Sinead Delany-Moretlwe1, Carl Lombard2, Deborah Baron3, Linda-Gail Bekker4, Busi Nkala5, Khatija Ahmed6, Modulakgotla Sebe7, William Brumskine7, Maposhane Nchabeleng8, Thesla Palanee-Philips3, Julius Ntshangase9, Sidney Sibiya10, Emilee Smith11, Ravindre Panchia5, Landon Myer11, Jill L Schwartz12, Mark Marzinke13, Lynn Morris14, Elizabeth R Brown15, Gustavo F Doncel12, Glenda Gray16, Helen Rees3. 1. Wits RHI, University of the Witwatersrand, Johannesburg, South Africa. Electronic address: sdelany@wrhi.ac.za. 2. Biostatistics Unit, Cape Town, South Africa; Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa. 3. Wits RHI, University of the Witwatersrand, Johannesburg, South Africa. 4. Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa. 5. Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa. 6. Setshaba Research Centre, Soshanguve, South Africa. 7. Aurum Institute, Johannesburg, South Africa. 8. Mecru Clinical Research Unit, Sefako Makgatho Health Sciences University, Ga-Rankuwa, South Africa. 9. MATCH, University of the Witwatersrand, Johannesburg, South Africa. 10. Qhakaza Mbokodo Research Centre, Ladysmith, South Africa. 11. Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa. 12. CONRAD, Eastern Virginia Medical School, Arlington, VA, USA. 13. Johns Hopkins University School of Medicine, Baltimore, MD, USA. 14. National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa. 15. Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 16. Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; South African Medical Research Council, Cape Town, South Africa.
Abstract
BACKGROUND:Young women in southern Africa have substantial risk of HIV acquisition. Female-controlled biomedical interventions are needed to mitigate this risk. We aimed to assess the safety and efficacy of a pericoitally applied tenofovir 1% gel. METHODS: We did a phase 3, double-blind, randomised, placebo-controlled trial at nine community-based clinical trial sites in South Africa to evaluate the safety and efficacy of tenofovir 1% gel. Sexually active women who were HIV negative andaged 18-30 years were enrolled. Participants were randomly assigned (1:1) using sequential participant numbers to either tenofovir 1% gel or a placebo gel (one dose within 12 h before sex and one dose within 12 h after sex [BAT-24 regimen]), using dynamic permuted block sizes of 8 and 16 within each site. Women received monthly HIV-1 testing, risk reduction support, physical examinations, and product dispensing for up to 27 months. The primary efficacy outcome was incident HIV infection and the primary safety outcome was occurrence of grade 2-4 adverse events, both analysed in the modified intention-to-treat population. To assess the efficacy of tenofovir gel, the cumulative probability of HIV infection was calculated for each treatment using the Kaplan-Meier method. This trial is registered with ClinicalTrials.gov, number NCT01386294. FINDINGS:From Oct 11, 2011, to Aug 29, 2014, 3844 women were screened, 2059 enrolled, and 2029 included in the primary analysis (1032 in the tenofovir group and 1027 in the placebo group); 39 (4%) in the tenofovir group and 36 (4%) in theplacebo group were lost to follow-up. 123 HIV-1 infections occurred over 3036 woman-years of observation; 61 in the tenofovirgroup (HIV incidence 4·0 per 100 woman-years, 95% CI 3·1-5·2) and 62 in the placebogroup (4·0 per 100 woman-years, 3·1-5·2; incidence rate ratio [IRR] 0·98, 95% CI 0·7-1·4). A higher incidence of grade 2 adverse events was observed in the tenofovir group than in the placebogroup (IRR 1·09, 95% CI 1·0-1·2; p=0·02). The most common grade 2 or higher product-related adverse events were hypophosphataemia (n=22 for tenofovir vs n=22 for placebo), genital symptoms (n=6 for tenofovir vs n=2 for placebo), or elevated transaminases (n=2 for tenofovir vs n=2 for placebo). No product-related serious adverse events were reported, and no differences in product-related adverse events (p=0·78), grade 3 events (p=0·64), or grade 4 events (p=0·74) were observed between treatment groups. INTERPRETATION: Overall, pericoital tenofovir gel did not prevent HIV-1 acquisition in this population of young women at risk of HIV infection in South Africa. Alternate safe and effective products that are less user dependent than this product or do not require high adherence are needed. FUNDING: The US Agency for International Development (USAID), the Bill & Melinda Gates Foundation, and the South African Department of Science and Technology and Department of Health.
RCT Entities:
BACKGROUND: Young women in southern Africa have substantial risk of HIV acquisition. Female-controlled biomedical interventions are needed to mitigate this risk. We aimed to assess the safety and efficacy of a pericoitally applied tenofovir 1% gel. METHODS: We did a phase 3, double-blind, randomised, placebo-controlled trial at nine community-based clinical trial sites in South Africa to evaluate the safety and efficacy of tenofovir 1% gel. Sexually active women who were HIV negative and aged 18-30 years were enrolled. Participants were randomly assigned (1:1) using sequential participant numbers to either tenofovir 1% gel or a placebo gel (one dose within 12 h before sex and one dose within 12 h after sex [BAT-24 regimen]), using dynamic permuted block sizes of 8 and 16 within each site. Women received monthly HIV-1 testing, risk reduction support, physical examinations, and product dispensing for up to 27 months. The primary efficacy outcome was incident HIV infection and the primary safety outcome was occurrence of grade 2-4 adverse events, both analysed in the modified intention-to-treat population. To assess the efficacy of tenofovir gel, the cumulative probability of HIV infection was calculated for each treatment using the Kaplan-Meier method. This trial is registered with ClinicalTrials.gov, number NCT01386294. FINDINGS: From Oct 11, 2011, to Aug 29, 2014, 3844 women were screened, 2059 enrolled, and 2029 included in the primary analysis (1032 in the tenofovir group and 1027 in the placebo group); 39 (4%) in the tenofovir group and 36 (4%) in the placebo group were lost to follow-up. 123 HIV-1 infections occurred over 3036 woman-years of observation; 61 in the tenofovir group (HIV incidence 4·0 per 100 woman-years, 95% CI 3·1-5·2) and 62 in the placebo group (4·0 per 100 woman-years, 3·1-5·2; incidence rate ratio [IRR] 0·98, 95% CI 0·7-1·4). A higher incidence of grade 2 adverse events was observed in the tenofovir group than in the placebo group (IRR 1·09, 95% CI 1·0-1·2; p=0·02). The most common grade 2 or higher product-related adverse events were hypophosphataemia (n=22 for tenofovir vs n=22 for placebo), genital symptoms (n=6 for tenofovir vs n=2 for placebo), or elevated transaminases (n=2 for tenofovir vs n=2 for placebo). No product-related serious adverse events were reported, and no differences in product-related adverse events (p=0·78), grade 3 events (p=0·64), or grade 4 events (p=0·74) were observed between treatment groups. INTERPRETATION: Overall, pericoital tenofovir gel did not prevent HIV-1 acquisition in this population of young women at risk of HIV infection in South Africa. Alternate safe and effective products that are less user dependent than this product or do not require high adherence are needed. FUNDING: The US Agency for International Development (USAID), the Bill & Melinda Gates Foundation, and the South African Department of Science and Technology and Department of Health.
Authors: Marla J Keller; Lianna Wood; James M Billingsley; Laurie L Ray; Jessica Goymer; Shada Sinclair; Aileen P McGinn; Mark A Marzinke; Bruce Frank; Sujatha Srinivasan; Congzhou Liu; Jessica M Atrio; Lilia Espinoza; Nelly Mugo; Hans M L Spiegel; Peter L Anderson; David N Fredricks; Craig W Hendrix; Jeanne Marrazzo; Steven E Bosinger; Betsy C Herold Journal: Lancet HIV Date: 2019-07-15 Impact factor: 12.767
Authors: Sabrina Helmold Hait; Christopher James Hogge; Mohammad Arif Rahman; Eun-Ju Ko; Ruth Hunegnaw; Zuena Mushtaq; Gospel Enyindah-Asonye; Tanya Hoang; Lisa M Miller Jenkins; Ettore Appella; Daniel H Appella; Marjorie Robert-Guroff Journal: J Immunol Date: 2020-05-11 Impact factor: 5.422
Authors: Elizabeth T Montgomery; Sarah T Roberts; Annalene Nel; Mariette Malherbe; Kristine Torjesen; Katherine Bunge; Devika Singh; Jared M Baeten; Jeanne Marrazzo; Z Mike Chirenje; Samuel Kabwigu; Richard Beigi; Sharon A Riddler; Zakir Gaffour; Krishnaveni Reddy; Leila E Mansoor; Gonasagrie Nair; Kusbashni Woeber; Jayajothi Moodley; Nitesha Jeenarain; Samantha Siva; Logashvari Naidoo; Vaneshree Govender; Thesla Palanee-Phillips Journal: AIDS Date: 2019-11-15 Impact factor: 4.177
Authors: Joseph W Romano; Marc M Baum; Zach R Demkovich; Frank Diana; Charles Dobard; Paul L Feldman; J Gerardo Garcia-Lerma; Alessandro Grattoni; Manjula Gunawardana; Duy-Khiet Ho; Thomas J Hope; Ivana Massud; Mark Milad; John A Moss; Fernanda P Pons-Faudoa; Shane Roller; Ariane van der Straten; Selvi Srinivasan; Ronald S Veazey; Doris Zane Journal: AIDS Res Hum Retroviruses Date: 2021-06 Impact factor: 2.205
Authors: Albert Y Liu; Clara Dominguez Islas; Holly Gundacker; Blazej Neradilek; Craig Hoesley; Ariane van der Straten; Craig W Hendrix; May Beamer; Cindy E Jacobson; Tara McClure; Tanya Harrell; Katherine Bunge; Brid Devlin; Jeremy Nuttall; Patrick Spence; John Steytler; Jeanna M Piper; Mark A Marzinke Journal: J Int AIDS Soc Date: 2021-06 Impact factor: 6.707
Authors: Adam Akullian; Alain Vandormael; Joel C Miller; Anna Bershteyn; Edward Wenger; Diego Cuadros; Dickman Gareta; Till Bärnighausen; Kobus Herbst; Frank Tanser Journal: Proc Natl Acad Sci U S A Date: 2021-07-13 Impact factor: 12.779