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Pharmacokinetic and pharmacodynamic study of tenofovir and tenofovir alafenamide for PrEP in foreskin tissue
Background: Pre-exposure prophylaxis (PrEP) studies have focussed predominantly on the efficacy in female reproductive and colorectal tracts, with limited research on the efficacy of PrEP candidates in the male genital tract. We assessed the ex vivo pharmacological profile of Tenofovir (TFV) and Ten...
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Published in: | Journal of the International AIDS Society 2021-01, Vol.24 (S1), p.47 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | Background: Pre-exposure prophylaxis (PrEP) studies have focussed predominantly on the efficacy in female reproductive and colorectal tracts, with limited research on the efficacy of PrEP candidates in the male genital tract. We assessed the ex vivo pharmacological profile of Tenofovir (TFV) and Tenofovir alafenamide (TAF) in foreskin tissue to inform the design of the CHAPS oral PrEP trial (NCT03986970). Methods: Foreskin specimens were obtained with signed informed consent from HIV-negative males who voluntary requested medical circumcision. Inner mucosal and outer skin were cut in explants and exposed to serial dilutions of TFV or TAF for one hours prior to addition of HIV-[1.sub.BaL] at a high (HVT) or a low viral titre (LVT) for two hours. Infection was assessed at different time points during 15 days of culture by measurement of p24 in culture supernatants. TFV, TAF and TFV-diphosphate (TFV-DP) concentrations were measured in tissue, culture supernatants and dosing and washing solutions using LC-MS methods. Results: Dose-response curves were obtained for both drugs against the two viral titres tested with greater inhibitory potency observed against LVT. Inhibitory equivalency mimicking oral dosing was defined between 1 mg/mL of TFV and 15 [micro]g/mL of TAF against HVT for the dosing post-ex vivo challenge included in the design of CHAPS trial. Concentrations of TFV-DP in foreskin explants were at least 5 times higher after ex vivo dosing with TAF vs. TFV. Statistically significant negative linear correlations were observed between explant TFV-DP levels and p24 concentrations following HVT ([r.sup.2]=0.6867, p =0.0001 for TFV and [r.sup.2]=0.6696, p =0.0002 for TAF). Conclusions: Pre-clinical evaluation of TAF reveals greater potency than TFV against penile HIV transmission. Ex vivo dose-challenge studies in human foreskin explants can be used as surrogate for in vivo studies to compare doses and preventive agents to be included in clinical trials. |
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ISSN: | 1758-2652 1758-2652 |
DOI: | 10.1002/jia2.25659 |