CONRAD, Eastern Virginia Medical School, Norfolk and Arlington, VA, United States.
University of Colorado, Colorado Antiviral Pharmacology Lab, School of Pharmacy, Anschutz Medical Campus, Aurora, CO, United States.
Front Cell Infect Microbiol. 2023 Apr 19;13:1130101. doi: 10.3389/fcimb.2023.1130101. eCollection 2023.
New multi-purpose prevention technology (MPT) products are needed to prevent human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV2). In this study, we evaluated a fast-dissolve insert that may be used vaginally or rectally for prevention of infection.
To describe the safety, acceptability, multi-compartment pharmacokinetics (PK), and modeled pharmacodynamics (PD) after a single vaginal dose of an insert containing tenofovir alafenamide (TAF) and elvitegravir (EVG) in healthy women.
This was a Phase I, open-label, study. Women (n=16) applied one TAF (20mg)/EVG (16mg) vaginal insert and were randomized (1:1) to sample collection time groups for up to 7 days post dosing. Safety was assessed by treatment-emergent adverse events (TEAEs). EVG, TAF and tenofovir (TFV) concentrations were measured in plasma, vaginal fluid and tissue, and TFV-diphosphate (TFV-DP) concentration in vaginal tissue. PD was modeled by quantifying the change in inhibitory activity of vaginal fluid and vaginal tissue against HIV and HSV2 from baseline to after treatment. Acceptability data was collected by a quantitative survey at baseline and post treatment.
The TAF/EVG insert was safe, with all TEAEs graded as mild, and acceptable to participants. Systemic plasma exposure was low, consistent with topical delivery, while high mucosal levels were detected, with median TFV vaginal fluid concentrations exceeding 200,000 ng/mL and 1,000 ng/mL for up to 24 hours and 7 days post dosing, respectively. All participants had vaginal tissue EVG concentrations of > 1 ng/mg at 4 and 24 hours post dosing. The majority had tissue TFV-DP concentrations exceeding 1000 fmol/mg by 24 - 72 hours post dosing. Vaginal fluid inhibition of HIV-1 and HSV-2 significantly increased from baseline and was similarly high at 4 and 24 hours post dosing. Consistent with high tissue TFV-DP concentrations, p24 HIV antigen production from ectocervical tissues infected with HIV-1 significantly decreased from baseline at 4 hours post dosing. HSV-2 production from tissue also decreased post treatment.
A single dose of TAF/EVG inserts met PK benchmarks, with PK data supporting an extended window of high mucosal protection. PD modeling supports mucosal protection against both HIV-1 and HSV-2. The inserts were safe and highly acceptable.
ClinicalTrials.gov, identifier NCT03762772.
需要新的多用途预防技术（MPT）产品来预防人类免疫缺陷病毒（HIV）和单纯疱疹病毒 2 型（HSV2）。本研究评估了一种快速溶解的阴道或直肠插入物，用于预防感染。
描述单次阴道应用含有替诺福韦艾拉酚胺（TAF）和埃替拉韦（EVG）的插入物后在健康女性中的安全性、可接受性、多隔室药代动力学（PK）和模型药效学（PD）。
这是一项 I 期、开放性研究。女性（n=16）应用一片 TAF（20mg）/EVG（16mg）阴道插入物，并随机（1:1）分为采集时间组，在给药后最多 7 天内进行采样。通过治疗后出现的不良事件（TEAE）评估安全性。在血浆、阴道液和组织中测量 EVG、TAF 和替诺福韦（TFV）浓度，并在阴道组织中测量 TFV-二磷酸（TFV-DP）浓度。通过定量评估治疗前后阴道液和阴道组织对 HIV 和 HSV2 的抑制活性变化来建模 PD。在基线和治疗后收集可接受性数据，通过定量调查进行。
TAF/EVG 插入物安全，所有 TEAEs 均为轻度，且被参与者接受。全身血浆暴露水平低，与局部给药一致，同时检测到高黏膜水平，中位 TFV 阴道液浓度分别在给药后 24 小时和 7 天内超过 200,000ng/mL 和 1,000ng/mL。所有参与者在给药后 4 小时和 24 小时的阴道组织 EVG 浓度均>1ng/mg。大多数人在给药后 24-72 小时内的组织 TFV-DP 浓度超过 1000fmol/mg。阴道液对 HIV-1 和 HSV-2 的抑制作用从基线显著增加，在给药后 4 小时和 24 小时同样高。与高组织 TFV-DP 浓度一致，从给药后 4 小时开始，受 HIV-1 感染的宫颈组织中 p24 HIV 抗原的产生显著减少。组织中的 HSV-2 产生也减少。
单次 TAF/EVG 插入物剂量符合 PK 基准，PK 数据支持延长高黏膜保护窗口。PD 建模支持对 HIV-1 和 HSV-2 的黏膜保护。该插入物安全且高度可接受。
ClinicalTrials.gov，标识符 NCT03762772。
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