Phase I trial of pod-intravaginal rings delivering antiretroviral agents for HIV-1 prevention: Rectal drug exposure from vaginal dosing with tenofovir disoproxil fumarate, emtricitabine, and maraviroc

Abstract

BackgroundIntravaginal rings (IVRs) can deliver antiretroviral (ARV) agents for HIV pre-exposure prophylaxis (PrEP), theoretically overcoming adherence concerns associated with frequent dosing. However, topical vaginal ARV drug delivery has not simultaneously led to sufficient rectal drug exposure to likely protect from HIV infection as a result of receptive anal intercourse (RAI). Unprotected RAI has a higher risk of infection per sex act and, for women, also can be associated with vaginal exposure during a single sexual encounter, especially in higher-risk subsets of women. The physiologically inflamed, activated, immune-cell dense colorectal mucosa is increasingly appreciated as the sexual compartment with highly significant risk; this risk is increased in the setting of co-infections. Ex vivo studies have shown that colorectal tissue and rectal fluid concentrations correlated with HIV protection. Given these important results, efforts to document colorectal compartment ARV drug concentration from pod-IVR delivery was assessed to determine if vaginal application could provide protective ARV levels in both compartments.Methodology/Principal findingsA crossover clinical trial (N = 6) evaluated 7 d of continuous TDF pod-IVR use, a wash-out phase, followed by 7 d with a TDF-FTC pod-IVR. A subsequent clinical trial (N = 6) consisted of 7 d of continuous TDF-FTC-MVC pod-IVR use. Rectal fluids were collected on Day 7 at IVR removal in all three ARV-exposures (two Phase 1 trials) and drug concentrations quantified by LC-MS/MS.Median rectal fluid concentrations of TFV, the hydrolysis product of the prodrug TDF, were between 0.66 ng mg-1 (TDF pod-IVR group) and 1.11 ng mg-1 (TDF-FTC pod-IVR group), but below the analytical lower limit of quantitation in 5/6 samples in the TDF-FTC-MVC pod-IVR group. Unexpectedly, median FTC (TDF-FTC pod-IVR, 20.3 ng mg-1; TDF-FTC-MVC pod-IVR, 0.18 ng mg-1), and MVC rectal fluid concentrations (0.84 ng mg-1) were quantifiable and higher than their respective in vitro EC50 values in most samples. Due to participant burden in these exploratory trials, rectal fluid was used as a surrogate for rectal tissue, where drug concentrations are expected to be higher.Conclusions/SignificanceThe concentrations of FTC and MVC in rectal fluids obtained in two exploratory clinical trials of IVRs delivering ARV combinations exceeded levels associated with in vitro efficacy in HIV inhibition. Unexpectedly, MVC appeared to depress the distribution of TFV and FTC into the rectal lumen. Here we show that vaginal delivery of ARV combinations may provide adherence and coitally independent dual-compartment protection from HIV infection during both vaginal and receptive anal intercourse.

Antiretroviral agents in pre-exposure prophylaxis: emerging and advanced trends in HIV prevention

“…FTC and MVC concentrations found to be high in rectal fluids and provide high efficacy in HIV inhibition when the combination was delivered by IVR. Vaginal delivery of combined ART may allow coital‐independent protection from HIV acquisition though vaginal or rectal transmission . TFV, UC781 and dapivirine (DPV) with MVC showed that by inhibiting viral entry and reverse transcription, HIV transmission and infection can be prevented.…”

Efficacy of silk fibroin biomaterial vehicle for in vivo mucosal delivery of Griffithsin and protection against HIV and SHIV infection ex vivo

“…The use of insertable gels containing ARVs in clinical trials led to moderate success in the CAPRISA 004 study [7], and disappointing outcomes in the VOICE [6] and FACTS 001 trials, largely due to inconsistent adherence, especially among young women [6,7,9,10,60]. More recently, vaginal rings or infusions are being studied for the delivery of multiple anti-viral drugs, bNAbs or the viral entry inhibitor, 5P12-RANTES [61][62][63][64][65][66][67][68]. However, infusions will require the engagement of medical assistance and may not be easily accessible to women in different settings and geographic locations.…”

HIV Antiretroviral Pre‐Exposure Prophylaxis: Development Challenges and Pipeline Promise

“…Rings containing DPV, TFV, TDF, MVC, or FTC alone or in combination using matrix, reservoir, and pod‐IVR configurations are also in clinical development. As mentioned, the pod‐IVR design achieved potentially protective concentrations of FTC and MVC in rectal fluid, possibly solving the two sites of infection‐one site of application problems . An MPT IVR combining DPV and levonorgestrel designed to last 90 days achieved safety and drug concentration targets in a 14‐day clinical study (MTN‐030/IPM041) .…”

“…79 In contrast to TFV and DPV, a multidrug pod-IVR demonstrated emtricitabine and maraviroc colorectal tissue concentrations greater than the in vitro protein-adjusted IC 90 in women. 80 Other ARVs in development may also diffuse more efficiently into vaginal and rectal tissue, potentially providing protection for the vagina and rectum with application of a vaginal product. Another alternative would be to develop a product suitable for dosing in both the vagina and the rectum to provide women the flexibility of protecting themselves wherever needed.…”

“…As mentioned, the pod-IVR design achieved potentially protective concentrations of FTC and MVC in rectal fluid, possibly solving the two sites of infection-one site of application problems. 80 An MPT IVR combining DPV and levonorgestrel designed to last 90 days achieved safety and drug concentration targets in a 14-day clinical study (MTN-030/ IPM041). 111 A 90-day ring study is ongoing (MTN-044).…”