Intravaginal rings releasing tenofovir (TFV) or its prodrug, tenofovir disoproxil fumarate (TDF), are being evaluated for HIV and herpes simplex virus (HSV) prevention. The current studies were designed to determine the mechanisms of drug accumulation in human vaginal and immune cells. The exposure of vaginal epithelial or T cells to equimolar concentrations of radiolabeled TDF resulted in over 10-fold higher intracellular drug levels than exposure to TFV. Permeability studies demonstrated that TDF, but not TFV, entered cells by passive diffusion. TDF uptake was energy independent but its accumulation followed nonlinear kinetics, and excess unlabeled TDF inhibited radiolabeled TDF uptake in competition studies. The carboxylesterase inhibitor bis-nitrophenyl phosphate reduced TDF uptake, suggesting saturability of intracellular carboxylesterases. In contrast, although TFV uptake was energy dependent, no competition between unlabeled and radiolabeled TFV was observed, and the previously identified transporters, organic anion transporters ( T opical preexposure prophylaxis (PrEP) with tenofovir (TFV)-based drugs could provide a female-initiated method for the prevention of HIV and genital herpes simplex virus (HSV) infections in women (1). Pericoital dosing with 1% vaginal TFV gel reduced HIV acquisition by 39% overall and by 54% in highly adherent women (2, 3) and reduced HSV-2 acquisition by 51% in the CAPRISA 004 trial (4). However, the same gel did not provide protection against HIV in the Vaginal and Oral Interventions to Control the Epidemic (VOICE) and Follow-On Consortium for Tenofovir Studies (FACTS) 001 phase 3 trials, presumably reflecting low adherence (5, 6). Women with detectable TFV in their plasma at the first quarterly visit were less likely to acquire HIV than women with no drug detected (adjusted hazard ratio, 0.34; 95% confidence interval [CI], 0.13 to 0.87; P ϭ 0.02) in a secondary analysis of VOICE data, but the interpretation of this is complex, as women at highest risk for HIV acquisition were less likely to be adherent (5). These findings underscore the need for drugs and delivery systems that mitigate the difficulties associated with adherence.Intravaginal rings (IVRs) designed to deliver TFV and tenofovir disoproxil fumarate (TDF) are currently in early clinical development (7,8). A TDF ring completely protected macaques against 16 weekly intravaginal challenges with simian HIV (8) and also was highly protective in more susceptible, medroxyprogesteronetreated animals (9). Nonhuman primate challenge studies with the TFV IVR have not been published. Consistent with in vitro antiviral studies, 0.3% TDF gel provided significantly greater protection than 1% TFV gel in mice challenged intravaginally with HSV-2 (10). Moreover, the 0.3% TDF gel demonstrated significantly greater protection than 1% TFV gel in mice transgenic for human CD4, CCR5, and cyclin T1 against HIV and HSV-2 (11). These findings may reflect differences in drug pharmacokinetics (PK).The mechanisms of TFV and TDF cellular tran...
Tenofovir gel and dapivirine ring provided variable HIV protection in clinical trials, reflecting poor adherence and possibly biological factors. We hypothesized that vaginal microbiota modulates pharmacokinetics and tested the effects of pH, individual bacteria, and vaginal swabs from women on pharmacokinetics and antiviral activity. Tenofovir, but not dapivirine, uptake by human cells was reduced as pH increased. Lactobacillus crispatus actively transported tenofovir leading to a loss in drug bioavailability and culture supernatants from Gardnerella vaginalis, but not Atopobium vaginae, blocked tenofovir endocytosis. The inhibition of endocytosis mapped to adenine. Adenine increased from 65.5 μM in broth to 246 μM in Gardnerella, but decreased to 9.5 μM in Atopobium supernatants. This translated into a decrease in anti-HIV activity when Gardnerella supernatants or adenine were added to cultures. Dapivirine was also impacted by microbiota, as drug bound irreversibly to bacteria, resulting in decreased antiviral activity. When drugs were incubated with vaginal swabs, 30.7% ± 5.7% of dapivirine and 63.9% ± 8.8% of tenofovir were recovered in supernatants after centrifugation of the bacterial cell pellet. In contrast, no impact of microbiota on the pharmacokinetics of the prodrugs, tenofovir disoproxil fumarate or tenofovir alafenamide, was observed. Together, these results demonstrate that microbiota may impact pharmacokinetics and contribute to inconsistent efficacy.
dIncreased susceptibility to genital herpes in medroxyprogesterone-treated mice may provide a surrogate of increased HIV risk and a preclinical biomarker of topical preexposure prophylaxis safety. We evaluated tenofovir disoproxil fumarate (TDF) in this murine model because an intravaginal ring eluting this drug is being advanced into clinical trials. To avoid the complications of surgically inserting a ring, hydroxyethylcellulose (HEC)-stable formulations of TDF were prepared. One week of twice-daily 0.3% TDF gel was well tolerated and did not result in any increase in HSV-2 susceptibility but protected mice from herpes simplex virus 2 (HSV-2) disease compared to mice treated with the HEC placebo gel. No significant increase in inflammatory cytokines or chemokines in vaginal washes or change in cytokine, chemokine, or mitochondrial gene expression in RNA extracted from genital tract tissue was detected. To further evaluate efficacy, mice were treated with gel once daily beginning 12 h prior to high-dose HSV-2 challenge or 2 h before and after viral challenge (BAT24 dosing). The 0.3% TDF gel provided significant protection compared to the HEC gel following either daily (in 9/10 versus 1/10 mice, P < 0.01) or BAT24 (in 14/20 versus 4/20 mice, P < 0.01) dosing. In contrast, 1% tenofovir (TFV) gel protected only 4/10 mice treated with either regimen. Significant protection was also observed with daily 0.03% TDF compared to HEC. Protection was associated with greater murine cellular permeability of radiolabeled TDF than of TFV. Together, these findings suggest that TDF is safe, may provide substantially greater protection against HSV than TFV, and support the further clinical development of a TDF ring.
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