Abstract
Background Integrase mutations associated with dolutegravir resistance have been well characterized, but based on limited data from non-B subtypes.
Objectives We aim to identify integrase mutations not currently classified as integrase strand transfer inhibitor (INSTI) resistance mutations (DRMs) in individuals with viremia on dolutegravir-based regimens.
Methods Mutations in integrase sequences in the DTG RESIST study from African countries were detected using Stanford HIVdb v9.8. We used a viral genome-wide association study (GWAS) approach to identify mutations not classified as major or accessory INSTI DRMs but associated with dolutegravir resistance. We performed the same GWAS on drug-naïve sequences from the Los Alamos HIV-1 database to identify mutations associated with viraemia under DTG exposure.
Results Among 387 sequences, 107 (27.6%) showed at least intermediate dolutegravir resistance. Fourteen integrase mutations not classified as major or accessory DRMs (S39R, L45I, I72L, L74I, V79I, F100Y, I113V, S119R, V126A, K156N, Ǫ177L, I208M, A265V, and R284G) were significantly associated with resistance. V79I (adjusted odds ratio [aOR] 169.2, 95% credible interval [CrI] 18.2–2871.4) and I72L (aOR 67.7, 95% CrI 7.1–1326.2) were strongly associated with resistance. S39R, L45I, I72L, L74I, V79I, F100Y, S119R, and K156N were linked to established INSTI resistance pathways, and I72L, L74I, V79I, V126A, and K156N were associated with viraemia under DTG exposure.
Conclusions We identified several integrase mutations outside established DRM categories that are strongly associated with dolutegravir resistance. Dolutegravir resistance evolution is complex; likely involves mutations not currently classified as DRMs.
Competing Interest Statement
H. F. G. has received grants from the Swiss National Science Foundation, the Swiss HIV Cohort Study, the Yvonne Jacob Foundation, University of Zurich's Clinical Research Priority Program, Zurich Primary HIV Infection, Systems. X, the Bill & Melinda Gates Foundation, the US NIH, Gilead Sciences, ViiV Healthcare, and Roche; has received honoraria for advisory boards from Gilead Sciences, ViiV Healthcare, Janssen, GSK, Johnson & Johnson, and Novartis; has received honoraria for a data safety monitoring board from Merck; and has received a travel grant from Gilead Sciences. R. L. has received financial support (payment to the institution) for the present work from the NIH NIAID and has received grants (payment to institution) from the NIH NIAID for an unrelated project. R. D. K. receives grants from the Swiss National Science Foundation, the US NIH, and Gilead Sciences. All other authors: none to declare.
Funding Statement
This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID; award R01AI152772 to M. E.) and the Swiss National Science Foundation (award 32FP30_207285 to M. E. and award 324730_207957 to R. D. K. and award P5R5PM_225275 to N. A.).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The University of Bern from the Cantonal Ethics Committee of Bern (Ref. No: 2021-01504), the University of Kwazulu-Natal, South Africa (Ref No: BREC/00005146/2022), and all participating sites gave ethical approval for this work.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
Data availability
The sequence data are available in GenBank under accession numbers PV008448-PV008617, PV419540-PV419544, PV419550, PV419551, PV419554, PV419555, PV419557-PV419583, PV467483-PV467495, PV816612-PV816623, PV816625, PV816629-PV816633, PV816635-PV816650, PV816652-PV816682, PV816684, PV816687, PV816689-PV816692.
