Adherence–resistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitness

TLDR

The study compares how adherence levels affect resistance prevalence in patients on NNRTI or PI and investigates the underlying class‑specific adherence‑resistance mechanisms. The authors measured adherence via unannounced pill counts, performed viral load and genotypic resistance testing, and assessed replicative capacity of drug‑susceptible and drug‑resistant recombinants with a single‑cycle phenotypic assay while estimating drug exposure from population pharmacokinetics adjusted for individual adherence. Higher NNRTI resistance was observed at low adherence (69% vs 13% at high adherence), while PI resistance was lower (23% vs 69% for NNRTI); multivariate analysis showed PI resistance odds rose with better adherence, whereas NNRTI resistance odds fell, and the relative fitness of drug‑resistant versus wild‑type variants at clinically relevant drug levels explained these class‑specific adherence‑resistance patterns.

Abstract

To compare the prevalence of resistance by adherence level in patients treated with non-nucleoside reverse transcriptase inhibitors (NNRTI) or protease inhibitors (PI). Also to examine the mechanism of differential class-specific adherence-resistance relationships, focusing on the patient-derived capacity of wild-type and drug-resistant recombinant variants to replicate in vitro in the presence of variable drug levels.Participants received unannounced pill count measures to assess adherence, viral load monitoring, and genotypic resistance testing. The replicative capacity of drug-susceptible and drug-resistant recombinants was determined using a single-cycle recombinant phenotypic susceptibility assay. Drug exposure was estimated using population-averaged pharmacological measurements adjusted by participant-specific levels of adherence.In the NNRTI-treated group, 69% had resistance at 0-48% adherence compared to 13% at 95-100% (P = 0.01). PI resistance was less common than NNRTI resistance at 0-48% adherence (69% versus 23%; P = 0.01). In multivariate analysis, the odds for PI resistance increased (P = 0.03) while the odds for NNRTI resistance decreased (P = 0.04) with improving adherence. Individuals with drug-resistant variants were more likely to have levels of drug exposure where the resistant variant was more fit than the drug-susceptible variant in vitro, while those with drug-susceptible virus were more likely to have levels of drug exposure where the drug-susceptible virus was more fit than the drug-resistant variant (P = 0.005).NNRTI resistance was more common than PI resistance at low levels of adherence. Class-specific adherence-resistance relationships are associated with the relative replicative capacity of drug-resistant versus wild-type variants to replicate in the presence of clinically relevant drug levels.