A randomized clinical pharmacokinetic trial of Tenofovir in blood, plasma and urine in adults with perfect, moderate and low PrEP adherence: the TARGET study

Abstract

BackgroundTenofovir disoproxil fumarate (TDF) is key component of pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) for HIV, but existing tools to monitor drug adherence are often inaccurate. Detection of tenofovir (TFV) in accessible biological samples, such as fingerprick blood, urine or oral fluid samples could be a novel objective measure of recent TDF adherence. To measure TFV concentrations associated with different levels of TDF adherence, we designed a randomized clinical trial to assess the blood, urine and oral fluid concentrations of TFV in adults with perfect, moderate and low drug adherence.Methods/designA randomized, open-label, clinical pharmacokinetic study of tenofovir in healthy adult volunteers without HIV or Hepatitis B infection in Thailand. Consenting, eligible participants are randomized (1:1:1) among three groups to receive a controlled number of TDF (300 mg) doses in a combination pill with emtricitabine (FTC, 200 mg) for six weeks. Participants in Group 1 receive a single TDF/FTC tablet once daily (Perfect adherence); Group 2 receive a single TDF/FTC tablet 4 times/week (Moderate adherence); and Group 3 receive a single TDF/FTC tablet 2 times/week (Low adherence). Blood, plasma, urine and oral fluid samples are collected for drug measurement during three study phases: (i) initial 6-week treatment phase; (ii) intensive 24-h blood sampling phase after 6 weeks; (iii) 4-week washout phase. Thirty adults with evaluable pharmacokinetic samples (10 per group) will be enrolled [based on ensuring 25% precision in pharmacokinetic parameter estimates]. Pre-dose drug concentrations during the treatment phase will be descriptive and comparisons between groups performed using a Kruskal-Wallis test. A non-compartmental pharmacokinetic analysis will be performed on the intensive sampling data at Week 7 and the time course of TFV washout in the difference biological matrices will be reported based on the detected concentrations following drug cessation.DiscussionThe results of this randomized trial will define the target concentration thresholds of TFV in blood, urine and oral fluid that can distinguish between different levels of TDF adherence. Such adherence ‘benchmarks’ can be applied to real-time drug testing and novel point-of-care tests to identify individuals with poor PrEP or ART adherence.Trial registration ClinicalTrials.gov Identifier NCT03012607.

Novel Transmitted/Founder Simian-Human Immunodeficiency Viruses for Human Immunodeficiency Virus Latency and Cure Research

“…The equation used for estimating the maximum accrued diversity post-ATI for each RM is thus summarized as: (3.1 ϫ 10 Ϫ4 ϫ 3,693 ϫ [days elapsed post-ATI-4])/1.5. Data regarding the complete pharmacokinetic elimination and drug metabolism of tenofovir, emtricitabine, and dolutegravir in HIV-1-infected humans and SIV-and SHIV-infected rhesus macaques are limited, to date (60)(61)(62). This estimate was used to determine the maximum divergence one reactivating lineage unaffected by recombination could accrue during ATI, which allowed us to enumerate the minimum number of independent reactivation events during systemic viral rebound at the time of sampling based on divergence from neighboring lineages.…”

Dolutegravir for first-line antiretroviral therapy in low-income and middle-income countries: uncertainties and opportunities for implementation and research

“…measuring urine tenofovir levels) are being developed, and their potential as additional or alternative monitoring strategies should be evaluated as part of the dolutegravir roll-out. 30…”

Development and Validation of an Immunoassay for Tenofovir in Urine as a Real-Time Metric of Antiretroviral Adherence

“…This study shows the sensitivity, specificity, precision and correlation of an antibody-based immunoassay using samples from individuals taking TDF/FTC for the first time. The next step in the development of a TFV immunoassay with these test characteristics will be to package it into an easy-to-use, clinically-useful, low-cost tool to characterize adherence patterns over the past 7 days using interpretative cut-offs for the assay established by a completed directly-observed therapy (DOT) study of TDF/FTC [24] . The data from the DOT study of 2, 4 and 7 doses a week will allow us to determine the appropriate cut-off concentrations of TFV to create the fully-packaged POC test with three test lines indicating no/low, moderate, or high recent adherence, respectively.…”