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 S Ssemata; Azure-Dee Pillay; Patricia Namubiru; Thabiso B 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 Weiss; Saye Khoo; Francesca Chiodi; Clive M Gray; Pontiano Kaleebu; Emily L Webb; Neil Martinson; Julie Fox; CHAPS

doi:10.1016/j.ebiom.2023.104648

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

EBioMedicine. 2023 Jul:93:104648. doi: 10.1016/j.ebiom.2023.104648. Epub 2023 Jun 14.

Authors

Carolina Herrera¹, Jennifer Serwanga², Laura Else³, Lebina Limakatso⁴, Daniel Opoka², Andrew S Ssemata⁵, Azure-Dee Pillay⁶, Patricia Namubiru², Thabiso B Seiphetlo⁶, Geoffrey Odoch², Susan Mugaba², Portia Seatlholo⁴, Amara Alieu³, Sujan Dilly Penchala³, Richard Muhumuza², Berenice Alinde⁷, Stefan Petkov⁸, Kyle O'Hagan⁷, Christian Callebaut⁹, Janet Seeley¹⁰, Helen Weiss¹¹, Saye Khoo³, Francesca Chiodi⁸, Clive M Gray¹², Pontiano Kaleebu², Emily L Webb¹¹, Neil Martinson¹³, Julie Fox¹⁴; CHAPS

Collaborators

CHAPS:
Nadia Ahmed, Berenice Alinde, Amara Alieu, Millicent Atujuna, Esther Awino, Linda-Gail Bekker, Christian Callebaut, Francesca Chiodi, Mike Chirenje, Janan Dietrich, Jeffrey Dorfman, Laura Else, Julie Fox, Clive 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 Mukasa 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, Jim Rooney, Elzette Rousseau, Eugene Ruzagira, Alison Sango, Ntombexolo Seatlholo, Janet Seeley, Thabiso Seiphetlo, Jennifer Serwanga, Robin Shattock, Andrew S Ssemata, Lynda Stranix-Chibanda, Gugulethu Tshabalala, Emily Webb, Helen Weiss

Affiliations

¹ Department of Infectious Disease, Faculty of Medicine, Imperial College London, Norfolk Place, W2 1PG, London, UK.
² Medical Research Council/Uganda Virus Research Institute, and London School of Hygiene and Tropical Medicine, Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, Uganda.
³ Department of Molecular and Clinical Pharmacology, William Henry Duncan Building, University of Liverpool, 6 West Derby Street, Liverpool, L7 8TX, UK.
⁴ Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; Africa Health Research Unit, Durban, South Africa.
⁵ Medical Research Council/Uganda Virus Research Institute, and London School of Hygiene and Tropical Medicine, Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, Uganda; Department of Global Health and Development, London School of Hygiene & Tropical Medicine, 15-17 Tavistock Place, London, WC1H 9SH, UK.
⁶ Division of Immunology, University of Cape Town, South Africa based at Respiratory and Meningeal Pathogens Research Unit (RMPRU). Chris Hani Baragwanath Hospital, 30 Chris Hani Road, Diepkloof, Soweto, 1862, South Africa.
⁷ Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Department of Pathology, University of Cape Town, Cape Town, South Africa.
⁸ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solnavägen 9, 171 65 Solna, Sweden.
⁹ Gilead Sciences, Foster City, CA 94404, USA.
¹⁰ Department of Global Health and Development, London School of Hygiene & Tropical Medicine, 15-17 Tavistock Place, London, WC1H 9SH, UK; Medical Research Council/Uganda Virus Research Institute, and London School of Hygiene and Tropical Medicine, Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, Uganda.
¹¹ MRC International Statistics and Epidemiology Group, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
¹² Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Biomedical Research Institute, Stellenbosch University (Tygerberg Campus), Francie van Zijl Drive, Tygerberg, Cape Town, South Africa.
¹³ Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; Africa Health Research Unit, Durban, South Africa; Johns Hopkins University Center for TB Research, Baltimore, MD, USA.
¹⁴ Infection and Immunity, Borough Wing, Guys and St Thomas' NHS Foundation Trust and King's College London, St. Thomas Street, SE1 9RS, London, UK. Electronic address: Julie.fox@kcl.ac.uk.

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.

Keywords: Adolescents; Foreskin; HIV-1; Oral PrEP; PK/PD; Tissue explants.

Publication types

Randomized Controlled Trial

MeSH terms

Africa South of the Sahara
Anti-HIV Agents* / therapeutic use
Emtricitabine
HIV Infections* / drug therapy
HIV Infections* / prevention & control
Humans
Leukocytes, Mononuclear
Male
Pre-Exposure Prophylaxis*

Substances

Anti-HIV Agents
3-((3-cholamidopropyl)dimethylammonium)-1-propanesulfonate
Emtricitabine

Abstract

Publication types

MeSH terms

Substances

Grants and funding