Doravirine-associated resistance mutations in antiretroviral therapy naïve and experienced adults with HIV-1 subtype C infection in Botswana

Ontlametse T Bareng, Sekgabo Seselamarumo, Kaelo K Seatla, Wonderful T Choga, Blessing Bakae, Dorcas Maruapula, Nametso Kelentse, Natasha O Moraka, Baitshepi Mokaleng, Patrick T Mokgethi, Tsotlhe R Ditlhako, Molly Pretorius-Holme, Mpaphi B Mbulawa, Refeletswe Lebelonyane, Ebi Celestin Bile, Tendani Gaolathe, Roger Shapiro, Joseph M Makhema, Shahin Lockman, Max Essex, Vlad Novitsky, Sununguko W Mpoloka, Sikhulile Moyo, Simani Gaseitsiwe, Ontlametse T Bareng, Sekgabo Seselamarumo, Kaelo K Seatla, Wonderful T Choga, Blessing Bakae, Dorcas Maruapula, Nametso Kelentse, Natasha O Moraka, Baitshepi Mokaleng, Patrick T Mokgethi, Tsotlhe R Ditlhako, Molly Pretorius-Holme, Mpaphi B Mbulawa, Refeletswe Lebelonyane, Ebi Celestin Bile, Tendani Gaolathe, Roger Shapiro, Joseph M Makhema, Shahin Lockman, Max Essex, Vlad Novitsky, Sununguko W Mpoloka, Sikhulile Moyo, Simani Gaseitsiwe

Abstract

Objectives: There are limited data on the prevalence of doravirine (DOR)-associated drug resistance mutations in people with HIV (PWH) in Botswana. This cross-sectional, retrospective study aimed to explore the prevalence of DOR-associated resistance mutations among ART-naïve and -experienced PWH in Botswana enrolled in the population-based Botswana Combination Prevention Project (BCPP).

Methods: A total of 6078 HIV-1C pol sequences were analysed for DOR-associated resistance mutations using the Stanford HIV drug resistance database, and their levels were predicted according to the Stanford DRM penalty scores and resistance interpretation. Virologic failure was defined as HIV-1 RNA load (VL) >400 copies/mL.

Results: Among 6078 PWH, 5999 (99%) had known ART status, and 4529/5999 (79%) were on ART at time of sampling. The suppression rate among ART-experienced was 4517/4729 (96%). The overall prevalence of any DOR-associated resistance mutations was 181/1473 (12.3% [95% confidence interval {CI}: 10.7-14.1]); by ART status: 42/212 (19.8% [95% CI: 14.7-25.4]) among ART-failing individuals (VL ≥400 copies/mL) and 139/1261 (11.0% [95% CI: 9.3-12.9]) among ART-naïve individuals (P < 0.01). Intermediate DOR-associated resistance mutations were observed in 106/1261 (7.8% [95% CI: 6.9-10.1]) in ART-naïve individuals and 29/212 (13.7% [95% CI: 9.4-8.5]) among ART-experienced participants (P < 0.01). High-level DOR-associated resistance mutations were observed in 33/1261 (2.6% [95% CI: 1.8-3.7]) among ART-naïve and 13/212 (6.1% [95% CI: 3.6-10.8]) among ART-failing PWH (P < 0.01). PWH failing ART with at least one EFV/NVP-associated resistance mutation had high prevalence 13/67 (19.4%) of high-level DOR-associated resistance mutations.

Conclusion: DOR-associated mutations were rare (11.0%) among ART-naive PWH but present in 62.7% of Botswana individuals who failed NNRTI-based ART with at least one EFV/NVP-associated resistance mutation. Testing for HIV drug resistance should underpin the use of DOR in PWH who have taken first-generation NNRTIs.

Keywords: Antiretroviral (ART) experienced; Antiretroviral (ART) naive; Botswana; Doravirine; Drug resistance mutations; HIV-1C.

Conflict of interest statement

Declaration of Competing Interest None declared.

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Study schema for the participants used to determine the prevalence of DOR-associated resistance mutations.

References

    1. Viswanathan S, Detels R, Mehta SH, Macatangay BJ, Kirk GD, Jacobson LP. Level of adherence and HIV RNA suppression in the current era of highly active antiretroviral therapy (HAART) AIDS Behav. 2015;19:601–611. doi: 10.1007/s10461-014-0927-4.
    1. Chouraya C, Ashburn K, Khumalo P, Mpango L, Mthethwa N, Machekano R, et al. Association of antiretroviral drug regimen with viral suppression in HIV-positive children on antiretroviral therapy in Eswatini. Pediatr Infect Dis J. 2019;38:835–839. doi: 10.1097/inf.0000000000002347.
    1. Gulick RM. New HIV drugs: 2018 and beyond. 10.1097/coh.0000000000000478.
    1. Clayden P. Dolutegravir preconception signal: time is up for shoddy surveillance. . [Accessed 08 June 2021].
    1. Bertagnolio S, Perno CF, Vella S, Pillay D. The impact of HIV drug resistance on the selection of first- and second-line ART in resource-limited settings. J Infect Dis. 2013;207(Suppl. 2):S45–S48. doi: 10.1093/infdis/jit121.
    1. World Health Organization. HIV drug resistance report 2012. ; 2012. [Accessed 17 June 2021].
    1. Hong SY, Jonas A, DeKlerk M, Shiningavamwe A, Desta T, Badi A, et al. Population-based surveillance of HIV drug resistance emerging on treatment and associated factors at sentinel antiretroviral therapy sites in Namibia. Journal of acquired immune deficiency syndromes (1999) J Acquir Immune Defic Syndr. 2015;68:463–471.
    1. Rutstein SE, Chen JS, Nelson JAE, Phiri S, Miller WC, Hosseinipour MC. High rates of transmitted NNRTI resistance among persons with acute HIV infection in Malawi: implications for first-line dolutegravir scale-up. AIDS Res Ther. 2019;16:5. doi: 10.1186/s12981-019-0220-8.
    1. Rowley CF, MacLeod IJ, Maruapula D, Lekoko B, Gaseitsiwe S, Mine M, et al. Sharp increase in rates of HIV transmitted drug resistance at antenatal clinics in Botswana demonstrates the need for routine surveillance. J Antimicrob Chemother. 2016;71:1361–1366. doi: 10.1093/jac/dkv500.
    1. World Health Organization. Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy. ; 2017 [accessed 10 March 2020].
    1. Mondi A, Cozzi-Lepri A, Tavelli A, Rusconi S, Vichi F, Ceccherini-Silberstein F, et al. Effectiveness of dolutegravir-based regimens as either first-line or switch antiretroviral therapy: data from the Icona cohort. J Int AIDS Soc. 2019;22:e25227. doi: 10.1002/jia2.25227.
    1. World Health Organization. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidance. ; 2018. [Accessed 18 July 2021.]
    1. Seatla KK, Avalos A, Moyo S, Mine M, Diphoko T, Mosepele M, et al. Four-class drug-resistant HIV-1 subtype C in a treatment experienced individual on dolutegravir-based antiretroviral therapy in Botswana. AIDS. 2018;32:1899–1902. doi: 10.1097/QAD.0000000000001920.
    1. Seatla KK, Maruapula D, Choga WT, Ntsipe T, Mathiba N, Mogwele M, et al. HIV-1 subtype C drug resistance mutations in heavily treated patients failing integrase strand transfer inhibitor-based regimens in Botswana. Viruses. 2021:13. doi: 10.3390/v13040594.
    1. Rugemalila J, Kalluvya S. A heavily treated HIV-1 infected patient with multiclass drug resistance: a case report and review of management challenges in settings with a limited formulary. Med Case Rep. 2021;7
    1. Feng M, Sachs NA, Xu M, Grobler J, Blair W, Hazuda DJ, et al. Doravirine suppresses common nonnucleoside reverse transcriptase inhibitor-associated mutants at clinically relevant concentrations. Antimicrob Agents Chemother. 2016;60:2241–2247. doi: 10.1128/aac.02650-15.
    1. Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5:e211–e220. doi: 10.1016/s2352-3018(18)30021-3.
    1. Orkin C, Squires KE, Molina JM, Sax PE, Wong WW, Sussmann O, et al. Doravirine/lamivudine/tenofovir disoproxil fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results of the DRIVE-AHEAD Trial. Clin Infect Dis. 2019;68:535–544. doi: 10.1093/cid/ciy540.
    1. Asante-Appiah E, Lai J, Wan H, Yang D, Martin EA, Sklar P, et al. Impact of HIV-1 resistance-associated mutations on susceptibility to doravirine: analysis of real-world clinical isolates. Antimicrob Agents Chemother. 2021;65 doi: 10.1128/aac.01216-21.
    1. Makhema J, Wirth KE, Pretorius Holme M, Gaolathe T, Mmalane M, Kadima E, et al. Universal testing, expanded treatment, and incidence of HIV infection in Botswana. N Engl J Med. 2019;381:230–242. doi: 10.1056/NEJMoa1812281.
    1. Moyo S, Gaseitsiwe S, Zahralban-Steele M, Maruapula D, Nkhisang T, Mokaleng B, et al. Low rates of nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor drug resistance in Botswana. AIDS. 2019;33:1073–1082. doi: 10.1097/QAD.0000000000002166.
    1. Ministry of Health. Botswana integrated HIV clinical care guidelines 2016. . [Accessed 23 July 2021].
    1. Novitsky V, Zahralban-Steele M, McLane MF, Moyo S, van Widenfelt E, Gaseitsiwe S, et al. Long-range HIV genotyping using viral RNA and proviral DNA for analysis of HIV drug resistance and HIV clustering. J Clin Microbiol. 2015;53:2581–2592. doi: 10.1128/JCM.00756-15.
    1. Pineda-Peña A-C, Faria NR, Imbrechts S, Libin P, Barroso Abecasis A, Deforche K, et al. Automated subtyping of HIV-1 genetic sequences for clinical and surveillance purposes: performance evaluation of the new REGA version 3 and seven other tools. Infect Genet Evol. 2013;19:337–348. doi: 10.1016/j.meegid.2013.04.032.
    1. Struck D, Lawyer G, Ternes A-M, Schmit J-C, Bercoff DP. COMET: adaptive context-based modeling for ultrafast HIV-1 subtype identification. Nucleic Acids Res. 2014;42:e144. doi: 10.1093/nar/gku739.
    1. Rose PP, Korber BT. Detecting hypermutations in viral sequences with an emphasis on G –>A hypermutation. Bioinformatics. 2000;16:400–401. doi: 10.1093/bioinformatics/16.4.400.
    1. Scheibe K, Urbańska A, Jakubowski P, Hlebowicz M, Bociaga-Jasik M, Raczynska A, et al. Low prevalence of doravirine-associated resistance mutations among polish human immunodeficiency-1 (HIV-1)-infected patients. Antivir Ther. 2021;26:69–78. doi: 10.1177/13596535211043044.
    1. Sun Z, Lan Y, Liang S, Wang J, Ni M, Zhang X, et al. Prevalence of doravirine cross-resistance in HIV-infected adults who failed first-line ART in China, 2014–18. J Antimicrob Chemother. 2022;77:1119–1124. doi: 10.1093/jac/dkac016.
    1. El Bouzidi K, Datir RP, Kwaghe V, Roy S, Frampton D, Breuer J, et al. Deep sequencing of HIV-1 reveals extensive subtype variation and drug resistance after failure of first-line antiretroviral regimens in Nigeria. J Antimicrob Chemother. 2022;77:474–482. doi: 10.1093/jac/dkab385.
    1. Soulié C, Santoro M, Charpentier C, Storto A, Paraskevis D, Di Carlo D, et al. Rare occurrence of doravirine resistance-associated mutations in HIV-1-infected treatment-naive patients. J Antimicrob Chemother. 2018;74 doi: 10.1093/jac/dky464.
    1. Steegen K, Moorhouse M, Wensing AMJ, Venter WDF, Hans L. Is there a role for doravirine in African HIV treatment programmes? A large observational resistance study in South Africa. J Int AIDS Soc. 2021;24:e25706. doi: 10.1002/jia2.25706.
    1. Soulie C, Santoro MM, Storto A, Abdi B, Charpentier C, Armenia D, et al. Prevalence of doravirine-associated resistance mutations in HIV-1-infected antiretroviral-experienced patients from two large databases in France and Italy. J Antimicrob Chemother. 2020;75:1026–1030. doi: 10.1093/jac/dkz553.
    1. Sterrantino G, Borghi V, Callegaro AP, Bruzzone B, Saladini F, Maggiolo F, et al. Prevalence of predicted resistance to doravirine in HIV-1-positive patients after exposure to non-nucleoside reverse transcriptase inhibitors. Int J Antimicrob Agents. 2019;53:515–519. doi: 10.1016/j.ijantimicag.2019.02.007.
    1. Saladini F, Giammarino F, Hosseini BA, Giannini A, Boccuto A, Dragoni F, et al. In vitro cross-resistance to doravirine in a panel of HIV-1 clones harbouring multiple NNRTI resistance mutations. J Antimicrob Chemother. 2021;76:130–134. doi: 10.1093/jac/dkaa401.
    1. Moyo S, Gaseitsiwe S, Powis KM, Holme MP, Mohammed T, Zahralban-Steele M, et al. Undisclosed antiretroviral drug use in Botswana: implication for national estimates. AIDS. 2018;32:1543–1546. doi: 10.1097/qad.0000000000001862.
    1. Johnson M, Kumar P, Molina J-M, Rizzardini G, Cahn P, Bickel M, et al. Switching to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) maintains HIV-1 virologic suppression through 48 weeks: results of the DRIVE-SHIFT Trial. J Acquir Immune Defic Syndr. 2019;81 doi: 10.1097/qai.0000000000002056.

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