Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
Magee-Womens Research Institute, Pittsburgh, PA, USA.
J Int AIDS Soc. 2018 Aug;21(8):e25156. doi: 10.1002/jia2.25156.
Fast-dissolving vaginal film formulations release antiretroviral drugs directly into vaginal fluid and may be as efficient at drug delivery yet more acceptable to women than gels. In this Phase 1 vaginal film study, the safety, acceptability, pharmacokinetics and pharmacodynamics of two doses of tenofovir (TFV) film and TFV 1% gel were compared to corresponding placebo formulations.
Seventy-eight healthy HIV negative women were randomized to self-insert daily vaginal film (10 mg TFV, 40 mg TFV or placebo) or 4 mL of vaginal gel (TFV 1% [40 mg] or placebo) for seven days. Grade 2 and higher adverse events (AEs) related to study product were compared across study arms using Fisher's exact test. Plasma TFV concentrations were measured before and 2 hours after last product use. Paired cervical and vaginal tissue biopsies obtained 2 hours after the last dose were measured to determine tenofovir diphosphate (TFV-DP) concentrations and exposed to HIV in an ex vivo challenge assay. Acceptability was assessed through questionnaire.
There was only one grade 2 or higher related AE, the primary endpoint; it occurred in the placebo gel arm. AEs occurred in 90% of participants; the majority (91%) were grade 1. AEs were similar across study arms. TFV concentrations in plasma and TFV-DP concentrations in cervical and vaginal tissues were comparable between 40 mg TFV film and the TFV gel groups. There was a significant relationship between reduced viral replication and TFV-DP concentrations in cervical tissues. Film users were less likely to report product leakage than gel users (66% vs. 100%, p < 0.001).
Films were safe and well tolerated. Furthermore, films delivered TFV to mucosal tissues at concentrations similar to gel and were sufficient to block HIV infection of genital tissue ex vivo.
速溶阴道膜制剂将抗逆转录病毒药物直接释放到阴道液中，在药物输送方面可能与凝胶一样高效，而且更受女性欢迎。在这项 1 期阴道膜研究中，比较了两种剂量的替诺福韦（TFV）膜和 TFV 1%凝胶与相应安慰剂制剂的安全性、可接受性、药代动力学和药效学。
78 名健康的 HIV 阴性女性被随机分配到每天自我插入阴道膜（10mg TFV、40mg TFV 或安慰剂）或 4ml 阴道凝胶（TFV 1%[40mg]或安慰剂），连续 7 天。使用 Fisher 精确检验比较各研究组与研究产品相关的 2 级及以上不良事件（AE）。在最后一次使用产品前和 2 小时后测量血浆 TFV 浓度。在最后一次剂量后 2 小时获得的宫颈和阴道组织活检标本用于测量替诺福韦二磷酸（TFV-DP）浓度，并在体外挑战试验中暴露于 HIV。通过问卷评估可接受性。
只有一个 2 级或更高的相关 AE，即主要终点；它发生在安慰剂凝胶组。90%的参与者出现 AE；大多数（91%）为 1 级。各研究组的 AE 相似。40mg TFV 膜和 TFV 凝胶组的血浆 TFV 浓度和宫颈及阴道组织中的 TFV-DP 浓度相似。宫颈组织中病毒复制减少与 TFV-DP 浓度之间存在显著关系。与凝胶使用者相比，膜使用者报告产品泄漏的可能性较低（66%比 100%，p<0.001）。
膜是安全且耐受良好的。此外，膜将 TFV 递送到粘膜组织的浓度与凝胶相似，足以阻断 HIV 对生殖器组织的体外感染。
