HIV-1 drug resistance in people on dolutegravir-based ART: Collaborative analysis of cohort studies
Authors: Loosli Tom , Hossmann Stefanie , Ingle Suzanne M. , Okhai Hajra , Kusejko Katharina , Mouton Johannes , Bellecave Pantxika , van Sighem Ard , Stecher Melanie , Monforte Antonella d’Arminio , Gill M. John , Sabin Caroline A. , Maartens Gary , Günthard Huldrych F. , Sterne Jonathan A. C. , Lessells Richard , Egger Matthias , Kouyos Roger 
Published: April 2023

SummaryBackgroundThe 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.MethodsEight 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.ResultsWe 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 log10area under the viral load curve).InterpretationAmong 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.FundingUS National Institutes of Health, Swiss National Science Foundation.Research in contextEvidence before this studyWe searched SCOPUS on 20 March 2023 for all publications from inception using the terms “dolutegravir” or “DTG”, “resistant” or “resistance”, and “HIV”. The available evidence on resistance evolution in people living with HIV (PLHIV) with virological failure on DTG-based ART is limited. Most studies assessed the efficacy of DTG-based regimens in clinical studies and reported drug resistance in individuals experiencing virological failure as a secondary objective or reported single or multiple cases of patients developing resistance on DTG-based ART. Clinical trials such as the NADIA trial showed a high degree of viral suppression even in people with NRTI resistance. Consequently, previous analyses included only a small number of people experiencing failure on DTG; the SINGLE trial with 39 people with virologic failure on DTG was the largest. The highest number of individuals with DTG resistance was nine study participants in the NADIA trial. There is evidence that DTG resistance in PLHIV on a DTG monotherapy may be more likely. Other studies suggest that HIV subtype and mutations acquired during a first-generation INSTI-based regimen might affect the risk of DTG resistance.Added value of this studyTo our knowledge, this is the first study systematically investigating resistance in PLHIV experiencing virologic failure on DTG-based ART using a multi-cohort collaboration design reflecting real-world routine care. We collected genotypic resistance tests and clinical data from eight observational HIV cohorts. This resulted in a large dataset of PLHIV experiencing virologic failure on a DTG regimen (over 700 individuals). It allowed a robust assessment of drug resistance mutations and risk factors for DTG resistance. Cross-resistance of first-generation INSTIs does not appear to explain the mutation patterns in HIV-infected individuals who experience virological failure on DTG-based ART regimens. PLHIV who received DTG monotherapy or DTG lamivudine dual therapy and those infected with non-B subtypes were more likely to develop resistance. Resistance to NRTIs was a major risk factor for DTG resistance, indicating that PLHIV receiving functional monotherapy are more likely to develop DTG resistance.Implications of all the available evidenceHIV drug resistance is a significant threat to the sustainability of current and future antiretroviral therapy for combating the ongoing HIV pandemic. Our collaborative analysis shows that cases of DTG resistance are so far rare but not negligible. Given the global DTG roll-out, this might lead to increased frequencies and transmission of DTG resistance, particularly in PLHIV with resistance to NRTIs. While the evidence regarding subtype differences is tentative, it indicates that non-B subtypes, which are most relevant for the global roll-out of DTG, might be associated with an increased risk of resistance.