Pre-Clinical Evaluation of Tenofovir and Tenofovir Alafenamide for HIV-1 Pre-Exposure Prophylaxis in Foreskin Tissue
Laura Else,
Sujan D. Penchala,
Azure-Dee Pillay,
Thabiso B. Seiphetlo,
Limakatso Lebina,
Christian Callebaut,
Suks Minhas,
Roland Morley,
Tina Rashid,
Neil Martinson,
Julie Fox,
Saye Khoo,
Carolina Herrera
Affiliations
Laura Else
Bioanalytical Facility, Molecular and Clinical Pharmacology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK
Sujan D. Penchala
Bioanalytical Facility, Molecular and Clinical Pharmacology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK
Azure-Dee Pillay
Division of Immunology, University of Cape Town, Cape Town 7935, South Africa
Thabiso B. Seiphetlo
Division of Immunology, University of Cape Town, Cape Town 7935, South Africa
Limakatso Lebina
Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
Christian Callebaut
Gilead Sciences, Foster City, CA 94404, USA
Suks Minhas
Imperial College Healthcare NHS Trust, Charing Cross Hospital, London W6 8RF, UK
Roland Morley
Imperial College Healthcare NHS Trust, Charing Cross Hospital, London W6 8RF, UK
Tina Rashid
Imperial College Healthcare NHS Trust, Charing Cross Hospital, London W6 8RF, UK
Neil Martinson
Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa
Julie Fox
Guys and St. Thomas’ NHS Foundation Trust and King’s College London, London SE1 9RT, UK
Saye Khoo
Bioanalytical Facility, Molecular and Clinical Pharmacology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK
Carolina Herrera
Department of Infectious Diseases, Faculty of Medicine, Imperial College, London W2 1PG, UK
Background: HIV-1 pre-exposure prophylaxis (PrEP) has focused predominantly on protective efficacy in receptive sex, with limited research on the dosing requirements for insertive sex. We pre-clinically assessed the ex vivo pharmacokinetic–pharmacodynamic (PK–PD) profile of tenofovir (TFV) and tenofovir alafenamide (TAF) in foreskin tissue. Methods: Inner and outer foreskin explants were exposed to serial dilutions of TFV or TAF prior to addition of HIV-1BaL at a high (HVT) or a low viral titer (LVT). Infection was assessed by measurement of p24 in foreskin culture supernatants. TFV, TAF and TFV–diphosphate (TFV–DP) concentrations were measured in tissues, culture supernatants and dosing and washing solutions. Results: Dose–response curves were obtained for both drugs, with greater potency observed against LVT. Inhibitory equivalency mimicking oral dosing was defined between 1 mg/mL of TFV and 15 µg/mL of TAF against HVT challenge. Concentrations of TFV–DP in foreskin explants were approximately six-fold higher after ex vivo dosing with TAF than with TFV. Statistically significant negative linear correlations were observed between explant levels of TFV or TFV–DP and p24 concentrations following HVT. Conclusions: Pre-clinical evaluation of TAF in foreskin explants revealed greater potency than TFV against penile HIV transmission. Clinical evaluation is underway to support this finding.
