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Design :

*Randomisation was stratified by HIV RNA (< or ≥ 100,000 c/mL) at screening, participation in cardiovascular sub-study, and 10-year Framingham risk score

Objective :

• Evaluate regimen equivalence regarding virologic efficacy and tolerability over 96 weeks, by intention-to-treat analysis. Equivalence = 2-sided 97.5% CI on the pairwise difference in 96-week cumulative incidence of each individual or composite endpoint falling between - 10% and 10%, 90% power. If equivalence was not shown, superiority was defined as exclusion of 0 from the 97.5% CI

Endpoints :

• Virologic failure: confirmed HIV-1 RNA > 1,000 c/mL at or after W16, or > 200 c/mL at or after W24
• Tolerability failure: time from randomisation to discontinuation of the randomised regimen component for toxicity (substitution of TDF or FTC not considered as tolerability failure)
• Composite endpoint: virologic or tolerability failure, whichever occurred first
• ITT-TLOVR, with HIV-1 RNA threshold of 200 c/mL
• HIV-1 RNA < 50 c/ mL at W96 by ITT, snapshot
• Sensitivity analysis: as-treated (virologic failure including treatment discontinuation as a competing event)
• Key toxicity secondary endpoint: time from initiation of treatment to the first grade 2, 3, or 4 sign or symptom (grade 3 or 4 if after week 48) or any grade 3 or 4 laboratory abnormality while the patient was receiving the randomized treatment (as-treated)
  • Prespecified sensitivity analysis excluded hyperbilirubinemia and elevated CK levels
  • Further sensitivity analysis included all qualifying adverse events regardless of status on randomized treatment (ITT analysis)

Baseline characteristics and patient disposition :

Cumulative incidence of virologic failure (primary end point) :

• Cumulative probability of virologic failure by W96
  • ATV/r: 12.6%
  • DRV/r: 14.9%
  • RAL: 9.0%

Equivalence of the 3 regimens

Cumulative incidence of tolerability failure (primary end point) :

• RAL equivalent to DRV/r
• RAL superior to ATV/r
• DRV/r superior to ATV/r

Greater tolerability benefit of :

• RAL vs ATV/r in patients with baseline HIV RNA < 100,000 c/mL
• RAL vs DRV/r in women

Discontinuations of randomised antiretroviral therapy for toxicity :

Cumulative incidence of virologic or tolerability failure
(preplanned composite failure) :

• ATV/r inferior to DRV/r and to RAL
• DRV/r inferior to RAL

HIV-1 RNA level ≤ 50 copies/mL,regardless of ART change(ITT analysis)

HIV-1 RNA level ≤ 50 copies/mL andreceiving randomized ART
(ITT, snapshot analysis)

Genotypic analysis for resistance at virologic failure :

Patients may not have been on their randomised treatment at time of failure

Grade 2 or higher adverse events in ≥ 5% of participants in either group :

Other safety data :

* vs RAL

Mean (95% CI) changes from baseline in fasting lipids, mg/ dL

Mean percentage change in bone mineral density over 96 weeks

Mean (97.5%) % of body composition change at W96, ITT : limb fat, trunk fat and lean mass (DXA scan), visceral and subcutaneous abdominal fat (CT abdomen)

All p values (ATV/r vs DRV/r, PI/r vs RAL) not significant

Larger increases in waist circumference were observed with the RAL arm compared to DRV/r arm
at weeks 48 and 96 (all p ≤ 0.023) but not compared with the ATV/r arm (p ≥ 0.07)

Effect of baseline HIV RNA on fat changes at W96 in the 3 groups

• Changes in central fat correlated with changes in peripheral fat (r = 0.67 ; p < 0.001)
• No change in VAT:TAT ratio within or between regimens
• Greater gains in VAT associated with :
  • Lower baseline leptin
  • Higher baseline adiponectin
  • HIV RNA level
• Greater gains in SAT associated with the same baseline factors, with in addition higher IL-6
• Greater gains in lean body mass associated with :
  • Higher HIV RNA, IL-6 and D- dimer, and lower CD4 at baseline

Changes in Inflammation and Immune activation

• Substudy A5260S (328 patients) : 234 included (HIV RNA < 50 c/mL at W24) : 68 on ATV/r, 84 on DRV/r and 82 on RAL
  • Plasma biomarkers of inflammation and coagulation : hsCRP, IL-6, GlycA, D- dimer, sCD14, sCD163, and sIL-2r
  • Blood cellular markers : %CD38+DR+ of T-cell subsets and %CD14+CD16+ and %CD14(dim)CD16+ monocyte subsets
• Changes in biomarkers varied by regimen during the 96 weeks of follow-up :
  • hsCRP declined with ATV/r and RAL
  • IL-6 declined only with RAL
  • GLycA decreased in all groups
  • D-dimer declined with ATV/r and DRV/r and was unchanged with RAL
  • Markers of T-cell activation and sCD163 (but not sCD14 and CD14-+CD16+) declined in all groups
• Conclusion : no consistent evidence that the reduction of inflammation and immune activation with ART initiation was different between RAL and PI-based regimens