An apparent paradox: Resistance mutations in HIV-1 DNA predict improved virological responses to antiretroviral therapy

Background: In sub-Saharan Africa, detecting resistance-Associated mutations (RAMs) at failure of first-line ART with two NRTIs plus an NNRTI predicts improved virological responses to second-line therapy with two NRTIs plus a ritonavir-boosted PI (PI/r). This indicates residual NRTI activity in the presence of RAMs, although additional factors may contribute to the effect. Objectives: The aim of this study was to investigate the influence of pre-existing RAMs on the outcomes of maintenance monotherapy with ritonavir-boosted darunavir within a randomized trial in Cameroon. Methods: RAMs were detected in HIV-1 DNA using PBMCs collected at initiation of darunavir/ritonavir monotherapy. Adherence was assessed by pill count and visual analogue scale (VAS). Predictors of virological failure (confirmed or last available viral load .400 copies/mL) were explored by logistic regression analysis. Trial name"MANET (NCT02155101). Results: After NNRTI-based therapy, participants (n"81) had received PI/r-based therapy for amedian of 3.2 years and had a confirmed viral load ,60 copies/mL and a median CD4 count of 466cells/mm3. NRTI and NNRTI RAMs were detected in 39/60 (65.0%) and 41/60 (68.3%) HIV-1 DNA sequences, respectively. Over 48weeks of monotherapy, 16/81 (19.8%) patients experienced virological failure. After adjusting for age, HIV-1 DNA load, adherence by VAS and RAM status, virological failure was less likely with higher VAS-measured adherence (adjusted OR 0.04, 95%CI 0.01-0.37; P"0.004) and detectable HIV-1 DNA RAMs (adjusted OR 0.15, 95%CI 0.03-0.82; P"0.028). Conclusions: Pre-existing NRTI and NNRTI RAMs are associated with improved virological responses to NRTIsparing ART in sub-Saharan Africa, indicating a predictive effect that is independent of residual NRTI activity.