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
Intravaginal 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 p...
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| Published in: | PloS one Vol. 13; no. 8; p. e0201952 |
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| Main Authors: | , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
Public Library of Science
22-08-2018
Public Library of Science (PLoS) |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Intravaginal 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.
A 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.
The 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. |
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| Bibliography: | Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: KLV and RBP are consultants to ABL, Inc, to expand the ovine preclinical model; this was disclosed to UTMB Conflict of Interest, with money paid directly to KLV and RBP. CWH declares current financial interests in NIH, Gates, and Viiv/GSK funding for clinical research managed through employer (Johns Hopkins University). CWH was a consultant for 1-2 days in the past year to ViiV/GSK for product development of potentially competing product application; this was disclosed to Johns Hopkins Conflict of Interest, money paid directly to CWH. CWH is a current consultant to UCLA scientists for product development of potentially competing product application; this was disclosed to Johns Hopkins Conflict of Interest, money paid directly to CWH. JAM and MMB declare a paid salary for full time employment as faculty members at the Oak Crest Institute of Science. As faculty members JAM and MMB are investigators (NIH U19 Program) on research grants to Oak Crest from the National Institutes of Health (NIH) that funded the research in this manuscript. Additionally, as a faculty members, JAM and MMB are/were principal investigators or co-investigators on grants that funded other research into HIV prevention and intravaginal ring/subdermal implant drug delivery. The research grants not directly related to the research that is the subject of this manuscript were funded by NIH, International Partnership for Microbicides, and USAID (funding through the Population Council). Oak Crest receives funding for research in which JAM and MMB are participants. JAM and MMB are also co-inventors on patent applications that include aspects of the intravaginal ring device that was used in the clinical trial described in this manuscript. The following authors are former salaried employees of Auritec Pharmaceuticals, Inc.: IB, SAC, JMC Jr., and MG. During time of the study, IB and JMC Jr were employees of Auritec and participated in manufacturing the vaginal rings. Prior to August 2016, MG was a 50/50 shared employee for both Oak Crest and Auritec. SAC later performed CVL analysis as an Oak Crest employee. They were no longer employees during sample/data analysis and manuscript preparation. None of these authors have ownership of Auritec stocks or shares, hold Auritec Board membership, or are senior personnel on Auritec research grants. MG is an inventor on active patent applications as an Oak Crest employee. This does not alter our adherence to PLOS ONE policies on sharing data and materials. |
| ISSN: | 1932-6203 1932-6203 |
| DOI: | 10.1371/journal.pone.0201952 |