Authors: Loosli T, Hossmann S, Ingle SM, Okhai H, Kusejko K, Mouton J, Bellecave P, van Sighem A, Stecher M, Monforte AD, Gill MJ, Sabin CA, Maartens G, GŁnthard HF, Sterne JAC, Lessells R, Egger M, Kouyos R
Background: The widespread use of the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) in first- and second-line antiretroviral therapy (ART) may facilitate emerging resistance. We combined data from HIV cohorts to examine patterns of drug resistance mutations (DRMs) and identify risk factors for DTG resistance.
Methods: Eight cohorts from Canada, Europe, and South Africa contributed data on individuals with genotypic resistance testing on DTG-based ART. Resistance levels were categorised using the Stanford algorithm. We identified risk factors for resistance using mixed-effects ordinal logistic regression models.
Results: We included 750 people with genotypic resistance testing on DTG-based ART between 2013 and 2022. Most had HIV subtype B (N=444, 59∑2%) and were treatment-experienced; 134 (17.9%) were on DTG dual and 19 (2.5%) on DTG monotherapy. INSTI DRMs were detected in 100 (13∑3%) individuals; 21 (2∑8%) had more than one mutation. Most (N=713, 95∑1%) were susceptible to DTG, 8 (1∑1%) had potential-low, 5 (0∑7%) low, 18 (2∑4%) intermediate and 6 (0∑8%) high-level DTG resistance. The risk of DTG resistance was higher on DTG monotherapy (adjusted odds ratio (aOR) 37∑25, 95% CI 11∑17 to 124∑2) and DTG lamivudine dual therapy (aOR 6∑59, 95% CI 1∑70 to 25∑55) compared to combination ART, and higher in the presence of potential-low/low (aOR 4.62, 95% CI 1.24 to 17.2) or intermediate/high-level (aOR 7∑01, 95% CI 2∑52 to 19∑48) nucleoside reverse transcriptase inhibitors (NRTI) resistance. Viral load on DTG showed a trend towards increased DTG resistance (aOR 1∑42, 95% CI 0∑92 to 2∑19 per standard deviation of log 10 area under the viral load curve).
Interpretation: Among people experiencing virological failure on DTG-based ART, INSTI DRMs were uncommon, and DTG resistance was rare. DTG monotherapy and NRTI resistance substantially increased the risk for DTG resistance, which is of concern, notably in resource-limited settings.