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

Abstract

Introduction: In 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.

Methods: We 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.

Results: In 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.

Conclusions: PK 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.

Keywords: HIV; adherence measurement; microbicide; pharmacokinetic drug detection; pre-exposure prophylaxis.

Figure 1

VOICE Adherence Cohort Sample Selection. Sample selection for the adherence cohort among VOICE participants assigned to active arms in the oral and vaginal groups. Sixteen participants in the oral active arms and 22 in the vaginal gel active arm were excluded from the analysis because of missing behavioural data at a visit where biological data were available. PK=pharmacokinetic, TDF=Tenofovir Diproxil Fumarate, FTC=Emtricitabine, TFV=Tenofovir.

Figure 2

Evidence of non-adherence by route of administration and by different measures. Non-adherence in oral (N=314) and vaginal (N=158) groups is presented for the following measures: Plasma TFV level (oral group; plasma TFV) or VF TFV level from vaginal swab (vaginal group, swab TVF); audio computer-assisted self-interviewing (ACASI) 6-point self-rating scale assessing ability to use in the past month, dichotomized as less than very good versus very good/excellent (Rating <VG); ACASI reports of 0 doses in the past seven days (ACASI 0/seven days); face-to-face interview (FTFI) reports of 0 doses in the past seven days (FTFI 0/seven days); unused products returned to the clinic corresponding to 75% or less adherence in the past month (PC ≤ 75%).

Figure 3

Participants’ responses to the ACASI self-rating scale by PK non-adherence level. During quarterly audio computer-assisted self-interviewing (ACASI), participants completed a validated product adherence self-rating scale that asked, “Please rate your ability, over the past 4 weeks, to [take tablets/insert gel] exactly as you were instructed.” Participants could select one of six response categories (from very poor to excellent). The count of participants for each response category is displayed for the adherence subset (with one random quarterly visit selected for each participant) by route of administration. Within each response category, the percentage who were PK non-adherent (had no evidence of product use in the past seven days) is indicated in dark grey.

Figure 4

Receiver Operating Characteristic (ROC) Curves for combined behavioural measures of adherence by oral and vaginal groups. Behavioural adherence measures were evaluated using the area under the curve (AUC) to assess the ability of each measure, as well as all measures combined, to correctly discriminate between participants classified as PK adherent versus PK non-adherent. Here, ROC curves are presented based on the sensitivity and specificity of the fitted values from the multivariable logistic regression in predicting adherence with the combined behavioural adherence measures (audio computer-assisted self-interviewing [ACASI], face-to-face interviews [FTFI], pharmacy-returned product counts [PC]). For interpretation, an AUC of 0.50 to 0.60 indicates no discrimination, 0.60 to 0.70 indicates poor discrimination, 0.70 to 0.80 indicates fair discrimination, 0.80 to 0.90 indicates good discrimination and 0.90 to 1.0 indicates excellent discrimination.