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HIV drug resistance to integrase inhibitors in low- and middle-income countries

Nature Medicine volume 30, pages 618–619 (2024)Cite this article

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Dolutegravir (DTG)-based antiretroviral therapy (ART) is the cornerstone of HIV treatment in low- and middle-income countries (LMICs), recommended by the World Health Organization (WHO) for use in both first- and second-line treatment. This follows evidence from clinical trials showing better efficacy and safety when compared with previously recommended regimens1. DTG-based ART has led to an increased number of people living with HIV achieving viral suppression, raising hope that the epidemic control can be attained. Failure of DTG treatment was rarely accompanied by the emergence of drug resistance mutations in clinical studies of ART-naive populations2,3. Clinical trials conducted over 48–96 weeks showed very low risks (0.1%) of emergent resistance on first-line treatments, and low rates (0.6–3.8%) of emergent resistance on second-line DTG-containing regimens, with higher risks in children and settings in which ART selection was not guided by genotyping2. Although these findings are encouraging, they show that without adequate monitoring, there might be an earlier selection of DTG resistance, especially for those who transitioned or switched to DTG without viral suppression1. Surveillance of integrase strand-transfer inhibitor (INSTI)-associated mutations in LMICs that are transitioning to DTG-containing regimens is needed to monitor virological failure and acquired DTG resistance in routine clinical settings.

A recent review assessing DTG resistance among INSTI-naive individuals in 36 studies globally identified 99 individuals with resistance. Of these, 49.5% were on ART and receiving DTG plus two nucleoside reverse-transcriptase inhibitors (NRTIs), 11.1% were on ART (with viral suppression) and had switched to DTG monotherapy, 15.2% were ART-naive viremic individuals receiving DTG plus two NRTIs or DTG plus 3TC, and 24.2% were receiving other ART combinations. The study identified four major pathways of DTG resistance: R263K (n = 40); G118R (n = 24); N155H (n = 9); and Q148H/R/K (n = 9). Phenotypic data have shown that these mutations affect DTG efficacy; in terms of resistance, R263K, Q148HRK and N155H lead to a 2.0-, 1.4- and 0.8-fold reduction in DTG susceptibility if considered alone4,5,6. At the same time, the mutations also affect viral replication. At the time of writing, G118R has the highest impact in decreasing integration activity and replicative capacity4.

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Acknowledgements

N.N. is supported by the US NIH/NIAID R01 AI147331-02 and J.F. is supported by EDCTP RIA2020-EF3000.

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Authors and Affiliations

  1. Chantal BIYA International Reference Centre for research on HIV/AIDS prevention and management, Yaoundé, Cameroon

    Joseph Fokam & Carlo-Federico Perno

  2. Faculty of Health Sciences, University of Buea, Buea, Cameroon

    Joseph Fokam

  3. National HIV Drug Resistance Group, Ministry of Public Health, Yaoundé, Cameroon

    Joseph Fokam

  4. Faculty of Medicine and Biomedical Sciences, University of Yaoundé-I, Yaoundé, Cameroon

    Joseph Fokam

  5. Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands

    Seth Inzaule

  6. UNESCO Board of Biotechnology, University of Rome Tor Vergata, Rome, Italy

    Vittorio Colizzi

  7. Bambino Gesù IRCCS Pediatric Hospital, Rome, Italy

    Carlo-Federico Perno

  8. Africa Centres for Disease Control and Prevention, Addis Ababa, Ethiopia

    Jean Kaseya & Nicaise Ndembi

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

    Nicaise Ndembi

  10. Kanazawa University, Graduate School of Medical Sciences, Ishikawa, Japan

    Nicaise Ndembi

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  1. Joseph Fokam
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  5. Jean Kaseya
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Correspondence to Nicaise Ndembi.

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C.-F.P. has participated in boards, gave speeches at sponsored events, and/or received grants from Gilead, ViiV, GSK, Janssen, Astra Zeneca, Merck and Pfizer.

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Fokam, J., Inzaule, S., Colizzi, V. et al. HIV drug resistance to integrase inhibitors in low- and middle-income countries. Nat Med 30, 618–619 (2024). https://doi.org/10.1038/s41591-023-02763-0

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