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Comparison of NRTI combinations

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Comparison of NRTI combinations

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  1. Comparison of NRTI combinations • ZDV/3TC vs TDF + FTC • Study 934 • ABC/3TC vs TDF/FTC • HEAT Study • ACTG A5202 Study • ASSERT Study • FTC/TDF vs FTC/TAF • Studies GS-US-292-0104 and GS-US-292-0111

  2. Study 934: zidovudine/lamivudine fixed dose combination vs tenofovir + emtricitabine Study 934 • Design Randomisation* 1 : 1 Open-label W48 W144 N = 255 517 ARV-naïve patients > 18 years HIV RNA > 10,000 c/mL Any CD4 cell count N = 254 *Randomisation was stratified on CD4 cell count < 200 or > 200/mm3 • Objective • Non inferiority of TDF + FTC + EFV vs ZDV/3TC + EFV at W48: % HIV RNA < 400 c/mL, TLOVR algorithm (lower margin of the 95% CI for the difference = -13%, 85% power) Gallant JE. NEJM 2006;354:251-60

  3. Study 934: zidovudine/lamivudine fixed dose combination vs tenofovir + emtricitabine Study 934 Baseline characteristics * Excluded from primary endpoint analysis Note : TDF, FTC and EFV taken without regards to meals and preferably at bed time; Substitution of NVP for EFV allowed if EFV intolerance; not considered as treatment failure Gallant JE. NEJM 2006;354:251-60

  4. Study 934: zidovudine/lamivudine fixed dose combination vs tenofovir + emtricitabine Study 934 Response to treatment at week 48 Primaryendpoint TDF + FTC ZDV/3TC % /mm3 100 200 190 84 80 158 77 80 160 73 70 68 60 120 40 80 20 40 N = 244 243 244 243 255 254 0 0 HIV RNA < 400 c/mL TLOVR HIV RNA < 50 c/mL TLOVR HIV RNA < 50 c/mL ITT Mean CD4 increase (p = 0.002) 95% CI for the difference = 4; 19 (p = 0.002) 95% CI for the difference = 2; 17 (p = 0.02) 95% CI for the difference = 1; 16 (p = 0.03) Gallant JE. NEJM 2006;354:251-60

  5. Study 934 Study 934: zidovudine/lamivudine fixed dose combination vs tenofovir + emtricitabine • Safety and tolerability: TDF + FTC vs ZDV/3TC • Similar frequency of clinical adverse events grade 2 to 4 and laboratory abnormalities grade 2 to 4 in both groups, respectively 63% vs 63% and 56% vs 57% • Significantly more discontinuations for adverse events in the ZDV/3TC group: 9% vs 4% (p = 0.02); mainly for anemia (N = 14 vs 0) • Renal safety was similar in both groups and no patients discontinued because of renal events. Change in median GFR (MDRD) at W48 was similar in both groups (< - 1 mL/min/1.73 m2). No Fanconi’s syndrome occurred • Mean increase significantly lower in the TDF + FTC group for total cholesterol, LDL-cholesterol and HDL-cholesterol; increase in triglycerides modest and not different between groups • At week 48, DEXA substudy in 100 patients (no baseline evaluation): significantly less total limb fat with ZDV/3TC (mean 6.9 vs 8.9 kg; p = 0.03) Gallant JE. NEJM 2006;354:251-60

  6. Resistance data Genotypic analysis was done in patients without baseline NNRTI resistance if viral rebound (2 consecutive HIV RNA > 400 c/mL after achieving < 400 c/mL HIV RNA > 400 c/mL at W48 discontinuation before W48 with HIV RNA > 400 c/mL at the last visit Patients with baseline resistance (11 in each group) were excluded from this analysis of resistance Study 934 Study 934: zidovudine/lamivudine fixed dose combination vs tenofovir + emtricitabine * 1 technical failure; ** K103N mutation developed in 21 of 25 patients Gallant JE. NEJM 2006;354:251-60

  7. Study extended to 3 years of follow-up (W144) At week 96, patients on TDF + FTC swithed to fixed-dose combination TDF/FTC Study 934 Study 934: zidovudine/lamivudine fixed dose combination vs tenofovir + emtricitabine * No discontinuation for renal events Arribas JR. JAIDS 2008;47:74-8

  8. Study 934 Study 934: zidovudine/lamivudine fixed dose combination vs tenofovir + emtricitabine • Conclusions • TDF + FTC + EFV is non inferior to ZDV/3TC + EFV • Greater virologic response rates to TDF + FTC + EFV as compared with ZDV/3TC + EFV • Significantly greater CD4 response with TDF + FTC • Greater tolerability of TDF + FTC • This study shows superior outcome in the tenofovir-emtricitabine group • At week 144, TDF/FTC + EFV demonstrates superior durability of viral load suppression and an improved safety and morphologic profile compared with ZDV/3TC and EFV Gallant JE. NEJM 2006;354:251-60; Arribas JR. JAIDS 2008;47:74-8