BACKGROUND: Rectal human immunodeficiency virus (HIV) transmission is an important driver of the HIV epidemic. Optimally formulated gels of antiretroviral drugs are under development for preventing rectally acquired HIV. We investigated in a macaque model the pharmacokinetics and efficacy of 3 rectal gel formulations METHODS: Single-dose pharmacokinetics of low-osmolar 1% maraviroc (MVC), 1% tenofovir (TFV), or 1% MVC/1% TFV combination gel were evaluated in blood, rectal fluids, colorectal biopsy specimens, and rectal lymphocytes. Efficacy was evaluated over 10 twice-weekly rectal SHIV162p3 challenges in rhesus macaques that received either placebo (n = 7), MVC (n = 6), TFV (n = 6), or MVC/TFV (n = 6) gel 30 minutes before each challenge. RESULTS: MVC and TFV were detected in plasma 30 minutes after gel application and remained above 95% inhibitory concentrations in rectal fluids at 24 hours. MVC, TFV, and TFV diphosphate (TFV-DP) concentrations in colorectal tissues collected up to 30 cm from the anal margin were all high at 2 hours, demonstrating rapid and extended tissue dosing. TFV-DP concentrations in tissue homogenates and rectal lymphocytes were highly correlated (r(2) = 0.82). All 3 gel formulations were highly protective (82% efficacy; P ≤ .02 by the log-rank test). CONCLUSIONS: Desirable pharmacokinetic profiles and high efficacy in this macaque model support the clinical development of these gel formulations for preventing rectal HIV infection. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
BACKGROUND: Rectal human immunodeficiency virus (HIV) transmission is an important driver of the HIV epidemic. Optimally formulated gels of antiretroviral drugs are under development for preventing rectally acquired HIV. We investigated in a macaque model the pharmacokinetics and efficacy of 3 rectal gel formulations METHODS: Single-dose pharmacokinetics of low-osmolar 1% maraviroc (MVC), 1% tenofovir (TFV), or 1% MVC/1% TFV combination gel were evaluated in blood, rectal fluids, colorectal biopsy specimens, and rectal lymphocytes. Efficacy was evaluated over 10 twice-weekly rectal SHIV162p3 challenges in rhesus macaques that received either placebo (n = 7), MVC (n = 6), TFV (n = 6), or MVC/TFV (n = 6) gel 30 minutes before each challenge. RESULTS: MVC and TFV were detected in plasma 30 minutes after gel application and remained above 95% inhibitory concentrations in rectal fluids at 24 hours. MVC, TFV, and TFV diphosphate (TFV-DP) concentrations in colorectal tissues collected up to 30 cm from the anal margin were all high at 2 hours, demonstrating rapid and extended tissue dosing. TFV-DP concentrations in tissue homogenates and rectal lymphocytes were highly correlated (r(2) = 0.82). All 3 gel formulations were highly protective (82% efficacy; P ≤ .02 by the log-rank test). CONCLUSIONS: Desirable pharmacokinetic profiles and high efficacy in this macaque model support the clinical development of these gel formulations for preventing rectal HIV infection. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Entities:
Keywords:
HIV prevention; macaque model; maraviroc; rectal microbicides; repeat-challenge; tenofovir
Authors: Peter W Hunt; Nancy S Shulman; Timothy L Hayes; Viktor Dahl; Ma Somsouk; Nicholas T Funderburg; Bridget McLaughlin; Alan L Landay; Oluwatoyin Adeyemi; Lee E Gilman; Brian Clagett; Benigno Rodriguez; Jeffrey N Martin; Timothy W Schacker; Barbara L Shacklett; Sarah Palmer; Michael M Lederman; Steven G Deeks Journal: Blood Date: 2013-04-15 Impact factor: 22.113
Authors: Kenneth H Mayer; Lisa A Maslankowski; Fang Gai; Wafaa M El-Sadr; Jessica Justman; Antonia Kwiecien; Benoît Mâsse; Susan H Eshleman; Craig Hendrix; Kathleen Morrow; James F Rooney; Lydia Soto-Torres Journal: AIDS Date: 2006-02-28 Impact factor: 4.177
Authors: Francisco J Leyva; Rahul P Bakshi; Edward J Fuchs; Liye Li; Brian S Caffo; Arthur J Goldsmith; Ana Ventuneac; Alex Carballo-Diéguez; Yong Du; Jeffrey P Leal; Linda A Lee; Michael S Torbenson; Craig W Hendrix Journal: AIDS Res Hum Retroviruses Date: 2013-08-24 Impact factor: 2.205
Authors: Charlene S Dezzutti; Julie Russo; Lin Wang; Kaleab Z Abebe; Jie Li; David R Friend; Ian M McGowan; Lisa C Rohan Journal: PLoS One Date: 2014-07-15 Impact factor: 3.240
Authors: Ian McGowan; Craig Hoesley; Ross D Cranston; Philip Andrew; Laura Janocko; James Y Dai; Alex Carballo-Dieguez; Ratiya Kunjara Na Ayudhya; Jeanna Piper; Florian Hladik; Ken Mayer Journal: PLoS One Date: 2013-04-03 Impact factor: 3.240
Authors: J Gerardo García-Lerma; Ron A Otten; Shoukat H Qari; Eddie Jackson; Mian-Er Cong; Silvina Masciotra; Wei Luo; Caryn Kim; Debra R Adams; Michael Monsour; Jonathan Lipscomb; Jeffrey A Johnson; David Delinsky; Raymond F Schinazi; Robert Janssen; Thomas M Folks; Walid Heneine Journal: PLoS Med Date: 2008-02 Impact factor: 11.069
Authors: Martin Cranage; Sally Sharpe; Carolina Herrera; Alethea Cope; Mike Dennis; Neil Berry; Claire Ham; Jonathan Heeney; Naser Rezk; Angela Kashuba; Peter Anton; Ian McGowan; Robin Shattock Journal: PLoS Med Date: 2008-08-05 Impact factor: 11.069
Authors: Peng Xiao; Sanjeev Gumber; Mark A Marzinke; Abhijit A Date; Thuy Hoang; Justin Hanes; Laura M Ensign; Lin Wang; Lisa Rohan; Edward J Fuchs; Craig Hendrix; Francois Villinger Journal: Antimicrob Agents Chemother Date: 2017-12-21 Impact factor: 5.191
Authors: Ian McGowan; Timothy Wilkin; Raphael J Landovitz; Chunyuan Wu; Ying Chen; Mark A Marzinke; Craig W Hendrix; Paul Richardson; Susan H Eshleman; Adriana Andrade; Wairimu Chege; Peter L Anderson; Marybeth McCauley; Jason Farley; Kenneth H Mayer; Peter Anton; Rhonda M Brand; Ross D Cranston; Roy Gulick Journal: AIDS Date: 2019-02-01 Impact factor: 4.177
Authors: Egidio Brocca-Cofano; Cuiling Xu; Katherine S Wetzel; Mackenzie L Cottrell; Benjamin B Policicchio; Kevin D Raehtz; Dongzhu Ma; Tammy Dunsmore; George S Haret-Richter; Karam Musaitif; Brandon F Keele; Angela D Kashuba; Ronald G Collman; Ivona Pandrea; Cristian Apetrei Journal: J Virol Date: 2018-08-16 Impact factor: 5.103
Authors: Ian M McGowan; Sylvain Chawki; Craig W Hendrix; Peter A Anton; Mark A Marzinke; Rhonda M Brand; Jarret C Engstrom; Lisa C Rohan; Kaleab Z Abebe; Nicola Richardson-Harman; Aaron Siegel; Alex Reinhart; John Steytler; Ronald Stall; Hans Spiegel; Beatrice Chen; Sharon L Achilles; Cindy E Jacobson; Elena Khanukova; Ross D Cranston Journal: AIDS Res Hum Retroviruses Date: 2021-09-14 Impact factor: 1.723
Authors: Sabdat O Ekama; Margaret O Ilomuanya; Chukwuemeka P Azubuike; Tajudeen A Bamidele; Muinah A Fowora; Oluwagbemiga O Aina; Oliver C Ezechi; Cecilia I Igwilo Journal: HIV AIDS (Auckl) Date: 2021-04-08