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Comparison of INSTI vs EFV

Comparison of INSTI vs EFV. STARTMRK GS-US-236-0102 SINGLE. Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD. Design. Randomisation* 1 : 1 Double-blind. W48. W192. N = 348. > 18 years ARV-naïve HIV RNA > 5,000 c/mL Any CD4 cell count eGFR> 70 mL/min. N = 352.

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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. Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD • Design Randomisation* 1 : 1 Double-blind W48 W192 N = 348 > 18 years ARV-naïve HIV RNA > 5,000 c/mL Any CD4 cell count eGFR> 70 mL/min N = 352 *Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) at screening • Objective • Non inferiority of EVG/c/FTC/TDF at W48: % HIV RNA < 50 c/mL by intentionto treat, snapshot analysis (lower margin of the 2-sided 95% CI for the difference= -12%, 95% power) Sax PE. Lancet 2012;379:2439-48 GS-US-236-0102

  3. Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD Baseline characteristics and patient disposition Sax PE. Lancet 2012;379:2439-48 ; Zolopa A, JAIDS 2013;63:96-100 ; Wohl DA, JAIDS 2014;65:e118-121 GS-US-236-0102

  4. Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD Response to treatment at week 48 HIV RNA < 50 c/mL Primaryanalysis EVCG/c/FTC/TDF % 96.0 EFV/FTC/TDF 94.9 100 87.6 84.1 Viral suppression was high inboth treatment arms, for various Subgroups including patientswith HIV RNA > 100 000 c/mLat baseline 75 50 Mean CD4/mm3 increase at W48 : + 239 (EVG/c/FTC/TDF) vs + 206 (EFV/FTC/TDF), P = 0.009 25 0 ITT, snapshot Per protocol Adjusted difference (95% CI)= 3.6% (- 1.6 ; 8.8) Adjusted difference (95% CI)= -1.0 % (- 4.4 ; 2.4) Sax PE. Lancet 2012;379:2439-48 GS-US-236-0102

  5. Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD Response to treatment at week 96 and week 144 HIV RNA < 50 c/mL at week 96 HIV RNA < 50 c/mL at week 144 EVCG/c/FTC/TDF EVCG/c/FTC/TDF % % EFV/FTC/TDF EFV/FTC/TDF 100 100 86.7 85.4 83.3 82.2 82.3 80.2 78.1 75.3 75 75 50 50 25 25 0 0 ITT, snapshot ITT, M = F ITT, snapshot ITT, M = F Adjusted difference (95% CI)= 1.1 % (- 4.5 ; 6.7) Adjusted difference (95% CI)= 1.4 % (- 3.8 ; 6.5) Adjusted difference (95% CI)= 4.9 % (- 1.3; 11.1) Adjusted difference (95% CI)= 4.1 % (- 1.9 ; 10.0) Zolopa A, JAIDS 2013;63:96-100 ; Wohl DA, JAIDS 2014;65:e118-121 GS-236-0103

  6. Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD Secondary efficacy outcomes at week 144 Median (IQR) change in creatinine and eGFR at week 48 Sax PE. Lancet 2012;379:2439-48 ; Zolopa A, JAIDS 2013;63:96-100 ; Wohl DA, JAIDS 2014;65:e118-121 GS-236-0103

  7. Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD • Virologic failure definition • Suboptimal virologic response: 2 consecutive visits with HIV RNA ≥ 50 c/mLand < 1 log10 c/mL below baseline at or after week 8, • Virologic rebound: 2 consecutive visits with HIV RNA either ≥ 400 c/mL after achievingHIV RNA <50 c/mL, or > 1 log10 c/mL increase from nadir, • HIV RNA ≥ 400 c/mL at their last visit (at or after week 8) • Criteria for resistance testing • Virological failure or HIV RNA > 400 c/mL at study discontinuation (at or after W8 and taking study drug) Resistance data at week 48 * Q148R, N = 1, N155H, N = 1, E92Q, N = 7, T66I, N = 1 ; ** K103N, N = 7, K101E, N = 3, V108I, N = 1, Y188F/H/K, N = 1, G190A, N = 1 Sax PE. Lancet 2012;379:2439-48 GS-US-236-0102

  8. Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD Resistance data at week 144 Zolopa A, JAIDS 2013;63:96-100 ; Wohl DA, JAIDS 2014;65:e118-121 ; White KL. Antiviral Therapy 2015, ePub ahead of print GS-236-0103

  9. Treatment-emergent adverse events leading to premature discontinuation of study drugs Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD Sax PE. Lancet 2012;379:2439-48 ; Zolopa A, JAIDS 2013;63:96-100 ; Wohl DA, JAIDS 2014;65:e118-121 GS-US-236-0102

  10. Adverse events occurring in > 10% of patients in either group (W48) Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD • Laboratory test results at week 48 Sax PE. Lancet 2012;379:2439-48 GS-US-236-0102

  11. Discontinuation for renal event EVG/c/FTC/TDF 5 between D0 and W48: 4/5 patients developed signs of tubular toxicity (hypophosphataemia, and/or glycosuria, and/or proteinuria 2 between W48 and W96 : decreased GFR, renal failure 1 between W96 and W144 : creatinine increase, without tubulopathy EFV/FTC/TDF No discontinuation Discontinuation for neuropsychiatric event EVG/c/FTC/TDF 3 before W48, none after EFV/FTC/TDF 6 before W48, 4between W48 and W96, none between W96 and W144 Discontinuation for rash EVG/c/FTC/TDF No discontinuation EFV/FTC/TDF 4 before W48, none between W48 and W144 Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD Sax PE. Lancet 2012;379:2439-48 ; Zolopa A, JAIDS 2013;63:96-100 ; Wohl DA, JAIDS 2014;65:e118-121 GS-US-236-0102

  12. Summary of week 48 results EVG/c/FTC/TDF QD is virologically non inferior to EFV/FTC/TDF Similar virologic reponse of the 2 regimens in different subgroups of patients, including those high HIV RNA at enrolment Discontinuation because of adverse events : 4 % vs 5 % Development of major resistance mutations occurred in 8 patients on EVG/c/FTC/TDF : 7 with integrase mutations, 8 with NRTI mutations 8 patients on EFV/FTC/TDF : 8 with NNRTI mutations, 2 with NRTI mutations Incidence of adverse events was similar except for neuropsychiatric adverse events and rash (more frequent with EFV/FTC/TDF), and nausea (more frequent with EVG/c/FTC/TDF) Median increases in creatinine with decreases in estimated glomerular filtration rate more pronounced with EVG/c/FTC/TDF Five patients on EVG/c/FTC/TDF discontinued for renal events Week 144 results Durable efficacy of EVG/c/FTC/TDF, with no new renal safety signal and a longer-term safety profile that is differentiated from EFV/FTC/TDF Study GS-US-236-0102: EVG/c/FTC/TDF QD vs EFV/FTC/TDF QD Sax PE. Lancet 2012;379:2439-48 ; Wohl DA, JAIDS 2014;65:e118-121 GS-US-236-0102

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