Study ACTG A5202 : ABC/3TC vs TDF/FTC

Sax PE. N Engl J Med. 2009 Dec 3;361(23):2230-40 ; Daar ES. CROI 2010. Abs. 59LB

Type of ARV Trial
Head-to-head comparative trials for first line ART since 2006
» NNRTI vs PI/r
» ABC/3TC + EFV or ATV/r vs FTC/TDF + EFV or ATV/r
Drugs
DRV/c, DRV/r, ATV/r, EFV 600, FTC/TDF, ABC/3TC, TDF, ABC, FTC, 3TC

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  • 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 lower CD4 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
  • 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

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

Baseline characteristics of the patients with screening HIV RNA > 100,000 c/mL :

Time to virologic failure :

  • Median follow-up = 60 weeks
  • Discontinuation: 10% = 41 patients on 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)

Time to regimen failure* and Time to safety endpoint ::

* Regimen failure: virologic failure or NRTI modification (time to first event)

% of patients with HIV-1 RNA < 50 c/mL * :

* 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

Estimated effect of ABC/3TC (N=398) vs TDF/FTC (N=399) on the hazard of virologic failure :

Grade 3 or 4 signs, symptoms or laboratory abnormalities at least 1 grade higher than the grade at baseline, during the initial regimen :

Selected clinical and laboratory events :

Patients characteristics at screenning - combination with EFV vs ATV/r - Final results (all patients) :

  • 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)

Time to virologic failure - combination with EFV vs ATV/r - Final results (all patients) :

  • 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

Combination with EFV vs ATV/r - Final results (all patients) :

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

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