EBioMedicine (Jul 2023)
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 trialResearch in context
- 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,
- 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
- Carolina Herrera
- Department of Infectious Disease, Faculty of Medicine, Imperial College London, Norfolk Place, W2 1PG, London, UK
- Jennifer Serwanga
- Medical Research Council/Uganda Virus Research Institute, and London School of Hygiene and Tropical Medicine, Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, Uganda
- Laura Else
- Department of Molecular and Clinical Pharmacology, William Henry Duncan Building, University of Liverpool, 6 West Derby Street, Liverpool, L7 8TX, UK
- Lebina Limakatso
- Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; Africa Health Research Unit, Durban, South Africa
- Daniel Opoka
- Medical Research Council/Uganda Virus Research Institute, and London School of Hygiene and Tropical Medicine, Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, Uganda
- Andrew S. Ssemata
- 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
- Azure-Dee Pillay
- 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
- Patricia Namubiru
- Medical Research Council/Uganda Virus Research Institute, and London School of Hygiene and Tropical Medicine, Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, Uganda
- Thabiso B. Seiphetlo
- 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
- Geoffrey Odoch
- Medical Research Council/Uganda Virus Research Institute, and London School of Hygiene and Tropical Medicine, Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, Uganda
- Susan Mugaba
- Medical Research Council/Uganda Virus Research Institute, and London School of Hygiene and Tropical Medicine, Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, Uganda
- Portia Seatlholo
- Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa; Africa Health Research Unit, Durban, South Africa
- Amara Alieu
- Department of Molecular and Clinical Pharmacology, William Henry Duncan Building, University of Liverpool, 6 West Derby Street, Liverpool, L7 8TX, UK
- Sujan Dilly Penchala
- Department of Molecular and Clinical Pharmacology, William Henry Duncan Building, University of Liverpool, 6 West Derby Street, Liverpool, L7 8TX, UK
- Richard Muhumuza
- Medical Research Council/Uganda Virus Research Institute, and London School of Hygiene and Tropical Medicine, Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, Uganda
- Berenice Alinde
- Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Department of Pathology, University of Cape Town, Cape Town, South Africa
- Stefan Petkov
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solnavägen 9, 171 65 Solna, Sweden
- Kyle O'Hagan
- Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Department of Pathology, University of Cape Town, Cape Town, South Africa
- Christian Callebaut
- Gilead Sciences, Foster City, CA 94404, USA
- Janet Seeley
- 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
- Helen Weiss
- MRC International Statistics and Epidemiology Group, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
- Saye Khoo
- Department of Molecular and Clinical Pharmacology, William Henry Duncan Building, University of Liverpool, 6 West Derby Street, Liverpool, L7 8TX, UK
- Francesca Chiodi
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solnavägen 9, 171 65 Solna, Sweden
- Clive M. Gray
- 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
- Pontiano Kaleebu
- Medical Research Council/Uganda Virus Research Institute, and London School of Hygiene and Tropical Medicine, Uganda Research Unit, 51-59 Nakiwogo Road, Entebbe, Uganda
- Emily L. Webb
- MRC International Statistics and Epidemiology Group, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
- Neil Martinson
- 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
- Julie Fox
- Infection and Immunity, Borough Wing, Guys and St Thomas' NHS Foundation Trust and King's College London, St. Thomas Street, SE1 9RS, London, UK; Corresponding author. Infection and Immunity, Borough Wing, Guys and St Thomas' NHS Foundation Trust and King's College London, St. Thomas Street, SE1 9RS, London, UK.
- 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
- Journal volume & issue
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Vol. 93
p. 104648
Abstract
Summary: 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-1BaL 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 (p24day15 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.
