Low prevalence of archived integrase strand transfer inhibitors resistance associated mutations in Botswana before the roll out of dolutegravir based first line antiretroviral therapy

Dorcas Maruapula; Doreen Ditshwanelo; Marea N Pema; Ontlametse T Bareng; Wonderful T Choga; Natasha O Moraka; Patrick T Mokgethi; Kaelo K Seatla; Catherine K Koofhethile; Boitumelo J Zuze; Tendani Gaolathe; Molly Pretorius-Holme; Kebaneilwe Lebani; Joseph Makhema; Vlad Novitsky; Roger Shapiro; Shahin Lockman; Sikhulile Moyo; Simani Gaseitsiwe

doi:10.3389/fmicb.2024.1482348

Low prevalence of archived integrase strand transfer inhibitors resistance associated mutations in Botswana before the roll out of dolutegravir based first line antiretroviral therapy

Front Microbiol. 2024 Oct 24:15:1482348. doi: 10.3389/fmicb.2024.1482348. eCollection 2024.

Authors

Dorcas Maruapula¹, Doreen Ditshwanelo¹, Marea N Pema¹, Ontlametse T Bareng^{1

2}, Wonderful T Choga^{1

2}, Natasha O Moraka^{1

2}, Patrick T Mokgethi^{1

3}, Kaelo K Seatla¹, Catherine K Koofhethile^{1

4}, Boitumelo J Zuze¹, Tendani Gaolathe¹, Molly Pretorius-Holme⁴, Kebaneilwe Lebani⁵, Joseph Makhema^{1

4}, Vlad Novitsky¹, Roger Shapiro^{1

4}, Shahin Lockman^{1

4

6}, Sikhulile Moyo^{1

4

7}, Simani Gaseitsiwe^{1

4}

Affiliations

¹ Botswana Harvard Health Partnership, Gaborone, Botswana.
² Faculty of Health Sciences, Medical Laboratory Sciences, University of Botswana, Gaborone, Botswana.
³ Department of Biological Sciences, University of Botswana, Gaborone, Botswana.
⁴ Department of Immunology and Infectious Diseases, Harvard University T.H Chan School of Public Health, Boston, MA, United States.
⁵ Department of Biological Sciences and Biotechnology, Botswana International University of Science and Technology, Palapye, Botswana.
⁶ Division of Infectious Disease, Brigham and Women's Hospital, Boston, MA, United States.
⁷ School of Health Systems and Public Health, Faculty of Sciences, University of Pretoria, Pretoria, South Africa.

Abstract

Background: We evaluated the prevalence of archived proviral drug resistance mutations (DRMs) associated with resistance to integrase strand transfer inhibitors (INSTIs) shortly before Botswana transitioned in 2016 to using dolutegravir (DTG)-based antiretroviral treatment in first-line regimens.

Methods: We used the Stanford University HIV drug resistance database to analyze INSTI-resistance associated mutations (RAMs) in a large representative population-based cohort of adults recruited in 30 geographically dispersed communities as part of the Botswana Combination Prevention Project (BCPP) cohort from 2013 to 2018. A total of 5,144 HIV-1 proviral DNA sequences were included in our analysis; 1,281 sequences were from antiretroviral therapy (ART)-naïve individuals and 3,863 sequences were from non-nucleoside reverse transcriptase inhibitor (NNRTI) ART-experienced individuals. None of the sequences were from DTG-ART experienced participants.

Results: The overall prevalence of major INSTIs DRMs was 1.11% (95% CI 0.82-1.39%). The prevalence of INSTI DRMs in ART-naïve individuals was 1.64% (21/1,281) and 0.93% (36/3,863) in ART-experienced individuals. Major INSTI-RAMs detected in ART-naïve individuals were E138K (2/1,281; 0.16%), G140R (8/1,281;0.62%), E92G (2/1,281;0.16%), R263K (5/1,281; 0.4%), N155H (1/1,281; 0.08%), P145S (1/1,281;0.008%). Among the ART-experienced individuals, major INSTI RAMs detected were E138K (4/3,863; 0.10%), G140R (25/3,863;0.65%), G118R (2/3,863, 0.05%), R263K (4/3,863, 0.10%), T66I (1/3,863;0.03%), E138K + G140R (1/3,863, 0.03%|), G140R + R263K (1/3,863, 0.03%). High-level resistance to cabotegravir (CAB), elvitegravir (EVG), and raltegravir (RAL) was detected in 0.70, 0.16 and 0.06% of the individuals, respectively. Notably, bictegravir (BIC) and dolutegravir (DTG) showed no high-level resistance.

Conclusion: The overall prevalence of archived INSTI RAMs in Botswana was low prior to transitioning to first-line DTG-based ART regimens, and did not differ between ART-naïve and ART-experienced individuals. Ongoing surveillance of INSTI DRMs in Botswana will allow for re-assessment of INSTI resistance risk following nationwide DTG rollout.

Keywords: Botswana; HIV; HIV drug resistance mutations; antiretroviral therapy; integrase strand transfer inhibitor.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The BCPP Impact Evaluation was funded by the President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC, cooperative agreements U01 GH000447 and U2G GH001911). DM, SG, SM, WTC and NOM are partly supported through the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE 2.0) from the Bill & Melinda Gates Foundation (INV-033558). DM, OTB and NOM are supported by the Fogarty International Center at the US National Institutes of Health Award (D43 TW009610). SM is partially supported by the Fogarty International Center at the US National Institutes of Health Award (K43TW012350-01). WTC and SG are supported partly by NIH (award number 1G11TW012503-01). SM, DD, and OTB were supported by the Trials of Excellence in Southern Africa (TESA III), which is part of the EDCTP2 program supported by the European Union (CSA2020NoE-3104 TESAIII). KKS is supported by an Africa Research Excellence Fund Research Development Fellowship (reference AREF-312-SEAT-F-C0927). The views expressed in this publication are those of the authors and not necessarily those of the funding agencies. The funders had no role in the study design, data collection, decision The BCPP project was approved by both the US Centers for Disease Control and Prevention’s Institutional Review Board (IRB) and the Botswana IRB (HRDC). This study has been filled on ClinicalTrials.gov as NCT01965470. Study participants involved in the research provided written informed consent for their samples to be used in future studies. The views expressed in this publication are those of the authors and not necessarily those of the European Union, EDCTP, NIH, Bill & Melinda Gates Foundation or the UK government. The funders had no role in the study design, data collection and decision to publish, or in the preparation of the manuscript.