Limited emergence of resistance to integrase strand transfer inhibitors (INSTIs) in ART-experienced participants failing dolutegravir-based antiretroviral therapy: a cross-sectional analysis of a Northeast Nigerian cohort

Author:

Abdullahi Adam123ORCID,Kida Ibrahim Musa4,Maina Umar Abdullahi5,Ibrahim Amina Husaini6,Mshelia James4,Wisso Haruna3,Adamu Abdullahi5,Onyemata James Ezenwa3,Edun Martin3,Yusuph Haruna4,Aliyu Sani H7ORCID,Charurat Man8,Abimiku Alash’le3,Abeler-Dorner Lucie9,Fraser Christophe9,Bonsall David9,Abeler-Dörner Lucie,Ayles Helen,Bonsall David,Bowden Rory,Calvez Vincent,Essex Max,Fidler Sarah,Fraser Christophe,Grabowski Kate,Golubchik Tanya,Gupta Ravindra,Hayes Richard,Herbeck Joshua,Kagaayi Joseph,Kaleebu Pontiano,Lingappa Jairam,Moyo Sikhulile,Novitsky Vladimir,Ndung'u Thumbi,Pillay Deenan,Quinn Thomas,Rambaut Andrew,Ratmann Oliver,Seeley Janet,Ssemwanga Deogratius,Tanser Frank,Wawer Maria,Cohen Myron,D'Oliveira Tulio,Dennis Ann,Essex Max,Fidler Sarah,Frampton Dan,Fraser Christophe,Golubchik Tanya,Hayes Richard,Herbeck Josh,Hoppe Anne,Kaleebu Pontiano,Kellam Paul,Kityo Cissy,Leigh-Brown Andrew,Lingappa Jairam,Novitsky Vladimir,Paton Nick,Pillay Deenan,Quinn Tom,Ratmann Oliver,Ssemwanga Deogratius,Tanser Frank,Wawer Maria,Kemp Steven A129,Gupta Ravindra K1210ORCID,

Affiliation:

1. Department of Medicine, Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID) , Cambridge , UK

2. Department of Medicine, University of Cambridge , Cambridge , UK

3. Institute of Human Virology Nigeria , Abuja , Nigeria

4. Department of Infectious Disease and Clinical Immunology, University of Maiduguri , Borno , Nigeria

5. Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Maiduguri , Borno , Nigeria

6. Federal Medical Centre , Abuja , Nigeria

7. Department of Microbiology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust , Cambridge , UK

8. Institute of Human Virology, University of Maryland School of Medicine , Baltimore , USA

9. Nuffield Department of Medicine, Big Data Institute, University of Oxford , Oxford , UK

10. Africa Health Research Institute , Durban , South Africa

Abstract

Abstract Background Due to the high prevalence of resistance to NNRTI-based ART since 2018, consolidated recommendations from the WHO have indicated dolutegravir as the preferred drug of choice for HIV treatment globally. There is a paucity of resistance outcome data from HIV-1 non-B subtypes circulating across West Africa. Aims We characterized the mutational profiles of persons living with HIV from a cross-sectional cohort in North-East Nigeria failing a dolutegravir-based ART regimen. Methods WGS of plasma samples collected from 61 HIV-1-infected participants following virological failure of dolutegravir-based ART were sequenced using the Illumina platform. Sequencing was successfully completed for samples from 55 participants. Following quality control, 33 full genomes were analysed from participants with a median age of 40 years and median time on ART of 9 years. HIV-1 subtyping was performed using SNAPPy. Results Most participants had mutational profiles reflective of exposure to previous first- and second-line ART regimens comprised NRTIs and NNRTIs. More than half of participants had one or more drug resistance-associated mutations (DRMs) affecting susceptibility to NRTIs (17/33; 52%) and NNRTIs (24/33; 73%). Almost a quarter of participants (8/33; 24.4%) had one or more DRMs affecting tenofovir susceptibility. Only one participant, infected with HIV-1 subtype G, had evidence of DRMs affecting dolutegravir susceptibility—this was characterized by the T66A, G118R, E138K and R263K mutations. Conclusions This study found a low prevalence of resistance to dolutegravir; the data are therefore supportive of the continual rollout of dolutegravir as the primary first-line regimen for ART-naive participants and the preferred switch to second-line ART across the region. However, population-level, longer-term data collection on dolutegravir outcomes are required to further guide implementation and policy action across the region.

Funder

Africa Research Excellence Fund Research Development Fellowship

Bill and Melinda Gates Foundation

PANGEA

NIH

Wellcome Trust Senior Fellowship in Clinical Science

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology,Microbiology (medical)

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