Dataset Information

Pre-Clinical Evaluation of Tenofovir and Tenofovir Alafenamide for HIV-1 Pre-Exposure Prophylaxis in Foreskin Tissue.

ABSTRACT:

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-1_BaL 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.

SUBMITTER: Else L

PROVIDER: S-EPMC9227286 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

Pre-Clinical Evaluation of Tenofovir and Tenofovir Alafenamide for HIV-1 Pre-Exposure Prophylaxis in Foreskin Tissue.

Else Laura L Penchala Sujan D SD Pillay Azure-Dee AD Seiphetlo Thabiso B TB Lebina Limakatso L Callebaut Christian C Minhas Suks S Morley Roland R Rashid Tina T Martinson Neil N Fox Julie J Khoo Saye S Herrera Carolina C

Pharmaceutics 20220616 6

<h4>Background</h4>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.<h4>Methods</h4>Inner and outer foreskin explants were exposed to serial dilutions of TFV or TAF prior to addition of HIV-1<sub>BaL</sub> at a high (HV ...[more]

PMID: 35745857

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Project description:ImportancePre-exposure prophylaxis (PrEP) is an important tool for preventing HIV infection. However, PrEP's impact on cardiometabolic health is understudied.ObjectiveTo examine the risk of incident hypertension and statin initiation among adult (age ≥18 years) health plan members starting PrEP with tenofovir alafenamide fumarate (TAF) compared with propensity score-matched adults taking tenofovir disoproxil fumarate (TDF).Design, setting, and participantsThis retrospective cohort study used electronic health records (EHRs) from Kaiser Permanente Southern California. Adult members starting PrEP in Kaiser Permanente Southern California between October 2019 and May 2022 were included. Propensity score matching with multiple imputation (50 matched data sets) was conducted to generate 1 TAF:4 TDF matched data sets with balanced baseline covariates.ExposuresPrEP initiation with either TAF or TDF during the study period.Main outcomes and measuresIncident hypertension and statin initiation within 2 years of PrEP initiation were ascertained through blood pressure and outpatient pharmacy records, respectively. Risk differences and odds ratios (ORs) were estimated using logistic regression and g-computation.ResultsA total of 6824 eligible individuals were identified (mean [SD] age, 33.9 [10.3] years; 6618 [97%] male). This pool was used to generate 2 cohorts without baseline hypertension or statin use for matching (hypertension: n = 5523; statin: n = 6149) In both cohorts, those starting PrEP with TAF were older and were more likely to be non-Hispanic White compared with those starting with TDF. In matched analysis adjusting for baseline covariates, TAF use was associated with elevated risk of incident hypertension (TAF: n = 371; risk difference, 0.81 [95% CI, 0.12-1.50]; OR, 1.64 [95% CI, 1.05-2.56]). TAF use was also associated with elevated risk of statin initiation (TAF: n = 382; risk difference, 0.85 [95% CI, 0.37-1.33]; OR, 2.33 [95% CI, 1.41-3.85]). Subgroup analyses restricted to individuals 40 years and older at PrEP initiation showed similar results with larger risk difference in statin initiation (risk difference, 4.24 [95% CI, 1.82-6.26]; OR, 3.05 [95% CI, 1.64-5.67]).Conclusions and relevanceIn this study of people taking PrEP, TAF use was found to be associated with higher incident hypertension and statin initiation compared with TDF use, especially in those 40 years or older. Continued monitoring of blood pressure and lipids for TAF users is warranted.

Project description:IntroductionTight junctions (TJs) serve as permeability filters between the internal and external cellular environment. A large number of proteins have been identified to be localized at the TJs. Due to limitations in tissue collection, TJs in the male genital tract have been understudied.MethodsWe analysed the transcriptomics of 132 TJ genes in foreskin tissue of men requesting voluntary medical male circumcision (VMMC) and enrolled in the Combined HIV Adolescent Prevention Study (CHAPS) trial conducted in South Africa and Uganda (NCT03986970). The trial evaluated the dose requirements for event-driven HIV pre-exposure prophylaxis (PrEP) with emtricitabine-tenofovir (FTC-TDF) or emtricitabine-tenofovir alafenamide (FTC-TAF) during insertive sex. A total of 144 participants were randomized to either control arm or one of 8 PrEP arms (n=16/arm), receiving oral FTC-TDF or FTC-TAF over one or two days. Following in vivo oral PrEP dosing and VMMC, the expression level of three important TJ proteins (CLDN-1, OCN and ZO-1) was measured ex vivo in foreskin tissue by Western blot. The expression of cytokine genes implicated in TJ regulation was determined. Non-parametric Kruskal-Wallis tests were used to compare TJ gene expression and protein levels by type of PrEP received, and Spearman's correlation coefficients were calculated to assess whether TJ gene expression levels were related to cytokine gene levels or to PrEP drug concentrations and their active intracellularly phosphorylated metabolites.ResultsA high level of expression in foreskin tissue was found for 118 (of 132) TJ genes analysed; this finding contributed to create a map of TJ components within the male genital tract. Importantly, PrEP regimens tested in the CHAPS trial did not affect the expression of TJ genes and the analysed proteins in the foreskin; thus, further supporting the safety of this prevention strategy against HIV-1 transmission during insertive sex. Additionally, we identified the level of several cytokines' genes to be correlated to TJ gene expression: among them, IL-18, IL-33 and VEGF.DiscussionTJs can limit viral entry into target cells; to affect this biological function viruses can reduce the expression of TJ proteins. Our study, on the expression and regulation of TJs in the foreskin, contribute important knowledge for PrEP safety and further design of HIV-1 prophylaxis.

Dataset Information

Pre-Clinical Evaluation of Tenofovir and Tenofovir Alafenamide for HIV-1 Pre-Exposure Prophylaxis in Foreskin Tissue.

Background

Methods

Results

Conclusions

Publications

Pre-Clinical Evaluation of Tenofovir and Tenofovir Alafenamide for HIV-1 Pre-Exposure Prophylaxis in Foreskin Tissue.

Similar Datasets

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