CROI 2015 Program and Abstracts

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Poster Abstracts

THURSDAY, FEBRUARY 26, 2015 Session P-N8 Poster Session

Poster Hall

2:30 pm– 4:00 pm HCV Therapeutics: Preclinical Observations and Clinical Trials of DAAs 687 UNITY-1: Daclatasvir/Asunaprevir/Beclabuvir for HCV Genotype 1Without Cirrhosis Fred Poordad 1 ,William Sievert 2 , Norbert Brau 3 , Samuel Lee 4 , Jean-Pierre Bronowicki 5 , Ira Jacobson 6 , Eric Hughes 7 , Eugene Swenson 8 , PhilipYin 8 On behalf of the UNITY-1 StudyTeam

1 Texas Liver Institute, San Antonio, Texas, United States; 2 Monash Health and Monash University, Melbourne, Victoria, Australia; 3 Bronx Veterans Affairs Medical Center, New York, New York, United States; 4 University of Calgary, Alberta Health Services, Calgary, Alberta, Canada; 5 Centre Hospitalier Universitaire de Nancy, Universite de Lorraine, Vandoeuvre les Nancy, France; 6 Weill Cornell Medical College, New York, New York, United States; 7 Bristol-Myers Squibb Co, Princeton, New Jersey, United States; 8 Bristol-Myers Squibb Co, Wallingford, Connecticut, United States Background: The all-oral combination of daclatasvir (DCV; pangenotypic NS5A inhibitor), asunaprevir (ASV; NS3 protease inhibitor), and beclabuvir (BCV; non-nucleoside NS5B inhibitor) achieved high rates of SVR12 in a phase 2 clinical trial. This regimen, in a twice-daily fixed-dose combination tablet—DCV-TRIO regimen—was evaluated without ribavirin in HCV genotype (GT) 1-infected treatment-naive and -experienced patients without cirrhosis in a phase 3, open-label, international clinical trial. Methods: All patients received 12 weeks of treatment with the fixed-dose combination of DCV 30 mg, ASV 200 mg, and BCV 75 mg twice daily. Key efficacy outcomes were SVR12 rates in the treatment-naive and -experienced cohorts, assessed separately. Results: Baseline characteristics in the treatment-naive (N=312) and treatment-experienced (N=103) cohorts were comparable. Overall, patients were 58%male and 26% IL28B (rs1297860) CC genotype; 73%were infected with GT 1a and 27%with GT 1b. SVR12 was achieved by 92% and 89% of treatment-naive and –experienced patients, respectively. 17 patients with GT1b infection had NS5A resistance-associated variants (RAVs) at baseline; all 17 achieved SVR12. 25 of the 34 GT1a-infected patients with baseline NS5A RAVs achieved SVR12. Overall, 34 (8%) patients experienced virologic failure, including 21 with posttreatment relapse and 13 with on-treatment virologic failure. Among patients with GT1a infection who experienced failure, RAVs at positions NS5A-Q30, NS3-R155 and/or NS5B-P495 were the most frequently observed variants. One death occurred posttreatment and was considered not related to study treatment. There were 7 serious adverse events, all unrelated, and 3 (<1%) adverse events leading to treatment discontinuation. Adverse events (any grade) that were observed in >10% of patients included headache, fatigue, diarrhea, and nausea. Conclusions: Twelve weeks of all-oral treatment with the fixed-dose combination of DCV, ASV, and BCV achieved high SVR12 rates in 415 patients with chronic HCV GT 1 infection without cirrhosis, confirming the potent antiviral activity of the DCV-TRIO regimen. DCV-TRIO demonstrated a favorable safety and tolerability profile in both treatment-naive and treatment experienced patients. 688 UNITY-2: Daclatasvir/Asunaprevir/Beclabuvir ± RBV for HCV Genotype 1With Cirrhosis Andrew Muir 1 , Fred Poordad 2 , Jay Lalezari 3 , Gregory Dore 4 , Christophe Hezode 5 , Alnoor Ramji 6 , Eric Hughes 7 , Eugene Swenson 8 , PhilipYin 8 On behalf of the UNITY-2 StudyTeam 1 Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, United States; 2 Texas Liver Institute, University of Texas Health Science, San Antonio, Texas, United States; 3 Quest Clinical Research, San Francisco, California, United States; 4 Kirby Institute, University of New South Wales Australia, Sydney, New South Wales, Australia; 5 Hópital Henri Mondor, Université Paris-Est, Créteil, France; 6 University of British Columbia, Vancouver, British Columbia, Canada; 7 Bristol-Myers Squibb Co, Princeton, New Jersey, United States; 8 Bristol-Myers Squibb Co, Wallingford, Connecticut, United States Background: The presence of cirrhosis in patients with chronic HCV infection can reduce response to HCV therapies; potent and well tolerated oral regimens are needed. The all-oral DCV-TRIO regimen includes daclatasvir (DCV; pangenotypic NS5A inhibitor), asunaprevir (ASV; NS3 protease inhibitor), and beclabuvir (BCV; non-nucleoside NS5B inhibitor) in a fixed-dose combination (FDC). We evaluated this regimen, with and without ribavirin (RBV), in treatment-naive and -experienced patients with HCV genotype (GT) 1 infection and compensated cirrhosis in a randomized, phase 3 clinical trial. Methods: Patients were randomly assigned to receive a twice-daily FDC of DCV 30 mg, ASV 200 mg, and BCV 75 mg, with blinded RBV or placebo, for 12 weeks. SVR12 rates in the treatment-naive and experienced cohorts were evaluated separately as key efficacy outcomes. . Results: Baseline characteristics were comparable between treatment-naive (N=112) and treatment-experienced (N=90) patients. Overall, patients were 66%male and 27% IL28B (rs1297860) CC genotype; 74% of patients had GT1a infection and 26% had GT1b. SVR12 was achieved by 98% and 93% of treatment-naive patients treated with DCV-TRIO + RBV and DCV-TRIO, respectively. Corresponding SVR12 rates for the experienced cohort were 93% and 87%. The presence of NS5A or NS3 polymorphisms at baseline did not appear to impact SVR12. Virologic failure was observed in 13 (6%) patients, including posttreatment relapse (10/13) and on-treatment failure (3/13). Ten of 13 patients with virologic failure had both NS5A and NS3 resistance variants at failure. Three serious adverse events (SAEs) were considered related to treatment, and there was 1 DCV-TRIO discontinuation due to adverse events. There were no deaths. Adverse events reported in >10% of patients included fatigue, headache, nausea, diarrhea, insomnia and pruritus. Reduction of hemoglobin to <9 g/dL during treatment was reported in 5% of patients who received RBV-containing therapy but in none of the patients receiving DCV-TRIO alone. Conclusions: The all-oral fixed dose combination of DCV, ASV, and BCV, with or without ribavirin, achieved high rates of SVR12 after 12 weeks of therapy in patients with GT1 infection and compensated cirrhosis. The DCV-TRIO regimen with or without RBV was well tolerated. 689 Utility of Hepatitis C Viral-Load MonitoringWith Ledipasvir and Sofosbuvir Therapy Sreetha Sidharthan 2 ; Anita Kohli 3 ; Anu Osinusi 2 ; Amy Nelson 1 ; Zayani Sims 2 ; Kerry S.Townsend 4 ; LydiaTang 1 ; Michael Polis 4 ; Henry Masur 2 ; Shyam Kottilil 1 1 Institute of Human Virology, University of Maryland, Baltimore, MD, US; 2 NIH Clinical Center, Bethesda, MD, US; 3 Leidos Biomedical Research, Inc., Frederick, MD, US; 4 National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, US Background: Directly acting antivirals (DAA) are replacing interferon-based hepatitis C therapy. On interferon-based treatment, HCV RNA plasma levels were early predictors of treatment response and mainstays for response-guided therapy. However, the clinical utility of HCV RNA levels to guide duration of DAA therapy has not yet been determined. The aim of this study was to determine the ability of on-treatment plasma HCV RNA levels to predict treatment outcome in HCV mono-infected and HIV/HCV co-infected patients treated with ledipasvir and sofosbuvir. Methods: In two NIAID clinical trials, SYNERGY A (HCV mono-infected, n=17) and ERADICATE (HIV/HCV co-infected, ARV naïve n=13, on cART n=37), subjects were treated with a fixed dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) for 12 weeks. In both trials, patients were treatment-naïve, non-cirrhotics, and infected with HCV genotype 1. Serial measurements of plasma HCV RNA were performed by the Roche COBAS TaqMan HCV test v1.0 and the Abbott real-time PCR assay. The positive predictive value and negative predictive value at week 4 and end of treatment (EOT) for both assays were calculated.

Poster Abstracts

426

CROI 2015