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Comparison of INSTI vs EFV

Comparison of INSTI vs EFV. STARTMRK GS-US-236-0102 SINGLE. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC. Design. Randomisation* 1 : 1 Double-blind. W48. W240. > 18 years ARV-naïve HIV RNA > 5,000 c/mL Any CD4 cell count No resistance to

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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. STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC • Design Randomisation* 1 : 1 Double-blind W48 W240 > 18 years ARV-naïve HIV RNA > 5,000 c/mL Any CD4 cell count No resistance to EFV, TDF or FTC N = 282 N = 284 *Randomisation was stratified by baseline HIV RNA (< or > 50,000 c/mL) and viral hepatitis co-infection status • Objective • Non inferiority of RAL vs EFV: % HIV RNA < 50 c/mL by per protocol, non-completer = failure analysis (lower margin of the 2-sided 95% CI for the difference = - 12%, 90% power) Lennox JL. Lancet 2009;374:796-806 STARTMRK

  3. STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Baseline characteristics and patient disposition RAL was administered with or without food, EFV on an empty stomach at bedtime, TDF/FTC in the morning with food Lennox JL. Lancet 2009;374:796-806 STARTMRK

  4. RAL EFV STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Response to treatment at week 48 HIV RNA < 50 c/mL HIV RNA < 50 c/mL at W48(observed-failure analysis) by baseline factors % Primaryanalysis Per protocol, observed-failure * 91.6 100 89.1 86.1 81.9 75 50 25 Mean CD4/mm3 increase at W48 (observed-failure analysis): 189 (RAL) vs 163 (EFV) (P = 0.0184) N = 281 282 263 258 PP, NC = F 95% CI for the difference = - 1.9; 10.3 95% CI for the difference = - 2.6; 7.7 * Exclusion of discontinuations due to intolerability or reasons unrelated to treatment Lennox JL. Lancet 2009;374:796-806 STARTMRK

  5. Safety at W48 STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Lennox JL. Lancet 2009;374:796-806 STARTMRK

  6. Safety: neuropsychiatric symptoms At Week 8 CNS-related adverse events had occurred in 10% of RAL patients vs 18% of EFV patients (P = 0.0149) Retrospective sensitivity analysis (additional symptoms): > 1 CNS-related adverse event: 20% vs 52% (P < 0.0001) Most symptoms were self-limited At Week 48 Cumulative incidence of CNS-related adverse event was significantly lower in patients on RAL: 14% vs 23% in the main analysis (P = 0.0044); 26% vs 59% in the sensitivity analysis (P < 0.0001) These events were generally mild: 62% of RAL vs 79% of EFV Only 1 patient, on EFV, discontinued the trial because of CNS-related adverse event STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Lennox JL. Lancet 2009;374:796-806 STARTMRK

  7. STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Cumulative treatment outcome for the entire 5 years study Rockstroh JK, JAIDS 2013;63:77-85 STARTMRK

  8. RAL EFV STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Cumulative Discontinuation Rate due to AE (%) 20 18 16 Log rank P-value = 0,023 14 12 10 8 6 4 2 0 0 16 32 48 60 72 84 96 120 140 168 192 216 240 Weeks Number at risk 281 272 265 262 255 246 236 231 227 223 217 190 282 272 257 254 245 235 221 213 203 200 196 183 Rockstroh JK, JAIDS 2013;63:77-85 STARTMRK

  9. RAL EFV STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Response to treatment at week 240 (5 years) HIV RNA < 50 c/mL HIV RNA < 50 c/mL (observed-failure analysis) by baseline factors % Per protocol, observed-failure * Primary analysis PP, NC = F 100 89.2 80.7 71.0 75 61.3 50 25 Increases in fasting serum triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol from baseline were significantly lower at W240 (P < 0.005) in RAL than EFV N = 279 279 263 258 Difference (95% CI) = 9.5% (1.7 ; 17.3)Superiority Difference (95% CI) = 8.6% (1.9 ; 15.5)  Superiority * Exclusion of discontinuations due to intolerability or reasons unrelated to treatment Rockstroh JK, JAIDS 2013;63:77-85 STARTMRK

  10. STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Cumulative summary of genotypicresistance data for patients with RNA > 400 c/mL at the time of virologic failure out to week 240 • Emergence of RAL resistance in 4 patients (1.4%)Sequencing data of the 4 patients with emergence of RAL-associated mutations • Q148H + G140S, • Q148R + G140S, • Y143Y/H + L74L/M + E92Q +T97A, • Y143R * Integrase gene could not be amplified in 5 cases Rockstroh JK, JAIDS 2013;63:77-85 STARTMRK

  11. STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Drug-related adverse events in > 5% in either group over 5 years Rockstroh JK, JAIDS 2013;63:77-85 STARTMRK

  12. Summary – Conclusion At 48 weeks of treatment, RAL was non-inferior to EFV, in combination with TDF/FTC. Virologic non-inferiority of RAL was confirmed through W24. RAL was superior to EFV for virologic outcome at week 240 RAL + TDF/FTC led to more rapid viral load decline (significantly more patients with HIV RNA < 50 c/mL for weeks 2 to 16) Greater increase in CD4 was observed in the RAL group. It was significant from W156 Upon virologic failure, resistance mutations to RAL was found in few cases RAL was associated with significantly fewer overall and drug-related clinical adverse events, and CNS-related adverse events than was EFV Mean changes in lipid parameters were smaller for RAL than for EFV RAL + TDF/FTC is an alternative to EFV + TDF/FTC as a first-line combination regimen in treatment-naïve HIV-infected patients STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Lennox JL. Lancet 2009;374:796-806; Rockstroh JK, JAIDS 2013;63:77-85 STARTMRK

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