HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis.

Background: The widespread use of the integrase strand transfer inhibitor (INSTI) dolutegravir in first-line and second-line antiretroviral therapy (ART) might facilitate emerging resistance. The DTG RESIST study combined data from HIV cohorts to examine patterns of drug resistance mutations (DRMs) and identify risk factors for dolutegravir resistance.
Methods: We included cohorts with INSTI resistance data from two collaborations (ART Cohort Collaboration, International epidemiology Databases to Evaluate AIDS in Southern Africa), and the UK Collaborative HIV Cohort. Eight cohorts from Canada, France, Germany, Italy, the Netherlands, Switzerland, South Africa, and the UK contributed data on individuals who were viraemic on dolutegravir-based ART and underwent genotypic resistance testing. Individuals with unknown dolutegravir initiation date were excluded. Resistance levels were categorised using the Stanford algorithm. We identified risk factors for resistance using mixed-effects ordinal logistic regression models.
Findings: We included 599 people with genotypic resistance testing on dolutegravir-based ART between May 22, 2013, and Dec 20, 2021. Most had HIV-1 subtype B (n=351, 59%), a third had been exposed to first-generation INSTIs (n=193, 32%), 70 (12%) were on dolutegravir dual therapy, and 18 (3%) were on dolutegravir monotherapy. INSTI DRMs were detected in 86 (14%) individuals; 20 (3%) had more than one mutation. Most (n=563, 94%) were susceptible to dolutegravir, seven (1%) had potential low, six (1%) low, 17 (3%) intermediate, and six (1%) high-level dolutegravir resistance. The risk of dolutegravir resistance was higher on dolutegravir monotherapy (adjusted odds ratio [aOR] 34·1, 95% CI 9·93-117) and dolutegravir plus lamivudine dual therapy (aOR 9·21, 2·20-38·6) compared with combination ART, and in the presence of potential low or low (aOR 5·23, 1·32-20·7) or intermediate or high-level (aOR 13·4, 4·55-39·7) nucleoside reverse transcriptase inhibitor (NRTI) resistance.
Interpretation: Among people with viraemia on dolutegravir-based ART, INSTI DRMs and dolutegravir resistance were rare. NRTI resistance substantially increased the risk of dolutegravir resistance, which is of concern, notably in resource-limited settings. Monitoring is important to prevent resistance at the individual and population level and ensure the long-term sustainability of ART.
Funding: US National Institutes of Health, Swiss National Science Foundation.
Competing Interests: Declaration of interests SMI reports grant funding from the US National Institutes of Health (NIH) National Institute on Alcohol Abuse and Alcoholism for the work of ART-CC (payment to institution). AvS reports funding from the Dutch Ministry of Health, Welfare and Sport for the maintenance of the ATHENA database, and grant funding from the European Centre for Disease Prevention and Control (payment to institution). MJG reports honoraria as an ad-hoc member of HIV National Advisory Boards from Merck, Gilead Sciences, and ViiV, and a leadership position as Medical Director of the Southern Alberta HIV Clinic. CAS has received funding from Gilead Sciences, ViiV Healthcare, and Janssen-Cilag for membership of Data Safety and Monitoring Committees and Advisory Committees and for preparation of educational material. HFG has received personal fees from Merck, Gilead Sciences, ViiV, GSK, Janssen, Johnson and Johnson, and Novartis, as an advisor or consultant or for Data Safety Monitoring Board membership, and has received a travel grant from Gilead. JACS reports funding for research in this publication from the NIH National Institute on Alcohol Abuse and Alcoholism (payment to institution), UK National Institute for Health and Care Research (payment to institution), and the University of Bern (payment to institution). RL reports support for research in this publication by the NIH National Institute of Allergy and Infectious Diseases under award number R01AI152772, and support from the NIH National Institute of Allergy and Infectious Diseases under award number R01AI167699 for a separate project pertaining to HIV treatment strategies. ME reports funding for research in this publication from the Swiss National Science Foundation (32FP30-18949) and the NIH (Cooperative Agreement AI069924 and R01 AI152772-01). RDK reports funding for research in this publication from the Swiss National Science Foundation and the NIH National Institute of Allergy and Infectious Diseases, and reports grant funding from Gilead Sciences. All other authors declare no competing interests.
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