K Steegen1, M Bronze2, M A Papathanasopoulos3, G van Zyl2,4, D Goedhals2,5, E Variava6,7,8, W MacLeod9,10, I Sanne11, W S Stevens3,2, S Carmona3,2. 1. Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, South Africa kim.steegen@nhls.ac.za. 2. National Health Laboratory Service, Johannesburg, South Africa. 3. Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, South Africa. 4. Division of Medical Virology, Stellenbosch University, Stellenbosch, South Africa. 5. Department of Medical Microbiology and Virology, University of the Free State, Bloemfontein, South Africa. 6. Department of Internal Medicine, Klerksdorp Tshepong Hospital Complex, Klerksdorp, South Africa. 7. Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa. 8. Perinatal HIV Research Unit, Johannesburg, South Africa. 9. Center for Global Health and Development, Boston University School of Public Health, Boston, MA, USA. 10. Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. 11. Right to Care, Johannesburg, South Africa.
Abstract
BACKGROUND: Routine HIV-1 antiretroviral drug resistance testing for patients failing NNRTI-based regimens is not recommended in resource-limited settings. Therefore, surveys are required to monitor resistance profiles in patients failing ART. METHODS: A cross-sectional survey was conducted amongst patients failing NNRTI-based regimens in the public sector throughout South Africa. Virological failure was defined as two consecutive HIV-1 viral load results >1000 RNA copies/mL. Pol sequences were obtained using RT-PCR and Sanger sequencing and submitted to Stanford HIVdb v7.0.1. RESULTS: A total of 788 sequences were available for analysis. Most patients failed a tenofovir-based NRTI backbone (74.4%) in combination with efavirenz (82.1%) after median treatment duration of 36 months. K103N (48.9%) and V106M (34.9%) were the most common NNRTI mutations. Only one-third of patients retained full susceptibility to second-generation NNRTIs such as etravirine (36.5%) and rilpivirine (27.3%). After M184V/I (82.7%), K65R was the most common NRTI mutation (45.8%). The prevalence of K65R increased to 57.5% in patients failing a tenofovir regimen without prior stavudine exposure. Cross-resistance to NRTIs was often observed, but did not seem to affect the predicted activity of zidovudine as 82.9% of patients remained fully susceptible to this drug. CONCLUSIONS: The introduction of tenofovir-based first-line regimens has dramatically increased the prevalence of K65R mutations in the HIV-1-infected South African population. However, most patients failing tenofovir-based regimens remained fully susceptible to zidovudine. Based on these data, there is currently no need to change either the recommended first- or second-line ART regimens in South Africa.
BACKGROUND: Routine HIV-1 antiretroviral drug resistance testing for patients failing NNRTI-based regimens is not recommended in resource-limited settings. Therefore, surveys are required to monitor resistance profiles in patients failing ART. METHODS: A cross-sectional survey was conducted amongst patients failing NNRTI-based regimens in the public sector throughout South Africa. Virological failure was defined as two consecutive HIV-1 viral load results >1000 RNA copies/mL. Pol sequences were obtained using RT-PCR and Sanger sequencing and submitted to Stanford HIVdb v7.0.1. RESULTS: A total of 788 sequences were available for analysis. Most patients failed a tenofovir-based NRTI backbone (74.4%) in combination with efavirenz (82.1%) after median treatment duration of 36 months. K103N (48.9%) and V106M (34.9%) were the most common NNRTI mutations. Only one-third of patients retained full susceptibility to second-generation NNRTIs such as etravirine (36.5%) and rilpivirine (27.3%). After M184V/I (82.7%), K65R was the most common NRTI mutation (45.8%). The prevalence of K65R increased to 57.5% in patients failing a tenofovir regimen without prior stavudine exposure. Cross-resistance to NRTIs was often observed, but did not seem to affect the predicted activity of zidovudine as 82.9% of patients remained fully susceptible to this drug. CONCLUSIONS: The introduction of tenofovir-based first-line regimens has dramatically increased the prevalence of K65R mutations in the HIV-1-infected South African population. However, most patients failing tenofovir-based regimens remained fully susceptible to zidovudine. Based on these data, there is currently no need to change either the recommended first- or second-line ART regimens in South Africa.
Authors: Benjamin Chimukangara; Ayesha B M Kharsany; Richard J Lessells; Kogieleum Naidoo; Soo-Yon Rhee; Justen Manasa; Tiago Gräf; Lara Lewis; Cherie Cawood; David Khanyile; Karidia Diallo; Kassahun A Ayalew; Robert W Shafer; Gillian Hunt; Deenan Pillay; Salim Karim Abdool; Tulio de Oliveira Journal: AIDS Res Hum Retroviruses Date: 2019-01-07 Impact factor: 2.205
Authors: Philip J Palumbo; Jessica M Fogel; Sarah E Hudelson; Ethan A Wilson; Stephen Hart; Laura Hovind; Estelle Piwowar-Manning; Carole Wallis; Maria A Papathanasopoulos; Mariza G Morgado; Shanmugam Saravanan; Srikanth Tripathy; Joseph J Eron; Joel E Gallant; Marybeth McCauley; Theresa Gamble; Mina C Hosseinipour; Nagalingeswaran Kumarasamy; James G Hakim; Jose H Pilotto; Johnstone Kumwenda; Victor Akelo; Sheela V Godbole; Breno R Santos; Beatriz Grinsztejn; Ravindre Panchia; Suwat Chariyalertsak; Joseph Makhema; Sharlaa Badal-Faesen; Ying Q Chen; Myron S Cohen; Susan H Eshleman Journal: J Acquir Immune Defic Syndr Date: 2018-04-15 Impact factor: 3.731
Authors: Suzanne M McCluskey; Toby Pepperrell; Andrew Hill; Willem D F Venter; Ravindra K Gupta; Mark J Siedner Journal: AIDS Date: 2021-12-15 Impact factor: 4.177
Authors: Jaysingh Brijkumar; Johnathan A Edwards; Brent A Johnson; Claudia Ordonez; Henry Sunpath; Mitch Lee; Mathew R Dudgeon; Lydia Rautman; Selvan Pillay; Pravi Moodley; Y V Sun; José Castillo-Mancilla; Jonathan Z Li; Daniel R Kuritzkes; Mohamed Y S Moosa; Vincent Charles Marconi Journal: HIV Med Date: 2022-01-12 Impact factor: 3.094
Authors: Lauren Jennings; Tracy Kellermann; Matthew Spinelli; Zukiswa Nkantsu; Dolphina Cogill; Marije van Schalkwyk; Eric Decloedt; Gert van Zyl; Catherine Orrell; Monica Gandhi Journal: AIDS Res Hum Retroviruses Date: 2021-12-29 Impact factor: 1.723
Authors: J Gregson; S Y Rhee; R Datir; D Pillay; C F Perno; A Derache; R S Shafer; R K Gupta Journal: J Infect Dis Date: 2020-09-01 Impact factor: 5.226
Authors: Benjamin Chimukangara; Richard J Lessells; Soo-Yon Rhee; Jennifer Giandhari; Ayesha B M Kharsany; Kogieleum Naidoo; Lara Lewis; Cherie Cawood; David Khanyile; Kassahun A Ayalew; Karidia Diallo; Reshmi Samuel; Gillian Hunt; Alain Vandormael; Babill Stray-Pedersen; Michelle Gordon; Tariro Makadzange; Photini Kiepiela; Gita Ramjee; Johanna Ledwaba; Monalisa Kalimashe; Lynn Morris; Urvi M Parikh; John W Mellors; Robert W Shafer; David Katzenstein; Pravi Moodley; Ravindra K Gupta; Deenan Pillay; Salim S Abdool Karim; Tulio de Oliveira Journal: EClinicalMedicine Date: 2019-03-18