Accumulation of drug resistance and loss of therapeutic options precede commonly used criteria for treatment failure in HIV-1 subtype-C-infected patients

Background: Virological monitoring is essential to identify antiretroviral treatment (ART) failure, but not widely available. Here, accumulation of resistance and consequences for second-line therapy were investigated in African HIV-1 subtype-C-infected patients. Methods: A total of 836 patients initiated non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART and received biannual HIV RNA monitoring. When first-line ART was continued despite virological failure (HIV RNA>1,000 copies/ml), genotypic resistance analysis was performed at baseline, first failure (t1), and 6 or 12 months later (t2). Major resistance mutations (IAS), Stanford genotypic sensitivity scores (GSSs) and proportions of patients meeting WHO-defined failure criteria were compared between time points. Results: Most patients (642/836, 77%) reached viral suppression and 145/642 patients (23%) experienced subsequent failure after a median of 18 months. Counselling resulted in virological re-suppression in 27% (39/145) and 40% (58/145) continued first-line ART despite virological failure; 26 patients were included for genotypic analysis. The mean number of major drug resistance mutations per person increased from 2.8 (t1) to 4.3 (t2). Initially, NNRTI-associated mutations (n=47) predominated; only 25 nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations (mainly M184V) were detected. During prolonged viraemia, NRTI resistance increased (n=44, +76%), in particular thymidine analogue mutations (from 4 to 14) and K65R (from 3 to 6). Consequently, GSSs declined from baseline to t1 and t2: from 3.8 to 1.0 to 0.7 (NNRTIs) and from 6.8 to 5.1 to 4.0 (NRTIs). Despite broad resistance, immunological failure was limited at t2. Conclusions: Rapid accumulation of drug resistance occurred when ART was continued despite virological failure. Treatment options were lost, even when WHO-defined failure criteria were not met. This study calls for wider access to virological monitoring.