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Comparison of INSTI vs EFV

Comparison of INSTI vs EFV

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Comparison of INSTI vs EFV

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  1. Comparison of INSTI vs EFV • STARTMRK • GS-US-236-0102 • SINGLE

  2. SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD • Design Randomisation* 1 : 1 Double-blind W96 W144 > 18 years ARV-naïve HIV RNA > 1,000 c/mL Any CD4 cell count HBsAg negative No genotypic resistance HLA-B*5701 negative N = 422 Open-label N = 422 *Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) and CD4/mm3 (< or > 200) at screening • Objective • Non inferiority of DTG at W48: % HIV RNA < 50 c/mL by intention to treat, snapshot analysis (1-sided significance level of 2.5%, lower margin of the 95% CI for the difference = -10%, 90% power) Walmsley S. NEJM 2013;369:1807-18 SINGLE

  3. SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD Baseline characteristics and patient disposition Walmsley S. NEJM 2013;369:1807-18 SINGLE

  4. SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD Response to treatment at week 48 HIV RNA < 50 c/mL Primaryanalysis DTG + ABC/3TC % TDF/FTC/EFV 100 87.9 89.8 81.3 80.7 Differences in viral suppression were also seen in key demographic subgroups including race, sex, age and patients with HIV RNA > 100,000 c/mL at baseline 75 50 25 Adjusted mean CD4/mm3 increase at W48 : + 267 for DTG + ABC/3TC + 208 for TDF/FTC/EFV (p<0.001) 0 ITT, snapshot Per protocol Adjusted difference (95% CI)= 7% (2; 12) Adjusted difference (95% CI)= 9% (4; 13)  Superiority of DTG + ABC/3TC Walmsley S. NEJM 2013;369:1807-18 SINGLE

  5. SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD HIV-1 RNA < 50 c/mL at week 48 by stratification factors Walmsley S. NEJM 2013;369:1807-18 SINGLE

  6. SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD Response to treatment at week 96 HIV-1 RNA < 50 c/ml (ITT, snapshot) DTG + ABC/3TC TDF/FTC/EFV % 100 DTG : 80% 80 EFV : 72% 60 Adjusted difference at W96 (95 % CI) :+ 8.0 % (+ 2.3 % ; + 13.8 %) ; P = 0.006 40 20 0 0 4 8 12 16 24 32 40 48 60 72 84 96 Weeks Walmsley S, CROI 2014, Abs. 543 SINGLE

  7. SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD • Virologic failure definition • 2 consecutive plasma HIV-1 RNA > 50 c/mL, on or after W24 • Criteria for resistance testing • All patients with protocol defined virologic failure (PDVF) • Genotype of RT and integrase on baseline and suspected virologic failure samples Resistance data at PDVF * E157Q/P polymorphism in 1 patient with no change in phenotype ** N = 1 with K101E, N = 1 with K103N, N = 1 with G190A, N = 1 with K103N + G190A ; **** N = 2 with K103K/N SINGLE Walmsley S, ICAAC 2012, Abs.H556b ; Walmsley S. NEJM 2013;369:807-18 ; Walmsley S, CROI 2014, Abs.543

  8. SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD Adverse events and laboratory abnormalities at week 48 Walmsley S. NEJM 2013;369:1807-18 SINGLE

  9. SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD • Insomnia was more frequent in DTG group (15% vs 10%) • Serious adverse events related to study drug at week 48 • DTG + ABC/3TC, N = 1 • Suspected drug hypersensitivity • TDF/FTC/EFV, N = 8 • Psychiatric event, N = 4 • Drug hypersensitivity, N = 2 • Cerebrovascular accident, N = 1 • Renal failure, N = 1 • Mean change in creatinine at W48 on DTG: + 0.12 to 0.15 mg/dL (10.56 to 13.2 mmol/L), peak at W2, then stable Walmsley S. NEJM 2013;369:1807-18 SINGLE

  10. Conclusion DTG + ABC/3TC QD had a better safety profile and was superior through 48 weeks to TDF/FTC/EFV for first-line antiretroviral therapy Superior virologic response with DTG + ABC/3TC also seen in key demographic subgroups and in patients with low or high baseline viral load Statistical superiority in CD4 response for DTG + ABC/3TC Virologic superiority of DTG + ABC/3TC confirmed at W96 No INSTI major mutations were detected through 96 weeks with DTG Lower occurrence of adverse events leading to discontinuation with DTG : 2% vs 10% Significant lower reported rates of neuro-psychiatric and rash events with DTG + ABC/3TC Except for insomnia (15% vs 10%) SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD SINGLE Walmsley S. NEJM 2013;369:807-18 ; Walmsley S, CROI 2014, Abs.543