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Comparison of NRTI combinations

Study 934, HEAT Study, ACTG A5202 Study, and ASSERT Study compared antiviral activity, safety, and tolerability of ZDV/3TC and TDF/FTC in HIV-1 infected patients. Results showed inferior virologic efficacy of ZDV/3TC in patients with high HIV RNA levels.

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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. ACTG A5202 Study: ABC/3TC vs TDF/FTC A5202 • Multicenter, randomized, blinded equivalence study in 1858 HIV-1 infected patients • Comparison of antiviral activity, safety and tolerability of ABC/3TC and TDF/FTC, given with EFV or ATV/r • Scheduled interim review by the DSMB of the NIAID: inferior virologic efficacy of ABC/3TC in patients with a screening HIV RNA > 100,000 c/mL • Report of data from the 797 patients with screening HIV RNA > 100,000 c/mL • Inclusion criteria: HIV-1 infection, > 16 years, < 7 days of prior antiretroviral therapy, acceptable laboratory values • Design: randomized, partially blinded study comparing 4 once-daily regimens for the initial treatment of HIV-1 infection: • EFV 600 mg or ATV/r 300/100 mg, in combination with ABC/3TC or TDF/FTC (double-blinding for the NRTIs) • Randomisation was stratified on screening HIV RNA (> or < 100,000 c/mL) • Planned study duration was 96 weeks after enrolment of the last patient • Genotypic resistance test was required in patients with recent HIV-1 acquisition • Testing for HLA-B*5701 was permitted but not required Sax PE. NEJM 2009;361:2230-40

  3. A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC Statistical analysis • Primary efficacy endpoint: time to virologic failure (confirmed HIV RNA > 1,000 c/mL at or after W16 and before W24, or > 200 c/mL at or after W24) • Primary hypotheses: • Equivalence of ABC/3TC and TDF/FTC (for each regimens with ATV/r and EFV) • Equivalence of ATV/r and EFV (for each NRTI regimen) • Equivalence if the two-sided 95% CI for the hazard ratio was between 0.71 and 1.40 (power of 89.8%) • Pre specified early-stopping rules for inferiority at annual efficacy review by DSMB • Analyses of efficacy by ITT, stratified according to the screening HIV RNA • Kaplan-Meier estimation of time-to-event, with comparison by two-sided log-rank tests. Hazard ratios estimated by Cox models • Primary safety endpoint: time to the first grade 3 or 4 sign, symptom, or laboratory abnormality at least 1 grade higher than at baseline (except isolated unconjugated bilirubin and creatine kinase) while on randomly assigned treatment Sax PE. NEJM 2009;361:2230-40

  4. A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL) Baseline characteristics of the patients with screening HIV RNA > 100,000 c/mL * Geometric mean of screening and entry visits; ** mean of screening and entry visits Sax PE. NEJM 2009;361:2230-40

  5. Median follow-up = 60 weeks Discontinuation: 10% = 41 patientson ABC/3TC and 38 on TDF/FTC Risk of subsequent virologic failure among 448 patients with > 2 consecutive HIV RNA < 50 c/mL = 12 in ABC/3TC group vs 9 in TDF/FTC group (p = 0.25) Median CD4/mm3 increase at W48:194 (ABC/3TC) vs 199 (TDF/FTC) A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL) Time to virologic failure 100 TDF/FTC (26 events) 80 ABC/3TC (57 events) 60 Probability of NoVirologic Failure (%) p < 0.001, log-rank test 40 Hazard ratio : 2.33 (95% CI : 1.46-3.72) 20 0 0 4 16 24 36 48 60 72 84 96 108 Weeks since randomisation No. at risk ABC/3TC 398 363 313 267 222 188 137 87 49 20 TDF/FTC 399 361 321 284 236 204 160 104 65 23 Sax PE. NEJM 2009;361:2230-40

  6. A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL) Time to regimen failure* Time to safety endpoint 100 100 TDF/FTC (78 events) TDF/FTC (68 events) 80 80 60 60 ABC/3TC (114 events) ABC/3TC (130 events) Probability of No Primary Safety Event (%) Probability of NoRegimen Failure (%) 40 40 p < 0.001, log-rank test Hazard ratio: 1.87 (95% CI: 1.38-2.54) p < 0.001, log-rank test Hazard ratio: 1.89 (95% CI: 1.43-2.50) 20 20 0 0 0 4 16 24 36 48 60 72 84 96 108 0 4 16 24 36 48 60 72 84 96 108 Weeks since treatment dispensation Weeks since randomisation No. at risk No. at risk ABC/3TC 396 341 290 247 206 173 124 78 46 19 ABC/3TC 397 258 219 177 148 118 82 49 27 5 TDF/FTC 397 355 316 281 235 204 158 101 63 21 TDF/FTC 397 299 272 233 188 156 112 71 35 12 * Regimen failure: virologic failure or NRTI modification (time to first event) Sax PE. NEJM 2009;361:2230-40

  7. A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL) % of patients with HIV-1 RNA < 50 c/mL * 100 TDF/FTC 80 ABC/3TC 60 p = 0.20, chi-square test at week 48 40 20 Weeks since randomisation 0 0 4 16 24 36 48 60 72 84 96 108 No. with RNA value ABC/3TC 388 357 324 293 245 212 163 114 59 TDF/FTC 393 352 325 285 244 211 169 109 69 * ITT analysis involving all patients, regardless of prior NRTI discontinuation or virologic failure This analysis represents the aggregate success of both initial (randomly assigned) and subsequent therapy Sax PE. NEJM 2009;361:2230-40

  8. A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL) Estimated effect of ABC/3TC (N=398) vs TDF/FTC (N=399) on the hazard of virologic failure 0.04 1 25 ABC/3TC better TDF/FTC better Sax PE. NEJM 2009;361:2230-40

  9. A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL) Grade 3 or 4 signs, symptoms or laboratory abnormalities at least 1 grade higher than the grade at baseline, during the initial regimen Sax PE. NEJM 2009;361:2230-40

  10. A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL) Selected clinical and laboratory events * 1 death after restarting ABC-containing study medication ** subsequent viriologic failure among patients with suspected HSR = 4 in ABC/3TC group, 3 in TDF/FTC group Sax PE. NEJM 2009;361:2230-40

  11. A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL) • Summary - Conclusion • For initial treatment of HIV-1 infection, patients with a screening HIV RNA > 100,000 c/mL whose regimen contains TDF/FTC as compared with ABC/3TC were significantly less likely • to experience virologic failure: TDF/FTC superiority in virologic outcome was observed throughout the duration of the study and in multiple sensitivity analyses • to experience tolerability failure • Possible explanation: ABC/3TC is less potent than TDF/FTC • Difference in virologic failure between NRTIs significantly increased with a lowerCD4 count • Differences in virologic failure persisted after adjustement for multiple baseline covariates • Occurrence of suspected hypersensitivity reactions did not influence study outcomes: equal number in both groups, virologic failure infrequent • Important implications for clinical practice of this double-blind, randomized, prospective study • Patients with high HIV RNA have a risk of virologic failure twice higher with ABC/3TC as compared with TDF/FTC • Treatment guidelines recommend to consider results of this study when selecting NRTIs for first-line antiretroviral therapy in patients with high HIV RNA Sax PE. NEJM 2009;361:2230-40

  12. A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC, in combination with EFV vs ATV/r - Final results (all patients) Patients characteristics at screenning • Results in the 797 patients with screening HIV RNA > 100,000 c/mL : • at DSMB action, time to virologic failure was significantly shorter with ABC/3TC as compared with TDF/FTC, independently of 3rd drug • [HR (95% CI)]: 2.33 (1.46-3.72) (Sax PE, NEJM 2009;361:2230-40) • with EFV: 2.46 (1.20-5.05) • with ATV/r: 2.22 (1.19-4.14) Sax PE, NEJM 2009;361:2230-40) ; Daar ES. CROI 2010; Abs. 59LB

  13. A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC, in combination with EFV vs ATV/r - Final results (all patients) Time to virologic failure • In patients with screening HIV RNA < 100,000 c/ml, ABC/3TC and TDF/FTC have similar time to virologic failure, with ATV/r and EFV • Overall, ATV/r and EFV have similar time to virologic failure, with both NRTIs Sax PE, NEJM 2009;361:2230-40) ; Daar ES. CROI 2010; Abs. 59LB

  14. A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC, in combination with EFV vs ATV/r - Final results (all patients) Daar ES. CROI 2010; Abs. 59LB

  15. In patients with screening HIV RNA < 100,000 c/ml: ABC/3TC compared with TDF/FTC Similar time to virologic failure with ATV/r and EFV Shorter time to safety event with EFV Shorter time to modification with ATV/r and EFV (difference driven by suspected hypersensitivity reactions in ABC/3TC arms) Greater increase in CD4 with EFV Greater increase in total cholesterol, LDL- and HDL-cholesterol with both ATV/r and EFV; greater increase in triglycerides with ATV/r Increase (ABC/3TC) versus modest decline (TDF/FTC) in creatinine clearance with ATV/r A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC: final results (screening HIV RNA < 100,000 c/ml ) Daar ES, CROI 2010, Abs. 59LB Daar ES. CROI 2010; Abs. 59LB

  16. ATV/r compared with EFV (all patients) Similar time to virologic failure with both NRTIs Pre-specified equivalence boundary on HR was not met, as observed W96 event rate was lower than projected (~15% vs 32%) Difference and CIs for probability of being failure free at W96 were within + 10% criteria often used for defining equivalence (post hoc analysis) Longer time to safety event and to 3rd drug modification with ABC/3TC Among virologic failures there was less resistance with both NRTIs Greater increase in CD4 with TDF/FTC Smaller increases in total cholesterol, LDL- and HDL-cholesterol with both NRTIs Modest decline in creatinine clearance with TDF/FTC vs increase with ABC/3TC A5202 ACTG A5202 Study: ABC/3TC vs TDF/FTC, in combination with EFV vs ATV/r - Final results (all patients) Daar ES, CROI 2010, Abs. 59LB Daar ES. CROI 2010; Abs. 59LB

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