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.

Background Strict adherence to antiretroviral-based microbicide use is important for effective HIV prevention. We previously developed a composite measure of product adherence, protocol compliance, and semen exposure for determining vaginal use of tenofovir (TFV) 1% gel applicators through biomarkers and residual drug analyses. In this study, we tested the ability of the composite measure in vaginally used TFV gel applicators from a Phase III HIV prevention clinical trial. Methods Used vaginal gel applicators from the FACTS 001 study were swabbed for detection of vaginal bacterial markers (vaginal insertion), semen DNA markers (semen exposure), and residual TFV gel (product use). Results Of 1,098 evaluable TFV and placebo applicators, 80% had detectable vaginal insertion biomarkers and 52% had semen biomarkers. Ninety-nine percent of vaginally inserted applicators TFV applicators had detectable residual TFV as measured by liquid chromatography with tandem mass spectroscopy (LC–MS/MS). Residual TFV levels were also successfully detected using Fourier Transform Infrared (FTIR)-based spectroscopy. Conclusions Vaginal insertion and semen exposure biomarkers were detectable on used TFV 1% gel applicators. Residual TFV on these gel applicators was detectable by LC–MS/MS and FTIR-based spectroscopy, which has potential to be a more convenient and quicker method for detecting drug use. With continual improvements, this composite measure of product adherence, protocol compliance, and semen exposure has potential to assess use of not only TFV gel but also other topical microbicides or products.

Background: Adherence to topical microbicides for HIV prevention has been a challenge for women using them and those developing novel products. The Quatro Clinical Crossover Study investigated user preference and acceptability of four different placebo-based vaginal delivery forms among young African women. The objective of this sub-study was to test the ability of objective adherence measures in assessing placebo product usage. Methods: A total of two hundred women from Zimbabwe and South Africa used placebo vaginal gel, insert, and film once per week, with or without sex, for 1 month and an intravaginal ring continuously for one month (Months 1-4).Women then chose their preferred product and used it with sex each week during Month 5. Women self-collected vaginal swabs after using the gel, insert and film. Collected vaginal swabs and used intravaginal rings were analysed for placebobased adherence measures using spectroscopy and excipient-based analyses to determine product use. Vaginal insertion and semen exposure was determined using previously developed and published adherence biomarkers. Intravaginal rings were extracted for residual excipient (glycerin) and penetrated bioanalytes.Results: Both methodologies showed that women used gel the most during Months 1-4 (75% by excipient methods, 85% by spectroscopy). The methodologies This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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