Combining information to estimate adherence in studies of pre-exposure prophylaxis for HIV prevention: Application to HPTN 067

Abstract

In trials of oral HIV pre-exposure prophylaxis (PrEP), multiple approaches have been used to measure adherence, including self-report, pill counts, electronic dose monitoring devices, and biological measures such as drug levels in plasma, peripheral blood mononuclear cells, hair, and/or dried blood spots. No one of these measures is ideal and each has strengths and weaknesses. However, accurate estimates of adherence to oral PrEP are important as drug efficacy is closely tied to adherence, and secondary analyses of trial data within identified adherent/non-adherent subgroups may yield important insights into real-world drug effectiveness. We develop a statistical approach to combining multiple measures of adherence and show in simulated data that the proposed method provides a more accurate measure of true adherence than self-report. We then apply the method to estimate adherence in the ADAPT study (HPTN 067) in South African women.

Trial registration: ClinicalTrials.gov NCT01327651.

Keywords: HIV; adherence; latent variable; pharmacokinetic model; pre-exposure prophylaxis.

FIGURE 1

Estimated adherence over the self-administered dosing phase of the study for three participants. Vertical lines represent blood sampling times. Days when the participant self-reported taking a pill are in blue and estimated adherence associated with self-reports of no pill taking are depicted in red.

FIGURE 1

Pharmacokinetic model for oral tenofovir in plasma and PBMC

FIGURE 2

Comparison of estimated values for adherence (p), over-reporting (ϕ) and under-reporting (ψ) versus true values from simulations based on the HPTN 067 design and data collection schedule as designed, with additional samples during the DOT period, and with additional samples during the SA period

FIGURE 3

Data for HPTN 067 Cape Town daily arm participants over follow-up: (a) weekly average self-reported adherence during the self-administered dosing phase, with 95% confidence intervals, beginning with week 6 (b) Boxplots of plasma (shaded boxes) and PBMC (white boxes) drug levels at blood sampling times. By design, plasma samples were not collected at weeks 5 and 6.

FIGURE 4

Estimated posterior means for adherence (${\widehat{p}}_i$), over-reporting (${\widehat{\varphi }}_i$) and under-reporting (${\widehat{\psi }}_i$) for HPTN 067 Cape Town daily arm participants.

FIGURE 5

Estimated individual-level average adherence (${\widehat{p}}_i$) versus average self-reported adherence for HPTN 067 Cape Town daily arm participants.

FIGURE 6

Plasma (plots A and B) and PBMC drug levels (plots C and D) versus number of pills taken in the past week (plasma) or two weeks (PBMC) as measured by self-report (A and C) and average estimated pill-taking (average P(A_ij = 1 | R_i, P_i, B_i)) (B and D)