Archived Rilpivirine-associated Resistance Mutations Among ART-naive and Virologically Suppressed People Living with HIV-1 Subtype C in Botswana: Implications for Cabotegravir/rilpivirine Use

Overview

Journal J Antimicrob Chemother

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2023 Aug 16

PMID 37585352

Authors

Dorcas Maruapula

Natasha O Moraka

Ontlametse T Bareng

Patrick T Mokgethi

Wonderful T Choga

Kaelo K Seatla

Nametso Kelentse

Catherine K Koofhethille

Boitumelo J L Zuze

Tendani Gaolathe

Molly Pretorius-Holme

Joseph Makhema

Vlad Novitsky

Roger Shapiro

Sikhulile Moyo

Shahin Lockman

Simani Gaseitsiwe

Affiliations

Soon will be listed here.

Abstract

Objectives: Pre-existing rilpivirine resistance-associated mutations (RVP-RAMs) have been found to predict HIV-1 virological failure in those switching to long-acting injectable cabotegravir/rilpivirine. We here evaluated the prevalence of archived RPV-RAMs in a cohort of people living with HIV (PWH).

Methods: We analysed near full-length HIV-1 pol sequences from proviral DNA for the presence of RPV-RAMs, which were defined according to the 2022 IAS-USA drug resistance mutation list and Stanford HIV drug resistance database.

Results: RPV-RAMs were identified in 757/5805 sequences, giving a prevalence of 13.0% (95% CI 12%-13.9%). Amongst the ART-naive group, 137/1281 (10.7%, 95% CI 9.1%-12.5%) had at least one RPV-RAM. Of the 4524 PWH with viral suppression on ART (VL <400 copies/mL), 620 (13.7%, 95% CI 12.7%-14.7%) had at least one RPV-RAM. E138A was the most prevalent RPV-RAM in the ART-naive group (7.9%) and the ART-suppressed group (9.3%). The rest of the mutations observed (L100I, K101E, E138G, E138K, E138Q, Y181C, H221Y, M230L, A98G, V179D, G190A, G190E and M230I) were below a prevalence of 1%.

Conclusions: RPV-RAMs were present in 10.7% of ART-naive and 13.7% of ART-suppressed PWH in Botswana. The most common RPV-RAM in both groups was E138A. Since individuals with the E138A mutation may be more likely to fail cabotegravir/rilpivirine, monitoring RPV-RAMs will be crucial for effective cabotegravir/rilpivirine implementation in this setting.

Citing Articles

Phylogenetic Network Analyses Reveal the Influence of Transmission Clustering on the Spread of HIV Drug Resistance in Quebec from 2002 to 2022.

Brenner B, Ibanescu R, Oliveira M, Margaillan G, Lebouche B, Thomas R Viruses. 2024; 16(8).

PMID: 39205204 PMC: 11359670. DOI: 10.3390/v16081230.

HIV transmission dynamics and population-wide drug resistance in rural South Africa.

Kemp S, Kamelian K, Cuadros D, Cheng M, Okango E, Hanekom W Nat Commun. 2024; 15(1):3644.

PMID: 38684655 PMC: 11059351. DOI: 10.1038/s41467-024-47254-z.

HIV transmission dynamics and population-wide drug resistance in rural South Africa.

Kemp S, Kamelian K, Cuadros D, Gupta R, Cheng M, Okango E Res Sq. 2023; .

PMID: 38076835 PMC: 10705695. DOI: 10.21203/rs.3.rs-3640717/v1.

References

da Silva J, Siedner M, McCluskey S, Chandiwana N, Venter F, Raizes E . Drug resistance and use of long-acting ART. Lancet HIV. 2022; 9(6):e374-e375. DOI: 10.1016/S2352-3018(22)00059-5. View

Gaolathe T, Wirth K, Pretorius Holme M, Makhema J, Moyo S, Chakalisa U . Botswana's progress toward achieving the 2020 UNAIDS 90-90-90 antiretroviral therapy and virological suppression goals: a population-based survey. Lancet HIV. 2016; 3(5):e221-30. PMC: 5146754. DOI: 10.1016/S2352-3018(16)00037-0. View

Imaz A, Podzamczer D . The role of rilpivirine in clinical practice: strengths and weaknesses of the new nonnucleoside reverse transcriptase inhibitor for HIV therapy. AIDS Rev. 2012; 14(4):268-78. View

Moyo S, Gaseitsiwe S, Powis K, Pretorius Holme M, Mohammed T, Zahralban-Steele M . Undisclosed antiretroviral drug use in Botswana: implication for national estimates. AIDS. 2018; 32(11):1543-1546. PMC: 6047897. DOI: 10.1097/QAD.0000000000001862. View

Nguyen H, Thorball C, Fellay J, Boni J, Yerly S, Perreau M . Systematic screening of viral and human genetic variation identifies antiretroviral resistance and immune escape link. Elife. 2021; 10. PMC: 8169104. DOI: 10.7554/eLife.67388. View

Struck D, Lawyer G, Ternes A, Schmit J, Perez Bercoff D . COMET: adaptive context-based modeling for ultrafast HIV-1 subtype identification. Nucleic Acids Res. 2014; 42(18):e144. PMC: 4191385. DOI: 10.1093/nar/gku739. View

Calvez V, Marcelin A, Vingerhoets J, Hill A, Hadacek B, Moecklinghoff C . Systematic review to determine the prevalence of transmitted drug resistance mutations to rilpivirine in HIV-infected treatment-naive persons. Antivir Ther. 2016; 21(5):405-12. DOI: 10.3851/IMP3024. View

Overton E, Richmond G, Rizzardini G, Jaeger H, Orrell C, Nagimova F . Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet. 2020; 396(10267):1994-2005. DOI: 10.1016/S0140-6736(20)32666-0. View

James C, Preininger L, Sweet M . Rilpivirine: a second-generation nonnucleoside reverse transcriptase inhibitor. Am J Health Syst Pharm. 2012; 69(10):857-61. DOI: 10.2146/ajhp110395. View

10.

Ren J, Nichols C, Chamberlain P, Weaver K, Short S, Chan J . Relationship of potency and resilience to drug resistant mutations for GW420867X revealed by crystal structures of inhibitor complexes for wild-type, Leu100Ile, Lys101Glu, and Tyr188Cys mutant HIV-1 reverse transcriptases. J Med Chem. 2007; 50(10):2301-9. DOI: 10.1021/jm061117m. View

11.

Steegen K, Chandiwana N, Sokhela S, Venter W, Hans L . Impact of rilpivirine cross-resistance on long-acting cabotegravir-rilpivirine in low and middle-income countries. AIDS. 2023; 37(6):1009-1011. PMC: 10090297. DOI: 10.1097/QAD.0000000000003505. View

12.

Ren J, Nichols C, Chamberlain P, Weaver K, Short S, Stammers D . Crystal structures of HIV-1 reverse transcriptases mutated at codons 100, 106 and 108 and mechanisms of resistance to non-nucleoside inhibitors. J Mol Biol. 2004; 336(3):569-78. DOI: 10.1016/j.jmb.2003.12.055. View

13.

Rizzardini G, Overton E, Orkin C, Swindells S, Arasteh K, Gorgolas Hernandez-Mora M . Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials. J Acquir Immune Defic Syndr. 2020; 85(4):498-506. PMC: 7592884. DOI: 10.1097/QAI.0000000000002466. View

14.

Wohrl B, Krebs R, Thrall S, Le Grice S, Scheidig A, Goody R . Kinetic analysis of four HIV-1 reverse transcriptase enzymes mutated in the primer grip region of p66. Implications for DNA synthesis and dimerization. J Biol Chem. 1997; 272(28):17581-7. DOI: 10.1074/jbc.272.28.17581. View

15.

Makhema J, Wirth K, Pretorius Holme M, Gaolathe T, Mmalane M, Kadima E . Universal Testing, Expanded Treatment, and Incidence of HIV Infection in Botswana. N Engl J Med. 2019; 381(3):230-242. PMC: 6800102. DOI: 10.1056/NEJMoa1812281. View

16.

Orkin C, Arasteh K, Gorgolas Hernandez-Mora M, Pokrovsky V, Overton E, Girard P . Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. N Engl J Med. 2020; 382(12):1124-1135. DOI: 10.1056/NEJMoa1909512. View

17.

Kityo C, Cortes C, Phanuphak N, Grinsztejn B, Venter F . Barriers to Uptake of Long-Acting Antiretroviral Products for Treatment and Prevention of HIV in Low- and Middle-Income Countries (LMICs). Clin Infect Dis. 2022; 75(Suppl 4):S549-S556. DOI: 10.1093/cid/ciac752. View

18.

Lansdon E, Brendza K, Hung M, Wang R, Mukund S, Jin D . Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): implications for drug design. J Med Chem. 2010; 53(10):4295-9. DOI: 10.1021/jm1002233. View

19.

Gatanaga H, Murakoshi H, Hachiya A, Hayashida T, Chikata T, Ode H . Naturally selected rilpivirine-resistant HIV-1 variants by host cellular immunity. Clin Infect Dis. 2013; 57(7):1051-5. DOI: 10.1093/cid/cit430. View

20.

Swindells S, Andrade-Villanueva J, Richmond G, Rizzardini G, Baumgarten A, Masia M . Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression. N Engl J Med. 2020; 382(12):1112-1123. DOI: 10.1056/NEJMoa1904398. View