Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

Abstract

Little is known about the impact of pretreatment drug resistance (PDR) on the efficacy of second generation integrase inhibitors. We sequenced pretreatment plasma specimens from the ADVANCE trial (NCT03122262). Our primary outcome was 96-week virologic success, defined as a sustained viral load <1000 copies/mL from 12 weeks onwards, <200 copies/mL from 24 weeks onwards, and <50 copies/mL after 48 weeks. Here we report how this outcome was impacted by PDR, defined by the World Health Organization (WHO) mutation list. Of 1053 trial participants, 874 (83%) have successful sequencing, including 289 (33%) randomized to EFV-based therapy and 585 (67%) randomized to DTG-based therapy. Fourteen percent (122/874) have ≥1 WHO-defined mutation, of which 98% (120/122) are NNRTI mutations. Rates of virologic suppression are lower in the total cohort among those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001), and for those on EFV-based treatment (60% [12/20] vs 86% [214/248], P = 0.002) and for those on DTG-based treatment (61/92 [66%] vs 84% [391/465] P < 0.001, P for interaction by regimen 0.49). Results are similar in multivariable models adjusted for clinical characteristics and adherence. NNRTI resistance prior to treatment is associated with long-term failure of integrase inhibitor-containing first-line regimens, and portends high rates of first-line failure in sub Saharan Africa.

Conflict of interest statement

R.K.G. has received ad hoc consulting fees from Gilead, ViiV and UMOVIS Lab. W.D.F.V. received drug donations from ViiV Healthcare and Gilead Sciences for investigator-led clinical studies, including ADVANCE. In addition, he receives honoraria for talks and board membership for: Gilead, ViiV, Mylan, Merck, Adcock-Ingram, Aspen, Abbott, Roche, J&J. M.A.M. received drug donations from ViiV Healthcare and Gilead Sciences for investigator-led clinical studies, including ADVANCE. In addition, she received honoraria for talks and board membership for: Gilead, ViiV, Mylan, Aspen, AbbVie, Johnson & Johnson, Sanofi, Pfizer and Southern African HIV Clinicians Society. She also received meeting/conference sponsorship from Johnson and Johnson, BD, Gilead, Merck, Cipla, Mylan and Canopy Growth. No other authors have any conflict of interest.

Figures

Fig. 1. Study schema.

Study schema showing numbers of participants with plasma samples, successful sequencing and numbers in primary and secondary outcomes.

Fig. 2. Distribution of WHO-defined pretreatment drug resistance in the ADVANCE trial, using the WHO Surveillance Drug Mutations list for mutations detected at >20% of the viral quasispecies.

Error bars indicate 95% confidence intervals around the proportion estimates.

Fig. 3. Virologic success in the ADVANCE Trial divided by the presence or absence of WHO-defined pretreatment major drug mutations and by use of efavirenz- or dolutegravir-based regimen.

Results are for virologic success defined by our primary outcome (a), secondary outcome (b), FDA 48-week Snapshot (c), and FDA 96-week Snapshot (d). Error bars indicate 95% confidence intervals around the proportion estimates. P values represent results of two-sided two-proportion Z tests.

Fig. 4. 96-week treatment outcomes among participants in the ADVANCE Trial divided by treatment arm, presence or absence of WHO-defined pretreatment drug resistance, and achievement of greater than vs less than 95% adherence based on pharmacy pill count.

Error bars represent 95% confidence intervals of the proportion estimates.