Baseline integrase drug resistance mutations and conserved regions across HIV-1 clades in Cameroon: implications for transition to dolutegravir in resource-limited settings.

Ezechiel Ngoufack Jagni Semengue, Daniele Armenia, Seth Inzaule, Maria Mercedes Santoro, Béatrice Dambaya, Désiré Takou, Georges Teto, Alex Durand Nka, Bouba Yagai, Lavinia Fabeni, Collins Chenwi, Grâce Angong Beloumou, Sandrine Claire Djupsa Ndjeyep, Vittorio Colizzi, Carlo-Federico Perno, Francesca Ceccherini-Silberstein, Joseph Fokam

Journal: The Journal of antimicrobial chemotherapy 2021;76(5):1277-1285

PMID: 33501504

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Abstract

BACKGROUND

Transition to dolutegravir-based regimens in resource-limited settings (RLS) requires prior understanding of HIV-1 integrase variants and conserved regions. Therefore, we evaluated integrase drug resistance mutations (DRMs) and conserved regions amongst integrase strand transfer inhibitor (INSTI)-naive patients harbouring diverse HIV-1 clades in Cameroon.

METHODS

A cross-sectional study was conducted amongst 918 INSTI-naive patients from Cameroon (89 ART-naive and 829 ART-experienced patients). HIV-1 sequences were interpreted regarding INSTI-DRMs using the Stanford HIVdb v8.9-1 and the 2019 IAS-USA list. Amino acid positions with <1% variability were considered as highly conserved. Subtyping was performed by phylogeny.

RESULTS

Overall prevalence (95% CI) of INSTI-DRMs was 0.8% (0.4-1.7), with 0.0% (0.0-4.0) amongst ART-naive versus 0.9% (0.5-1.9) amongst ART-experienced patients; P = 0.44. Accessory mutations (95% CI) were found in 33.8% (30.9-37.0), with 38.2% (28.1-49.1) amongst ART-naive versus 33.4% (30.4-36.7) amongst ART-experienced patients; P = 0.21. Of 288 HIV-1 integrase amino acid positions, 58.3% were highly conserved across subtypes in the following major regions: V75-G82, E85-P90, H114-G118, K127-W132, E138-G149, Q168-L172, T174-V180, W235-A239 and L241-D253. Wide genetic diversity was found (37 clades), including groups M (92.3%), N (1.4%), O (6.2%) and P (0.1%). Amongst group M, CRF02_AG was predominant (47.4%), with a significantly higher frequency (95% CI) of accessory mutations compared with non-AG [41.4% (36.8-46.0) versus 27.1% (23.3-31.2) respectively; P < 0.001].

CONCLUSIONS

The low baseline of INSTI-DRMs (<1%) in Cameroon suggests effectiveness of dolutegravir-based regimens. In spite of high conservation across clades, the variability of accessory mutations between major circulating strains underscores the need for monitoring the selection of INSTI-DRMs while scaling up dolutegravir-based regimens in RLS.

Address: Virology Laboratory, Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management (CIRCB), Yaoundé, Cameroon.; Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.; Evangelical University of Cameroon, Bandjoun, Cameroon.; Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.; Saint Camillus International University of Health and Medical Sciences, Rome, Italy.; Department of Global Health, Academic Medical Center of the University of Amsterdam and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands.; Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.; Virology Laboratory, Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management (CIRCB), Yaoundé, Cameroon.; Faculty of Sciences, University of Yaoundé I, Yaoundé, Cameroon.; Virology Laboratory, Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management (CIRCB), Yaoundé, Cameroon.; Virology Laboratory, Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management (CIRCB), Yaoundé, Cameroon.; Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.; Laboratory of Virology, National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy.; Virology Laboratory, Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management (CIRCB), Yaoundé, Cameroon.; Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon.; Virology Laboratory, Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management (CIRCB), Yaoundé, Cameroon.; Bambino Gesu Children's Hospital, IRCCS, Rome, Italy.; Virology Laboratory, Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management (CIRCB), Yaoundé, Cameroon.; Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon.; National HIV Drug Resistance Working Group, Ministry of Public Health, Cameroon.; Faculty of Health Sciences, University of Buea, Buea, Cameroon.

DOI: 10.1093/jac/dkab004

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MeSH Terms: Cameroon, Cross-Sectional Studies, Drug Resistance, Viral, Genotype, HIV Infections, HIV Integrase, HIV Integrase Inhibitors, HIV-1, Heterocyclic Compounds, 3-Ring, Humans, Mutation, Oxazines, Piperazines, Pyridones