An intravaginal ring for HIV pre-exposure prophylaxis: assessment of safety and pharmacokinetics in a randomized, placebo-controlled clinical trial.
Vincent Kathleen L KL, Moss John A JA, Marzinke Mark A MA, Pyles Richard B RB et al.
In Eastern and Southern Africa, 63% of new HIV infections occurred in women and girls, with adolescent girls and young women representing a particularly vulnerable subpopulation. Effective vaginal products for HIV prevention are desirable because they are underrepresented in the currently approved portfolio and have attributes motivating product use. In this trial, we evaluated an innovative intravaginal ring (pod-IVR) as a platform for HIV pre-exposure prophylaxis (PrEP). To measure the safety and multicompartment pharmacokinetics (PKs) of a pod-IVR delivering tenofovir disoproxil fumarate (TDF) combined with emtricitabine (FTC) in healthy women over 28 days. The Phase 1 clinical trial consisted of a randomized order, controlled, double-blinded, crossover design. Ten women received either an active TDF-FTC pod-IVR or a placebo pod-IVR for 28 days, determined by 1:1 randomization, followed by product crossover for another 28 days. Safety was assessed in terms of adverse events related to product use, colposcopic examination, cervicovaginal epithelium thickness measurement by optical coherence tomography, and culture-independent assessment of the vaginal microbiome. Drug and/or drug metabolite concentrations were measured in cervicovaginal fluid (CVF), vaginal tissue, rectal tissue, rectal fluid, and plasma. There was no evidence of a statistically significant difference in related adverse-event counts between study products. There also was no evidence suggesting the study product altered the vaginal microbiome systematically or reproducibly. Systemic plasma exposure to tenofovir (TFV) and FTC was low, consistent with topical delivery. High median CVF concentrations of TFV (38.9 ng mg-1; 135×103 fmol mg-1) and FTC (239 ng mg-1; 966×103 fmol mg-1) were measured. Median vaginal tissue concentrations of the anabolites responsible for inhibition of HIV reverse transcriptase exceeded our target concentrations: TFV diphosphate 0.651×103 fmol mg-1 and FTC triphosphate 0.180×103 fmol mg-1. Drug concentrations in rectal tissue samples generally were below the analytical lower limits of quantification, but were quantifiable in rectal fluids, 130 (TFV) and 300 (FTC) times lower than in CVF. The TDF-FTC pod-IVRs were safe and well-tolerated over the 28 days of consecutive use. The PK data met the target benchmarks associated with protection from vaginal HIV infection. https://clinicaltrials.gov/study/NCT03255915, identifier NCT03255915.