Development and clinical assessment of new objective adherence markers for four microbicide delivery systems used in HIV prevention studies

Abstract

Background Adherence is critical for successful topical, vaginally delivered anti-retroviral (ARV)-based HIV pre-exposure prophylaxis (PrEP). Quantitating systemic or tissue ARV levels through LC–MS/MS is currently viewed as the most reliable measure of adherence. However, for placebo-controlled trials, this is a high cost analysis that measures adherence only in the drug treatment group. A desirable marker of adherence is one that is measured in both placebo and drug treatment groups using a simple on-site clinical laboratory test, which allows necessary interventions for supporting participant adherence. Our objective was to develop adherence markers for four vaginal placebo products currently used as microbicide delivery systems: gel, film, insert, and intravaginal ring. Excipient and spectroscopy-based approaches were used for preclinical development of the placebo markers and subsequently validated by the CONRAD 135 study. The study collected vaginal swabs collected each day for 1 week post vaginal application of gel, film, or insert in the clinic with or without sex. Intravaginal rings were collected after 1 day, 7, and 30 days of use. Results Placebo gel, film, and insert in vaginal swabs were successfully detected by specific excipient colorimetric or probe-based assays for hydroxyethylcellulose, glycerin, and sorbitol respectively, as well as spectroscopy-based prediction models. The range of detection for gel, film, and insert in swabs collected up to 16 h post vaginal application was 70-100% of the total swabs per time point, with some markers showing potential for longer duration. Decreasing residual glycerin levels and increasing bioanalyte penetration of vaginally used intravaginal rings showed significant changes between 1 and 30 days of use. Conclusions We demonstrated clinical proof-of-concept that adherence markers for placebo product can be measured using simple, lower cost approaches. Measuring adherence in both placebo and drug arms of a HIV PrEP study would better inform future trial designs. Electronic supplementary material The online version of this article (10.1186/s40169-018-0213-6) contains supplementary material, which is available to authorized users.

Genital Mucosal Drug Concentrations and anti-HIV Activity in Tenofovir-Based PrEP Products: Intravaginal Ring vs. Oral Administration

“…The mean penetrated CBQCA concentration in the IVR core was 5536 mg/mL (66521 mg/mL) with a median concentration of 3545 mg/mL (range 1920-23,590 mg/mL). Based on previous validation data, 31 these values are consistent with proper, per protocol, use of the IVR.…”

“…Procedures for processing the IVRs and measuring glycerin concentrations remaining in the IVR after in vivo use and penetration of biologic analytes into the IVR from vaginal fluids have been previously described. 31 Glycerin was measured in water extracts of the inner core of the IVRs using an enzymatic, colorimetric assay according to manufacturer's instructions (Sigma-Aldrich, St. Louis, MO). Bioanalytes that could penetrate the IVRs were quantitated using the 3-(4carboxybenzoyl) quinoline-2-carboxaldehyde) (CBQCA) assay (Thermo Fisher Scientific).…”

The use of objective adherence measures targeting four placebo microbicide delivery forms in the Quatro Clinical Crossover Study

“…Our pilot study, CONRAD 135, detected the ondemand placebo products on nearly 100% of vaginal swabs up to 12 h post-application, with or without sex, followed by a decay of detection beginning at 24 h post-product application. 17 Since women in the Quatro Study were asked to swab immediately after sex with the product or within 2 h after product use, 16 it is possible that swabs with no detectable product were vaginally inserted beyond the window of detection, for example, the day after coital activity occurred. Difficulty in adhering to a post-coital regimen was also observed in a previous study whereby subjects using post-coital oral PrEP were less adherent that those using daily or intermittent oral PrEP.…”

“…The presence of placebo product in vaginal swab extracts and residual excipient/penetrated bioanalytes in ring extracts were determined by the two methodologies. 17 Both methodologies were able to detect all placebo products in swab extracts consistently up to 12 h post-vaginal use. Time dependent decreases in residual excipient (glycerin) levels and increasing penetrated bioanalytes concentrations were measured from the rings collected at the different time points.…”

The ins and outs of drug-releasing vaginal rings: a literature review of expulsions and removals

“…It is widely appreciatedand a lesson hard learned within the HIV microbicide fieldthat relying primarily on user self-report often leads to over-reporting [203][204][205]. Subsequent results published in 2016 from the two Phase III clinical studies of the 25 mg dapivirine ring in which adherence (and in turn efficacy) in some groups of women was much lower than anticipatedclearly illustrate the dangers in relying too heavily on self-reporting of ring removals [206,207].…”