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.

HIV-1 Subtype C Drug Resistance Mutations in Heavily Treated Patients Failing Integrase Strand Transfer Inhibitor-Based Regimens in Botswana

“…For the 68% of participants with VF while on DTG/INSTI based regimens but devoid of INSTI DRMs, we did not assess for other mutations in nef, reverse transcriptase and protease genes that could contribute to VF [32,33].…”

Short Communication: Integrase Strand Transfer Inhibitors Drug Resistance Mutations in Puerto Rico HIV-Positive Individuals

“…A recent study established that drug susceptibility and viral fitness may be affected by potential cross-class mutational interactions. Siedner et al observed that non-nucleoside reverse transcriptase inhibitor resistance before treatment with HIV-1 integrase inhibitors is associated with the long-term failure of integrase-inhibitor-containing first-line regimens [ 50 ].…”

CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations—Implication for Drug Safety, Dosing, and Individualized Therapy

“…Therefore, long term use of DTG is still under concern (Kouanfack et al, 2019 ; Bourgi et al, 2020 ; Sax et al, 2020 ). A recent communication in December 2020 by Siedner et al found that patients with drug resistant mutation in the reverse transcriptase are unlikely to benefit from the HIV integrase inhibitor DTG (Siedner et al, 2020 ). That implies EFV and NVP might still be in use for specific group of patients (Vitoria et al, 2018 ).…”