BACKGROUND: The development of interventions for systemic pre-exposure prophylaxis (PrEP) faces several significant challenges following the US Food and Drug Administration's approval of emtricitabine/tenofovir (FTC/TDF) for HIV prevention. This development is particularly complex because of inconsistency of efficacy results of FTC/TDF PrEP trials for HIV prevention. METHODS: Possible designs for a PrEP phase 3 efficacy trial are obtained by considering scenarios for potential experimental PrEP and control regimens, including consideration of placebo and active controls, longer acting PrEP and alternate dosing schedules. RESULTS: Noninferiority (NI) trials with hazard ratio NI margins ranging from 1.10 to 1.25 can be justified in the contexts of the 3 PrEP trials demonstrating efficacy of FTC/TDF. However, these HIV endpoint trials may require extremely large number of participants, particularly in settings where FTC/TDF has been shown to reduce the risk of HIV acquisition. NI trials also are often difficult to interpret because they depend on previous placebo-controlled efficacy results. Superiority trials for PrEP are plausible in settings where FTC/TDF efficacy is not yet established, possibly due to low adherence (ie, women at risk as in FemPrEP and VOICE): a new product with potential for higher adherence and potency would be a promising candidate in this setting. CONCLUSIONS: Following Food and Drug Administration's approval of FTC/TDF for PrEP, trials to establish efficacy of new PrEP regimens require stringent design standards, together with rigorous debate about adherence within study populations and many important ethical issues.
BACKGROUND: The development of interventions for systemic pre-exposure prophylaxis (PrEP) faces several significant challenges following the US Food and Drug Administration's approval of emtricitabine/tenofovir (FTC/TDF) for HIV prevention. This development is particularly complex because of inconsistency of efficacy results of FTC/TDF PrEP trials for HIV prevention. METHODS: Possible designs for a PrEP phase 3 efficacy trial are obtained by considering scenarios for potential experimental PrEP and control regimens, including consideration of placebo and active controls, longer acting PrEP and alternate dosing schedules. RESULTS: Noninferiority (NI) trials with hazard ratio NI margins ranging from 1.10 to 1.25 can be justified in the contexts of the 3 PrEP trials demonstrating efficacy of FTC/TDF. However, these HIV endpoint trials may require extremely large number of participants, particularly in settings where FTC/TDF has been shown to reduce the risk of HIV acquisition. NI trials also are often difficult to interpret because they depend on previous placebo-controlled efficacy results. Superiority trials for PrEP are plausible in settings where FTC/TDF efficacy is not yet established, possibly due to low adherence (ie, women at risk as in FemPrEP and VOICE): a new product with potential for higher adherence and potency would be a promising candidate in this setting. CONCLUSIONS: Following Food and Drug Administration's approval of FTC/TDF for PrEP, trials to establish efficacy of new PrEP regimens require stringent design standards, together with rigorous debate about adherence within study populations and many important ethical issues.
Authors: Quarraisha Abdool Karim; Salim S Abdool Karim; Janet A Frohlich; Anneke C Grobler; Cheryl Baxter; Leila E Mansoor; Ayesha B M Kharsany; Sengeziwe Sibeko; Koleka P Mlisana; Zaheen Omar; Tanuja N Gengiah; Silvia Maarschalk; Natasha Arulappan; Mukelisiwe Mlotshwa; Lynn Morris; Douglas Taylor Journal: Science Date: 2010-07-19 Impact factor: 47.728
Authors: Robert M Grant; Javier R Lama; Peter L Anderson; Vanessa McMahan; Albert Y Liu; Lorena Vargas; Pedro Goicochea; Martín Casapía; Juan Vicente Guanira-Carranza; Maria E Ramirez-Cardich; Orlando Montoya-Herrera; Telmo Fernández; Valdilea G Veloso; Susan P Buchbinder; Suwat Chariyalertsak; Mauro Schechter; Linda-Gail Bekker; Kenneth H Mayer; Esper Georges Kallás; K Rivet Amico; Kathleen Mulligan; Lane R Bushman; Robert J Hance; Carmela Ganoza; Patricia Defechereux; Brian Postle; Furong Wang; J Jeff McConnell; Jia-Hua Zheng; Jeanny Lee; James F Rooney; Howard S Jaffe; Ana I Martinez; David N Burns; David V Glidden Journal: N Engl J Med Date: 2010-11-23 Impact factor: 91.245
Authors: Michael C Thigpen; Poloko M Kebaabetswe; Lynn A Paxton; Dawn K Smith; Charles E Rose; Tebogo M Segolodi; Faith L Henderson; Sonal R Pathak; Fatma A Soud; Kata L Chillag; Rodreck Mutanhaurwa; Lovemore Ian Chirwa; Michael Kasonde; Daniel Abebe; Evans Buliva; Roman J Gvetadze; Sandra Johnson; Thom Sukalac; Vasavi T Thomas; Clyde Hart; Jeffrey A Johnson; C Kevin Malotte; Craig W Hendrix; John T Brooks Journal: N Engl J Med Date: 2012-07-11 Impact factor: 91.245
Authors: Jared M Baeten; Deborah Donnell; Patrick Ndase; Nelly R Mugo; James D Campbell; Jonathan Wangisi; Jordan W Tappero; Elizabeth A Bukusi; Craig R Cohen; Elly Katabira; Allan Ronald; Elioda Tumwesigye; Edwin Were; Kenneth H Fife; James Kiarie; Carey Farquhar; Grace John-Stewart; Aloysious Kakia; Josephine Odoyo; Akasiima Mucunguzi; Edith Nakku-Joloba; Rogers Twesigye; Kenneth Ngure; Cosmas Apaka; Harrison Tamooh; Fridah Gabona; Andrew Mujugira; Dana Panteleeff; Katherine K Thomas; Lara Kidoguchi; Meighan Krows; Jennifer Revall; Susan Morrison; Harald Haugen; Mira Emmanuel-Ogier; Lisa Ondrejcek; Robert W Coombs; Lisa Frenkel; Craig Hendrix; Namandjé N Bumpus; David Bangsberg; Jessica E Haberer; Wendy S Stevens; Jairam R Lingappa; Connie Celum Journal: N Engl J Med Date: 2012-07-11 Impact factor: 91.245
Authors: Albert Y Liu; Aliza Norwood; Holly Gundacker; Alex Carballo-Diéguez; Sherri Johnson; Karen Patterson; Linda-Gail Bekker; Suwat Chariyalertsak; Anupong Chitwarakorn; Pedro Gonzales; Timothy H Holtz; Kenneth H Mayer; Carmen Zorrilla; Susan Buchbinder; Jeanna M Piper; Javier R Lama; Ross D Cranston Journal: J Acquir Immune Defic Syndr Date: 2019-08-15 Impact factor: 3.731
Authors: Amy Cutrell; Deborah Donnell; David T Dunn; David V Glidden; Anneke Grobler; Brett Hanscom; Britt S Stancil; R Daniel Meyer; Ronnie Wang; Robert L Cuffe Journal: HIV Clin Trials Date: 2017-10-17