Safety and pharmacokinetics of single, dual, and triple antiretroviral drug formulations delivered by pod-intravaginal rings designed for HIV-1 prevention: A Phase I trial

Abstract

BackgroundIntravaginal 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.Methodology and findingsThis 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/106 cells (TDF), 289 (110–603) fmol/106 cells (TDF-FTC), and 302 (177.1–823.8) fmol/106 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....

Highly synergistic drug combination prevents vaginal HIV infection in humanized mice

“…Using this binary combination, we achieved full protection from simian/human immunodeficiency virus (SHIV) infection in the rigorous, repeat low-dose vaginal exposure model using normally cycling female pigtailed macaques 29 as well as from vaginal and rectal HIV-1 infection in humanized BLT mice 27 . We also showed that topical delivery of the combination from an intravaginal ring (IVR) was safe in a Phase I clinical trial ( N = 6) and led to drug concentrations in vaginal fluids and tissues exceeding those obtained by highly protective oral dosing, suggesting that efficacy for vaginal HIV-1 PrEP is achievable 30 . The TDF-FTC IVRs also led to unexpectedly high drug concentrations in rectal fluids, indicating that dual-compartment protection HIV-1 infection during both vaginal and receptive anal intercourse may be possible with minimal systemic drug exposure 31 .…”

Vaginal ring acceptability and related preferences among women in low- and middle-income countries: A systematic review and narrative synthesis

“…More recently, a dapivirine ring for HIV prevention demonstrated moderate efficacy for HIV pre-exposure prophylaxis (PrEP) [8, 9] and is under review by the European Medicines Agency, with upcoming regulatory submissions to the US Food and Drug Administration and South African Health Products Regulatory Authority. Other VRs for HIV PrEP and multi-purpose prevention technologies (MPTs) are at various stages in the development pipeline [8, 10–13]. MPT VRs are particularly promising, as they increase efficiencies for users and health systems by simultaneously addressing multiple sexual and reproductive health needs [14].…”

Are intravaginal practices associated with human papillomavirus and the development of cervical cancer? A systematic literature review

“…52 It will be important to promote clear public health advice on this topic going forwards, particularly with the potential advent of new evidence-based intravaginal devices such as antiretroviral intravaginal rings for HIV pre-exposure prophylaxis which have been undergoing clinical trials. [59][60][61]…”