Dose finding study for on-demand HIV pre-exposure prophylaxis for insertive sex in sub-Saharan Africa: results from the CHAPS open label randomised controlled trial
Carolina Herrera, Jennifer Serwanga, Laura Else, Lebina Limakatso, Daniel Opoka, Andrew Sentoogo Ssemata, Azure-Dee Pillay, Patricia Namubiru, Thabiso Seiphetlo, Geoffrey Odoch, Susan Mugaba, Portia Seatlholo, Amara Alieu, Sujan Dilly Penchala, Richard Muhumuza, Berenice Alinde, Stefan Petkov, Kyle O'Hagan, Christian Callebaut, Janet Seeley, Helen A. Weiss, Saye Khoo, Francesca Chiodi, Clive M. Gray, Pontiano Kaleebu, Emily L. Webb, Neil Martinson, Julie Fox, Nadia Ahmed, Berenice Alinde, Amara Alieu, Millicent Atujuna, Esther Awino, Linda‐Gail Bekker, Christian Callebaut, Francesca Chiodi, Mike Chirenje, Janan Dietrich, Jeffrey H. Dorfman, Laura Else, Julie Fox, Clive M. Gray, Christian Holm Hansen, Carolina Herrera, Stefanie Hornschuh, Ayoub Kakande, Pontiano Kaleebu, Charles Kelly, Saye Khoo, Mamkiri Khunwane, Limaktso Lebina, Joseph Makhura, Nomvuyo Mangxilana, Neil Martinson, Susan Mugaba, Richard Muhumuza, Freddie Kibengo, Gertrude Mutonyi, Lucia Mungate, Winnie Nabukeera, Rehema Nagawa, Phiona Nalubega, Patricia Namubiru, Stephen Nash, Denis Ndekezi, Teacler Nematadzira, Lumka Nobula, Kyle O'Hagan, Geoffrey Odoch, Daniel Opoka, Sujan Dilly Penchala, Stefan Petkov, Azure-Dee Pillay, J. Rooney, Elzette Rousseau, Eugene Ruzagira, Alison Sango, Ntombexolo Seatlholo, Janet Seeley, Thabiso Seiphetlo, Jennifer Serwanga, Robin J. Shattock, Andrew Sentoogo Ssemata, Lynda Stranix‐Chibanda, Gugulethu Tshabalala, Emily L. Webb, Helen A. Weiss
Abstract
Background The efficacy of on-demand HIV pre-exposure prophylaxis (PrEP) for men in sub-Saharan Africa has not been evaluated, and the on-demand PrEP dosing requirement for insertive sex remains unknown. Methods HIV-negative males 13–24 years, requesting voluntary medical male circumcision (VMMC), were enrolled into an open-label randomised controlled trial (NCT03986970), and randomised 1:1:1:1:1:1:1:1:1 to control arm or one of eight arms receiving emtricitabine-tenofovir disoproxil fumarate (F/TDF) or emtricitabine-tenofovir alafenamide (F/TAF) over one or two days, and circumcised 5 or 21 h thereafter. The primary outcome was foreskin p24 concentrations following ex vivo HIV-1 BaL challenge. Secondary outcomes included peripheral blood mononuclear cell (PBMC) p24 concentration, and drug concentrations in foreskin tissue, PBMCs, plasma and foreskin CD4+/CD4-cells. In the control arm, post-exposure prophylaxis (PEP) activity of non-formulated tenofovir-emtricitabine (TFV-FTC) or TAF-FTC was assessed with ex vivo dosing 1, 24, 48 or 72 h post-HIV-1 challenge. Findings 144 participants were analysed. PrEP with F/TDF or F/TAF prevented ex vivo infection of foreskins and PBMCs both 5 and 21 h after PrEP dosing. There was no difference between F/TDF and F/TAF (p24 day15 geometric mean ratio 1.06, 95% confidence interval: 0.65–1.74). Additional ex vivo dosing did not further increase inhibition. In the control arm, PEP ex vivo dosing was effective up to 48 post-exposure diminishing thereafter, with TAF-FTC showing prolonged protection compared to TFV-FTC. Participants receiving F/TAF had higher TFV-DP concentrations in foreskin tissue and PBMCs compared with F/TDF, irrespective of dose and sampling interval; but F/TAF did not confer preferential TFV-DP distribution into foreskin HIV target cells. FTC-TP concentrations with both drug regimens were equivalent and ∼1 log higher than TFV-DP in foreskin. Interpretation A double dose of either F/TDF or F/TAF given once either 5 or 21 h before ex vivo HIV-challenge provided protection across foreskin tissue. Further clinical evaluation of pre-coital PrEP for insertive sex is warranted. Funding EDCTP2, Gilead Sciences, Vetenskapsrådet.