The WHO recommends boosted protease inhibitor + nucleos(t)ide reverse transcriptase inhibitors (NRTI) for second-line ART, but concerns about NRTI toxicity and cross-resistance have motivated the search for NRTI-free regimens. We hypothesized that boosted lopinavir (LPV/r) + raltegravir (RAL) would be virologically non-inferior to LPV/r + NRTIs as second-line ART in resource-limited settings.
ACTG A5273 (SELECT) was a phase III, open-label, randomized, non-inferiority study conducted at 15 sites in 9 resource-limited countries. HIV-1-infected adults with viral load (VL) ≥1000 copies/mL (cpm) after 24 weeks (wks) of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen received LPV/r + RAL or LPV/r + NRTIs selected from an algorithm that included zidovudine for those failing tenofovir and vice versa. Non-inferiority was defined as the upper 2-sided 95% CI for the difference in cumulative probability of virologic failure (VF, confirmed VL >400 cpm at or after wk 24) estimated by Kaplan-Meier methods by wk 48 excluding 10%. Secondly, superiority was assessed by exclusion of 0. Genotypic drug resistance testing was performed retrospectively at study entry and VF.
512 eligible participants were randomized; the majority were female (52%), black (64%) and infected with subtype C (81%). At study entry, median CD4 count was 135 cells/mm3; VL 4.5 log10 cpm, 96% had ≥1 NRTI IAS mutation and 52% ≥3. By wk 48, the cumulative probability of VF was 10.3% (95% CI: 6.5%, 14.0%) in the RAL arm and 12.4% (8.3%, 16.5%) in the NRTI arm (See figure) with a weighted (by randomization stratification factors) difference (95% CI) of -3.4% (-8.4%, 1.5%) indicating LPV/r + RAL was non-inferior and not superior to LPV/r + NRTIs. Participants in the NRTI arm with a NRTI genotypic susceptibility score (GSS) >1 had a higher probability of VF versus those with GSS<1 (difference -8.4% [-16.6%, -0.3%]; P=0.04). In addition, having ≥3 NRTI mutations at study entry was associated with a lower probability of VF in both arms (HR 0.45 [0.30, 0.70], P<0.001).
In the setting of extensive NRTI resistance without resistance testing the WHO recommendation of LPV/r + NRTIs for second-line ART is supported by the current study. LPV/r + RAL should be considered an alternative if NRTI toxicity is limiting. The strong association between NRTI resistance at study entry and improved response to second-line ART deserves further evaluation of mechanisms other than better adherence.