MD, US; 6 NIH Clinical Center, Bethesda, MD, US Background: The SYNERGY trial demonstrated 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 (Kohli et al., The Lancet 2014) . Here we employed viral kinetic modeling to better understand the effect of each of these drugs in this very rapid and effective cure of HCV. Methods: In order to evaluate the effect of each agent, we conducted a pooled analysis of the early viral kinetics in patients treated with SOF + ribavirin (RBV) ( Osinusi et al., JAMA 2013 ), SOF + LDV and SOF+LDV+GS9669/GS9451. Viral kinetics were fitted using a multiscale model that allows one to distinguish the effect of each agent in blocking vRNA replication, ε α , from blocking viral assembly/secretion, ε s (Guedj et al., PNAS 2013) . 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 ( ε s =99.7%). In contrast, the delayed response in patients treated with SOF + RBV suggests that SOF has only a minimal effect in blocking assembly/secretion. However by day 3, patients treated with SOF + RBV achieved largely comparable levels of virus as the patients in all arms of Synergy (Fig 1), demonstrating a high effectiveness of SOF in blocking vRNA production ( ε α =99.96%). Surprisingly, the total effectiveness in blocking vRNA production was significantly lower in patients receiving SOF+LDV ± GS-9669 ( ε α =96.5%, P<10 -10 ) and, to a lesser extent, SOF+RBV ± GS-9451 ( ε α =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. Consistent with this slow final phase, the model predicted SVR rate of 85.2% after 24 weeks of SOF+RBV, but only 43% and 10% after 12 and 6 weeks of SOF+LDV and SOF+LDV+GS9669/GS9451, respectively, i.e., much lower than what was observed in the Synergy trial. rates were high regardless of time of

Oral Abstracts

Figure 1: Median observed viral load and median predicted viral decay curves using the multiscale model for different treatment combinations of Synergy and Spare trials. BLQ=below limit of quantification

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CROI 2015