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      Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial

      research-article
      , Prof, PhD a , * , , Prof, PhD c , , Prof, PhD d , , MD e , , MBChB f , , FCPHM g , , MMed h , , FRCP i , , MBChB f , , MBBCh a , , MBBCh g , , MPH j , , MPH f , , MMed f , , MMed k , , MBChB l , , MMed m , , PhD n , , MBBCh b , , MBChB g , , MPH f , , MS o , , BS o , , Prof, PharmD p , , Prof, PhD q , , Prof, MD q , r , , Prof, MD r , , BA c , , PhD s , , PhD o , , PhD o , , MD t , , MD u , , PhD v , , PhD v , , MD v , , PhD c , , Prof, MD w , , Prof, MD w , x , HPTN 084 study group
      Lancet (London, England)
      Elsevier

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          Summary

          Background

          Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women.

          Methods

          HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18–45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564.

          Findings

          From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22–30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73–1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06–0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3–2·57]; hazard ratio 0·12 [0·05–0·31]; p<0·0001; risk difference –1·6% [–1·0% to –2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9–1·7); no congenital birth anomalies were reported.

          Interpretation

          Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women.

          Funding

          National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support.

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          Most cited references26

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          Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV

          Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries.
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            Tenofovir-based preexposure prophylaxis for HIV infection among African women.

            Reproductive-age women need effective interventions to prevent the acquisition of human immunodeficiency virus type 1 (HIV-1) infection. We conducted a randomized, placebo-controlled trial to assess daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir-emtricitabine (TDF-FTC), or 1% tenofovir (TFV) vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma TFV levels were assessed quarterly. Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was -49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), -4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively. Independent predictors of TFV detection included being married, being older than 25 years of age, and being multiparous. Detection of TFV in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral TDF-FTC than among those assigned to receive oral placebo (1.3% vs. 0.2%, P=0.004). We observed no significant differences in the frequencies of other adverse events. None of the drug regimens we evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. (Funded by the National Institutes of Health; VOICE ClinicalTrials.gov number, NCT00705679.).
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              Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women

              Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection.
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                Author and article information

                Contributors
                Journal
                Lancet
                Lancet
                Lancet (London, England)
                Elsevier
                0140-6736
                1474-547X
                07 May 2022
                07 May 2022
                : 399
                : 10337
                : 1779-1789
                Affiliations
                [a ]Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa
                [b ]Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa
                [c ]Statistical Centre for HIV/AIDS Research and Prevention, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
                [d ]Desmond Tutu TB Centre, University of Stellenbosch, Stellenbosch, South Africa
                [e ]Kisumu Clinical Research Site, Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya
                [f ]Clinical Trials Research Centre, University of Zimbabwe, Harare, Zimbabwe
                [g ]HIV and other Infectious Diseases Research Unit, South African Medical Research Council, Durban, South Africa
                [h ]Blantyre Clinical Research Site, College of Medicine, University of Malawi, Blantyre, Malawi
                [i ]Botswana Harvard AIDS Institute Partnership (BHP), Gaborone, Botswana
                [j ]International AIDS Vaccine Initiative, Uganda Virus Research Institute, Entebbe, Uganda
                [k ]Baylor College of Medicine Children's Foundation Uganda, Kampala, Uganda
                [l ]Desmond Tutu Health Foundation, University of Cape Town, Cape Town, South Africa
                [m ]Makerere University–Johns Hopkins University Research Collaboration, Kampala, Uganda
                [n ]Eswatini Prevention Center, International Center for AIDS Care and Treatment Program at Columbia University Mailman School of Public Health, New York, NY, USA
                [o ]FHI 360, Durham, NC, USA
                [p ]Anschutz Medical Campus, University of Colorado, Aurora, CO, USA
                [q ]Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
                [r ]Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
                [s ]Department of Psychiatry, Stroger Hospital of Cook County, Chicago, IL, USA
                [t ]Division of AIDS, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA
                [u ]Gilead Sciences, Foster City, CA, USA
                [v ]ViiV Healthcare, Durham, NC, USA
                [w ]University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA
                [x ]UNC Project-Malawi, Lilongwe, Malawi
                Author notes
                [* ]Correspondence to: Dr Sinead Delany-Moretlwe, Wits Reproductive Health and HIV Institute, Johannesburg 2001, South Africa sdelany@ 123456wrhi.ac.za
                Article
                S0140-6736(22)00538-4
                10.1016/S0140-6736(22)00538-4
                9077443
                35378077
                91069102-8933-4f80-b547-a2fa5f3d5f8c
                © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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