Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America.
PLoS Med. 2018 Sep 28;15(9):e1002655. doi: 10.1371/journal.pmed.1002655. eCollection 2018 Sep.
Intravaginal rings (IVRs) for HIV pre-exposure prophylaxis (PrEP) theoretically overcome some adherence concerns associated with frequent dosing that can occur with oral or vaginal film/gel regimens. An innovative pod-IVR, composed of an elastomer scaffold that can hold up to 10 polymer-coated drug cores (or "pods"), is distinct from other IVR designs as drug release from each pod can be controlled independently. A pod-IVR has been developed for the delivery of tenofovir (TFV) disoproxil fumarate (TDF) in combination with emtricitabine (FTC), as daily oral TDF-FTC is the only Food and Drug Administration (FDA)-approved regimen for HIV PrEP. A triple combination IVR building on this platform and delivering TDF-FTC along with the antiretroviral (ARV) agent maraviroc (MVC) also is under development.
This pilot Phase I trial conducted between June 23, 2015, and July 15, 2016, evaluated the safety, pharmacokinetics (PKs), and acceptability of pod-IVRs delivering 3 different ARV regimens: 1) TDF only, 2) TDF-FTC, and 3) TDF-FTC-MVC over 7 d. The crossover, open-label portion of the trial (N = 6) consisted of 7 d of continuous TDF pod-IVR use, a wash-out phase, and 7 d of continuous TDF-FTC pod-IVR use. After a 3-mo pause to evaluate safety and PK of the TDF and TDF-FTC pod-IVRs, TDF-FTC-MVC pod-IVRs (N = 6) were evaluated over 7 d of continuous use. Safety was assessed by adverse events (AEs), colposcopy, and culture-independent analysis of the vaginal microbiome (VMB). Drug and drug metabolite concentrations in plasma, cervicovaginal fluids (CVFs), cervicovaginal lavages (CVLs), and vaginal tissue (VT) biopsies were determined via liquid chromatographic-tandem mass spectrometry (LC-MS/MS). Perceptibility and acceptability were assessed by surveys and interviews. Median participant age was as follows: TDF/TDF-FTC group, 26 y (range 24-35 y), 2 White, 2 Hispanic, and 2 African American; TDF-FTC-MVC group, 24.5 y (range 21-41 y), 3 White, 1 Hispanic, and 2 African American. Reported acceptability was high for all 3 products, and pod-IVR use was confirmed by residual drug levels in used IVRs. There were no serious adverse events (SAEs) during the study. There were 26 AEs reported during TDF/TDF-FTC IVR use (itching, discharge, discomfort), with no differences between TDF alone or in combination with FTC observed. In the TDF-FTC-MVC IVR group, there were 12 AEs (itching, discharge, discomfort) during IVR use regardless of attribution to study product. No epithelial disruption/thinning was seen by colposcopy, and no systematic VMB shifts were observed. Median (IQR) tenofovir diphosphate (TFV-DP) tissue concentrations of 303 (277-938) fmol/10(6) cells (TDF), 289 (110-603) fmol/10(6) cells (TDF-FTC), and 302 (177.1-823.8) fmol/10(6) cells (TDF-FTC-MVC) were sustained for 7 d, exceeding theoretical target concentrations for vaginal HIV prevention. The study's main limitations include the small sample size, short duration (7 d versus 28 d), and the lack of FTC triphosphate measurements in VT biopsies.
An innovative pod-IVR delivery device with 3 different formulations delivering different regimens of ARV drugs vaginally appeared to be safe and acceptable and provided drug concentrations in CVFs and tissues exceeding concentrations achieved by highly protective oral dosing, suggesting that efficacy for vaginal HIV PrEP is achievable. These results show that an alternate, more adherence-independent, longer-acting prevention device based on the only FDA-approved PrEP combination regimen can be advanced to safety and efficacy testing.
ClinicalTrials.gov NCT02431273.
阴道内环（IVR）可用于 HIV 暴露前预防（PrEP），理论上克服了一些与口服或阴道薄膜/凝胶方案相关的频繁剂量的依从性问题。一种创新的荚膜-IVR，由一个可以容纳多达 10 个聚合物涂层药物核心（或“荚膜”）的弹性体支架组成，与其他 IVR 设计不同，因为每个荚膜的药物释放可以独立控制。已经开发出一种荚膜-IVR 用于递送达福韦酯（TDF）双异丙氧肟酸富马酸盐（TDF）与恩曲他滨（FTC）的组合，因为每日口服 TDF-FTC 是唯一获得美国食品和药物管理局（FDA）批准的 HIV PrEP 方案。在此平台上开发的一种三重组合 IVR 也正在开发中，用于递送达福韦酯（TDF）-FTC 以及抗逆转录病毒（ARV）药物马拉维若（MVC）。
这项于 2015 年 6 月 23 日至 2016 年 7 月 15 日进行的 I 期试验评估了荚膜-IVR 递送达福韦酯（TDF）的安全性、药代动力学（PK）和可接受性。结果如下：1）仅 TDF，2）TDF-FTC，以及 3）TDF-FTC-MVC 持续 7 天。试验的交叉、开放标签部分（N = 6）包括 7 天持续使用 TDF 荚膜-IVR，洗脱期和 7 天持续使用 TDF-FTC 荚膜-IVR。在暂停 3 个月评估 TDF 和 TDF-FTC 荚膜-IVR 的安全性和 PK 后，评估了 TDF-FTC-MVC 荚膜-IVR（N = 6）持续使用 7 天。通过液相色谱-串联质谱（LC-MS/MS）测定血浆、宫颈阴道液（CVF）、宫颈阴道灌洗（CVL）和阴道组织（VT）活检中的药物和药物代谢物浓度。通过调查和访谈评估可感知性和可接受性。TDF/TDF-FTC 组的中位参与者年龄如下：26 岁（范围 24-35 岁），2 名白人，2 名西班牙裔，2 名非裔美国人；TDF-FTC-MVC 组，24.5 岁（范围 21-41 岁），3 名白人，1 名西班牙裔，2 名非裔美国人。所有 3 种产品的可接受性均较高，且通过使用过的 IVR 中的残留药物水平证实了荚膜-IVR 的使用。研究期间没有严重不良事件（SAE）。在使用 TDF/TDF-FTC IVR 期间报告了 26 例不良事件（瘙痒、分泌物、不适），单独使用 TDF 或与 FTC 联合使用均未观察到差异。在 TDF-FTC-MVC IVR 组中，无论归因于研究产品，在 IVR 使用期间均有 12 例不良事件（瘙痒、分泌物、不适）。阴道镜检查未见上皮破坏/变薄，未观察到系统的阴道微生物群（VMB）移位。中位（IQR）替诺福韦二磷酸（TFV-DP）组织浓度为 303（277-938）fmol/10（6）细胞（TDF），289（110-603）fmol/10（6）细胞（TDF-FTC），和 302（177.1-823.8）fmol/10（6）细胞（TDF-FTC-MVC）持续 7 天，超过阴道 HIV 预防的理论靶浓度。该研究的主要局限性包括样本量小、持续时间短（7 天与 28 天），以及 VT 活检中 FTC 三磷酸测量的缺乏。
一种具有 3 种不同配方的创新荚膜-IVR 输送装置，可阴道递送达福韦酯（TDF）-FTC 等不同方案的 ARV 药物，似乎是安全和可接受的，并提供了 CVF 和组织中超过高度保护的口服剂量的浓度，表明阴道 HIV 预防的疗效是可以实现的。这些结果表明，基于唯一获得 FDA 批准的 PrEP 联合方案的一种替代、更依赖于依从性的、长效预防装置可以进行安全性和疗效测试。
ClinicalTrials.gov NCT02431273。
