Divergent adherence estimates with pharmacokinetic and behavioural measures in the MTN‐003 (VOICE) study

Abstract

IntroductionIn the Microbicide Trial Network MTN-003 (VOICE) study, a Phase IIB pre-exposure prophylaxis trial of daily oral or vaginal tenofovir (TFV), product adherence was poor based on pharmacokinetic (PK) drug detection in a random subsample. Here, we sought to compare behavioural and PK measures of adherence and examined correlates of adherence misreporting.MethodsWe included participants with PK and behavioural data from VOICE random subsample. Behavioural assessments included face-to-face interviews (FTFI), audio computer-assisted self-interviewing (ACASI) and pharmacy-returned product counts (PC). TFV concentrations <0.31 ng/mL in plasma (oral group) and <8.5 ng/swab in vaginal group were defined as “PK non-adherent.” Logistic regression models were fit to calculate the combined predictive ability of the behavioural measures as summarized by area under the curve (AUC). Baseline characteristics associated with over-reporting daily product use relative to PK measures was assessed using a Generalized Linear Mixed Model.ResultsIn this random adherence cohort of VOICE participants assigned to active products, (N=472), PK non-adherence was 69% in the oral group (N=314) and 65% in the vaginal group (N=158). Behaviourally, ≤10% of the cohort reported low/none use with any behavioural measure and accuracy was low (≤43%). None of the regression models had an AUC >0.65 for any single or combined behavioural measures. Significant (p<0.05) correlates of over-reporting included being very worried about getting HIV and being unmarried for the oral group; whereas for the vaginal group, being somewhat worried about HIV was associated with lower risk of over-reporting.ConclusionsPK measures indicated similarly low adherence for the oral and vaginal groups. No behavioural measure accurately predicted PK non-adherence. Accurate real-time measures to monitor product adherence are urgently needed.Trial registration: ClinicalTrials.gov identifier: NCT00705679

Misreporting of Product Adherence in the MTN-003/VOICE Trial for HIV Prevention in Africa: Participants’ Explanations for Dishonesty

“…Indeed, several participants in this study suggested that objective testing with consequences, such as study termination, would be the best way to ensure participants took study products. While participants had diverging opinions on the pros and cons of face to face (FTF) versus ACASI modalities for improving honest responses, independent data from VOICE indicate that none of the behavioral assessments in the trial had any accuracy in estimating product use [8, 21]. …”

“…Equally challenging is the consistent over-reporting of product use, which gives false impressions during trial implementation, and limits researchers’ ability to estimate efficacy in intent-to-treat and subset analyses. Growing evidence of a stark discrepancy between self-reported accounts of product use, and biologic or pharmacokinetic evidence of drug present in plasma [2, 6–8], demands that clinical trialists critically examine the reasons research participants are compelled to over-report and misrepresent their actual product use [9]. Put more simply, why do participants misreport adherence?…”

Topical microbicides and HIV prevention in the female genital tract

“…Recently, two behavioral adherence measures, audio computer‐assisted self‐interviewing (ACASI) and clinic product counts (CPC), were found to be less than 50% accurate at predicting nonadherence in the VOICE trial . This poor predictive ability warrants consideration of objective measures for adherence monitoring in prevention studies.…”

Residual hormone levels in used contraceptive rings as a measurement of adherence to vaginal ring use

“…Measuring adherence to PrEP regimens has relied primarily on participant self-report that can be unreliable (e.g., overreporting, recall issues, social desirability) or blood ARV concentrations that may not provide accurate measures of cumulative drug exposure over extended periods of use [2]. HIV PrEP interventions currently in development include multipurpose vaginal rings containing ARVs to prevent sexual transmission of HIV in addition to hormonal contraceptives to prevent pregnancy [3].…”

“…HIV PrEP interventions currently in development include multipurpose vaginal rings containing ARVs to prevent sexual transmission of HIV in addition to hormonal contraceptives to prevent pregnancy [3]. New analytical approaches to assess adherence to multipurpose vaginal rings are needed to better evaluate the safety and efficacy of these new intervention strategies [2,4,5]. Residual levels of the ARV dapivirine in used vaginal rings have recently been used to inform measures of adherence and efficacy for vaginal rings in clinical trials for HIV prevention [5,6].…”