Comparison of RTV vs Cobi  GS-US

Gallant JE. JID 2013;208:32-9 GS-US  Design  Objective –Non inferiority of COBI compared with RTV at W48: % HIV RNA < 50 c/mL by intention to treat, snapshot analysis (lower limit for the 95% CI for the difference = -12%, 95% power) COBI + RTV placebo + ATV 300 mg + FTC/TDF QD COBI placebo + RTV + ATV 300 mg + FTC/TDF QD Randomisation* 1 : 1 Double-blind > 18 years ARV-naïve HIV RNA > 5,000 c/mL Any CD4 cell count eGFR > 70 mL/min Sensitivity to ATV, FTC And TDF on genotype * Randomisation was stratified by HIV RNA ( 100,000 c/mL) at screening Study GS-US : ATV + ritonavir + FTC/TDF QD vs ATV + cobicistat + FTC/TDF N = 348 N = 344 W48W192

COBI + ATV + FTC/TDF N = 344 RTV + ATV + FTC/TDF N = 348 Mean age, years3738 Female17%18% HIV RNA (log 10 c/mL), median HIV RNA > 100,000 c/mL38.4%41.1% CD4 cell count (/mm 3 ), mean CD4 < 200 per mm 3 12%16% Hepatitis B / hepatitis C coinfection5% / 6%3% / 5% Discontinuation by W4817%11% For lack of efficacyN = 2N = 0 For adverse eventN = 25 Lost to follow-upN = 11N = 4 Non-complianceN = 43 Baseline characteristics and patient disposition Gallant JE. JID 2013;208:32-9 GS-US Study GS-US : ATV + ritonavir + FTC/TDF QD vs ATV + cobicistat + FTC/TDF

HIV RNA < 50 c/mL Mean CD4/mm 3 increase at W48 : COBI vs RTV Response to treatment at week 48 Viral suppression was high in both treatment arms, for various subgroups, including patients with HIV RNA > 100,000 c/mL at baseline Gallant JE. JID 2013;208:32-9 GS-US Study GS-US : ATV + ritonavir + FTC/TDF QD vs ATV + cobicistat + FTC/TDF % Adjusted difference (95% CI) = -2.2%( ; 3.0) 98.0 Primary analysis Adjusted difference (95% CI) = -0.1 % ( ; 2.3) COBI + ATV + FTC/TDF RTV + ATV + FTC/TDF ITT, snapshotPer protocol

 Criteria for resistance testing : confirmed HIV-1 RNA load rebound of ≥ 400 c/mL or not obtaining HIV RNA < 400 c/mL by or after week 8 Resistance data at week 48 COBI + ATV + FTC/TDFRTV + ATV + FTC/TDF Analysed for the development of resistance 12 (3.5%)12 (3.4%) Available data 1012 Emergent reverse transcriptase resistance 20 M184V 2 Emergent mutations to protease inhibitors 00 COBI + ATV + FTC/TDFRTV + ATV + FTC/TDF Median increase of creatinine (mg/dL) at W (P < 0.001) Grade 3-4 hyperbilirubinemia65.3%56.6% Grade 3-4 elevation of ALT / AST3.2% / 2.9%2.0% / 2.0% Increase in total cholesterol (mg/dL) at week (NS) Increase in triglycerides (mg/dL) at week (NS)  Laboratory abnormalities Gallant JE. JID 2013;208:32-9 GS-US Study GS-US : ATV + ritonavir + FTC/TDF QD vs ATV + cobicistat + FTC/TDF

COBI + ATV + FTC/TDFRTV + ATV + FTC/TDFP Jaundice20.9%15.5%0.076 Scleral icterus17.7%18.4%- Nausea17.7%16.4%- Diarrhea15.4%20.4%0.093 Headache11.0%15.5%0.093 Nasopharyngitis10.8%15.2%0.09 Hyperbiluribinemia11.3%9.8%  Adverse events occurring in > 10% of patients in either group (W48)  Adverse events leading to discontinuation of study drug by W48 COBI + ATV + FTC/TDFRTV + ATV + FTC/TDF Total number of patients25 (7.3%)25 (7.2%) Scleral icterus84 Jaundice97 Hyperbilirubinemia12 Rash12 Allergic dermatitis20 Renal AEs6 (proximal tubulopathy in 5)5 (proximal tubulopathy in 2) Gallant JE. JID 2013;208:32-9 GS-US Study GS-US : ATV + ritonavir + FTC/TDF QD vs ATV + cobicistat + FTC/TDF

 Summary of week 48 results –COBI was non inferior to RTV in combination with ATV plus FTC/TDF at week 48 Both regimens achieved high rates of virologic success –Safety and tolerability profiles of the 2 regimens were comparable –Once-daily COBI is a safe and effective pharmaco-enhancer of the protease inhibitor ATV –Renal safety was comparable between treatment arms Discontinuation due to renal events was 1.7% in the COBI group and 1.4% in the RTV group Proximal tubulopathy occurred in 5 vs 2 patients A small, but significantly higher with COBI, increase in creatinine was seen in both groups, as early as week 2, with peak at week 8, and stabilization through 48 weeks Gallant JE. JID 2013;208:32-9 GS-US Study GS-US : ATV + ritonavir + FTC/TDF QD vs ATV + cobicistat + FTC/TDF