Increasing prevalence of pretreatment HIV drug resistance (PDR) has motivated guideline changes to avoid non-nucleoside reverse transcriptase (NNRTI)-based first-line antiretroviral therapy (ART) regimens. Empiric data on the performance of ART regimens in the face of PDR are lacking in sub-Saharan Africa.
The ADVANCE study is a randomized controlled trial in South Africa that compares efavirenz (EFV) with dolutegravir (DTG), both with two NNRTIs, as first-line ART. We performed pre-treatment genotypic drug resistance testing in 197 randomly selected participants with next generation sequencing using the Illumina platform at KRISP and set detection thresholds for resistant variants at >20%, 5-20%, 2-5%. For our primary outcome, we compared the proportion of individuals who achieved virologic suppression (<40 copies/mL) at 48-weeks with EFV versus DTG-based ART, by presence or absence of PDR at 20% threshold, defined with the WHO drug resistance mutation (DRM) list. In secondary analyses, we assessed the effect of resistance at 2 and 5% thresholds on outcomes and the effect of PDR on treatment failure, redefined as virologic failure, death or loss from observation.
We successfully sequenced pre-treatment HIV RNA from 165 individuals, of whom 48 (29%) received EFV and 117 (71%) received DTG. Twenty of 165 (12%) had ≥1 DRMs, with no difference in PDR by study arm, sex (56% female), age (median 32 years) or pre-treatment CD4 count (median 284). The most common mutation was K103N (9%); K65R and M184V were both found in only 2 (1%) of individuals. The proportion achieving our primary outcome was similar in the EFV (36/40, 90%) and DTG groups (93/101, 91%), P=0.69. However, rates of confirmed virologic suppression among those with and without PDR was 25% (1/4) and 97% (35/36) in the EFV-arm, and 89% (8/9) and 92% (85/93) in the DTG arms, respectively (P<0.001 for interaction between PDR and treatment arm). These trends were similar when redefining PDR thresholds at 2-5% and 5-20%, and when redefining failure to include death and loss from observation.
PDR, primarily to NNRTIs, was associated with significantly diminished efficacy of EFV-based, but not DTG-based three drug ART in South Africa. These data support the use of integrase inhibitors as initial therapy in individuals with known drug resistance or in populations with a very high prevalence of circulating NNRTI PDR.