Comparison of INSTI vs EFV STARTMRK GS-US-236-0102 SINGLE SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD Design Randomisation* 1:1 Double-blind > 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 W96 DTG 50 mg + ABC/3TC FDC QD TDF/FTC/EFV placebo N = 422 W144 Open-label TDF/FTC/EFV QD DTG placebo + ABC/3TC placebo *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) SINGLE Walmsley S. NEJM 2013;369:1807-18 SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD Baseline characteristics and patient disposition DTG + ABC/3TC N = 414 TDF/FTC/EFV N = 419 36 35 Female 16% 15% HIV RNA (log10 c/mL), median 4.67 4.70 HIV RNA > 100,000 c/mL 32% 31% CD4 cell count (/mm3), median 335 339 CD4 < 200 per mm3 14% 15% Hepatitis C coinfection 7% 7% Discontinuation by W48 51 (12.3%) 84 (20.0%) For lack of efficacy N = 14 N = 13 For adverse event N = 10 N = 42 Lost to follow-up N = 14 N=9 N=7/N=5 N = 7 / N = 11 Median age, years Protocol deviation / Withdrew consent SINGLE Walmsley S. NEJM 2013;369:1807-18 SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD Response to treatment at week 48 HIV RNA < 50 c/mL % 100 DTG + ABC/3TC TDF/FTC/EFV Primary analysis 87.9 89.8 80.7 81.3 75 50 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 25 0 ITT, snapshot Per protocol Adjusted difference (95% CI) = 7% (2; 12) Adjusted difference (95% CI) = 9% (4; 13) Adjusted mean CD4/mm3 increase at W48 : + 267 for DTG + ABC/3TC + 208 for TDF/FTC/EFV (p<0.001) Superiority of DTG + ABC/3TC SINGLE Walmsley S. NEJM 2013;369:1807-18 SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD HIV-1 RNA < 50 c/mL at week 48 by stratification factors DTG + ABC/3TC Baseline Plasma HIV-1 RNA TDF/FTC/EFV Number of Responders/Number Assessed ≤100,000 c/mL 253/280 (90.4%) 238/288 (82.6%) >100,000 c/mL 111/134 (82.8%) 100/131 (76.3%) > 200/mm3 319/357 (89.4%) 290/357 (81.2%) < 200/mm3 45/57 (78.9%) 48/62 (77.4%) Baseline CD4+ T cell count SINGLE Walmsley S. NEJM 2013;369:1807-18 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 SINGLE Walmsley S, CROI 2014, Abs. 543 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 DTG + ABC/3TC , N = 414 PDVF Integrase genotype results at baseline and time of PDVF Emergent integrase-resistance mutations Reverse transcriptase genotype results at baseline and time of PDVF Emergent NRTI-resistance mutations Emergent NNRTI-resistance mutations TDF/FTC/EFV, N = 419 D0-W48 W48-W96 D0-W48 W48-W96 18 (4.3%) 7 17 (4.1%) 8 7 - 7 - 0* 0 0 0 9 - 9 - 0 0 0 0 1 (K65R) 4** 0 2*** * 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 SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD Adverse events and laboratory abnormalities at week 48 Adverse event leading to discontinuation of study drug Psychiatric disorder, N Nervous system disorder, N Skin and subcutaneous-tissue disorder, N Gastrointestinal disorder, N General disorder or administration-site condition, N Adverse event of grade 2-4 in > 3% in either group Bronchitis Diarrhoea Nausea Insomnia Anxiety Depression Headache Dizziness Rash Grade 2-4 elevation of ALT Grade 2-4 elevation of AST SINGLE DTG + ABC/3TC TDF/FTC/EFV 10 (2.4%) 2 0 2 0 0 42 (10.0%) 15 13 8 8 7 2% 5% 2% 4% 2% 2% 3% < 1% 1% 2% 2% 3% 4% 3% 4% 3% 3% 3% 5% 5% 5% 5% Walmsley S. NEJM 2013;369:1807-18 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 SINGLE Walmsley S. NEJM 2013;369:1807-18 SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD 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 Walmsley S. NEJM 2013;369:807-18 ; Walmsley S, CROI 2014, Abs.543