University of Alabama at Birmingham.
School of Medicine, University of Pittsburgh, Pennsylvania.
Clin Infect Dis. 2019 Mar 19;68(7):1136-1143. doi: 10.1093/cid/ciy653.
Vaginal rings (VR) containing antiretroviral (ARV) drugs can be utilized for prevention of human immunodeficiency virus (HIV) with potential for improved adherence compared to daily pills. Combination ARV VRs could improve efficacy.
MTN-027, a single-blind, randomized, placebo-controlled trial in 48 women, evaluated VRs containing MK-2048 (30 mg) and vicriviroc (VCV, 182 mg), alone or in combination, and placebo used continuously for 28 days. Safety was assessed by recording adverse events. Drug concentrations were quantified in plasma, vaginal fluid, cervical tissue, and rectal fluid. Cervical tissue was utilized for ex vivo HIV inhibition analysis.
There was no difference in related genitourinary adverse events between treatment arms compared to placebo. VCV and MK-2048 released from single or combination VRs both achieved peak concentrations in vaginal fluids, which were substantially higher compared to plasma (200× for VCV, 30× for MK-2048) and rectal fluid. In an ex vivo challenge assay, the antiviral activity of VCV and/or MK-2048 was not correlated with tissue-associated drug concentrations. Most women (77%) were fully adherent to 28 days of continuous VR use and found the VR acceptable.
VCV and/or MK-2048 containing VRs were safe and acceptable. Both VCV and MK-2048 were quantifiable in all matrixes tested with peak compartmental drug concentrations similar for single and combination drug VRs. Tissue-associated VCV and/or MK-2048 did not correlate with inhibition of HIV infection. These data highlight the need to assess adequacy of drug dosing in the VR and measuring genital tissue drug concentrations to develop more precise concentration-response relationships.
含有抗逆转录病毒 (ARV) 药物的阴道环 (VR) 可用于预防人类免疫缺陷病毒 (HIV)，与每日服用药丸相比，其具有潜在的更高的依从性。联合 ARV VR 可以提高疗效。
MTN-027 是一项在 48 名女性中进行的单盲、随机、安慰剂对照试验，评估了单独或联合使用含有 MK-2048（30mg）和维立西罗（VCV，182mg）的 VR 以及安慰剂，连续使用 28 天。通过记录不良事件评估安全性。在血浆、阴道液、宫颈组织和直肠液中定量检测药物浓度。利用宫颈组织进行体外 HIV 抑制分析。
与安慰剂相比，治疗组与生殖泌尿系统不良事件无差异。单或联合 VR 释放的 VCV 和 MK-2048 均在阴道液中达到峰值浓度，与血浆（VCV 为 200 倍，MK-2048 为 30 倍）和直肠液相比，浓度显著更高。在体外挑战试验中，VCV 和/或 MK-2048 的抗病毒活性与组织相关药物浓度无关。大多数女性（77%）完全遵守 28 天连续 VR 使用，且认为 VR 可接受。
含有 VCV 和/或 MK-2048 的 VR 安全且可接受。所有测试基质中均可定量检测到 VCV 和 MK-2048，且单药和联合药物 VR 的药物峰值浓度相似。与抑制 HIV 感染相关的组织中 VCV 和/或 MK-2048 与抑制 HIV 感染无关。这些数据突出表明，需要评估 VR 中的药物剂量是否足够，并测量生殖器组织中的药物浓度，以建立更精确的浓度-反应关系。
