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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: BACKGROUND:Tenofovir 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/DESIGN:A 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. DISCUSSION:The 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 .

SUBMITTER: Cressey TR

PROVIDER: S-EPMC5513124 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Cressey Tim R TR Siriprakaisil Oraphan O Klinbuayaem Virat V Quame-Amaglo Justice J Kubiak Rachel W RW Sukrakanchana Pra-Ornsuda PO Than-In-At Kanchana K Baeten Jared J Sirirungsi Wasna W Cressey Ratchada R Drain Paul K PK

BMC infectious diseases 20170714 1

<h4>Background</h4>Tenofovir 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 ...[more]

PMID: 28705153

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Project description:IntroductionHIV incidence remains high among African adolescent girls and young women (AGYW), who would benefit from pre-exposure prophylaxis (PrEP). Strategies to increase PrEP adherence and persistence need to be evaluated in African AGY, including incentives conditional on high adherence.MethodsThe 3Ps for Prevention Study was a 12-month prospective cohort of 200 women ages 16 to 25 initiating PrEP in South Africa from 2017 to 2018. Participants received retrospective feedback about drug levels at Months 1, 2 and 3; half was randomized to receive a 200 Rand shopping voucher ($13 US) at Months 2, 3 and 4, conditioned on high intracellular tenofovir diphosphate (TFV-DP) levels in dried blood spots (≥500 fmol/punch at Month 1, ≥700 fmol/punch at Months 2 and 3). The primary analysis was intention-to-treat, comparing the proportion with high PrEP adherence (≥700 fmol/punch) at Month 3 by randomized group, based on 100% efficacy among men who have sex with men.ResultsMedian age of the 200 women was 19 years (interquartile range [IQR] 17, 21); 86% had a primary sexual partner. At Month 3, the mean TFV-DP level was 822 fmol/punch (SD 522) in the incentive group and 689 fmol/punch (SD 546) in the control group (p = 0.11). Forty-five (56%) of 85 women in the incentive group and 35 (41%) of 85 women in the control group had TFV-DP levels ≥700 fmol/punch (RR 1.35; 95% CI 0.98, 1.86; p = 0.067), which declined to 8% and 5% in the incentive and control groups at Month 12 (no significant difference by arm). 44% refilled PrEP without gaps, 14% had a gap of ≥3 weeks in coverage subsequently restarted PrEP and 54% accepted at the final dispensing visit at Month 9. No new HIV infections were observed after PrEP initiation.ConclusionsAmong South African AGYW initiating PrEP, drug levels indicated high PrEP adherence in almost half of women at Month 3, with a non-statistically significant higher proportion with high adherence among those in the incentive group. Over half persisted with the 12-month PrEP programme although high adherence declined after Month 3. Strategies to support PrEP adherence and persistence and longer-acting PrEP formulations are needed.

Project description:Background: HIV pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine is effective when taken daily. Previously, we developed a urine assay capable of detecting the prodrug tenofovir (TFV) in patients taking tenofovir disoproxil fumarate (TDF)-based PrEP. However, tenofovir alafenamide (TAF) has replaced TDF due to its different safety profile for HIV treatment and was recently approved as PrEP. Given the need to ensure the aforementioned assay remains available for the purpose of objective adherence monitoring, it is critical to ensure its accuracy for detecting TFV in patients taking TAF. Methods: Blood and urine samples were collected from 3 cohorts of patients: (1) 10 participants living with HIV (PLWH) with suppressed virus on a TAF-based regimen, (2) 10 HIV-participants administered 1 dose of TAF/FTC followed by urine and plasma sampling for 7 days starting 1-3 h post-dose, and (3) 10 HIV-participants administered 7 doses of TAF/FTC followed by urine and plasma sampling for 10 days starting 1-3 h after the last dose. Samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with high sensitivity and specificity for TFV. HIV-samples were compared to a historical cohort administered one dose of TDF/FTC. Results: PLWH were 90% male, 40% African American, and 10% Hispanic (mean age = 57 y; SD 8.88 y). HIV-participants were 55% male and 70% Caucasian (mean age = 31.6 y; SD 7.70 y). Samples from PLWH demonstrated TFV concentrations 2 logs higher in urine than plasma (1,000 ng/mL vs ±10 ng/mL) at the time of collection. Urine samples following a single dose of TAF in HIV-participants yielded TFV concentrations ranging from 100 to 1,000 ng/mL 1-3 h post-dose and remained >100 ng/mL for 6 days in 8 of 10 participants. Urine samples collected after 7 consecutive doses of TAF yielded TFV concentrations >1,000 ng/mL 1-3 h after dosing discontinuation, with TFV concentrations >1,00 ng/mL 7 days post discontinuation in 8 of 10 participants. Urine TFV concentrations following TAF administration were comparable to those from a historical cohort administered TDF/FTC. Plasma TFV concentrations were low(±10 ng/mL) in both HIV-cohorts at all time points. Conclusions: TFV persists in urine at detectable concentrations in participants taking TAF/FTC for at least 7 days despite largely undetectable plasma concentrations, with urine TFV concentrations comparable to patients taking TDF/FTC. This study demonstrates the ability of a urine TFV assay to measure recent TAF adherence.

Project description:Analytical methods for the quantification of the new 8-aminoquinoline antimalarial tafenoquine (TQ) in human blood, plasma and urine, and the 5,6-orthoquinone tafenoquine metabolite (5,6-OQTQ) in human plasma and urine have been validated. The procedure involved acetonitrile extraction of samples followed by ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Chromatography was performed using a Waters Atlantis T3 column with a gradient of 0.1% formic acid and acetonitrile at a flow rate of 0.5 mL per minute for blood and plasma. Urine analysis was the same but with methanol containing 0.1% formic acid replacing acetonitrile mobile phase. The calibration range for TQ and 5,6-OQTQ in plasma was 1 to 1200 ng/mL, and in urine was 10 to 1000 ng/mL. Blood calibration range for TQ was 1 to 1200 ng/mL. Blood could not be validated for 5,6-OQTQ due to significant signal suppression. The inter-assay precision (coefficient of variation %) was 9.9% for TQ at 1 ng/mL in blood (n = 14) and 8.2% for TQ and 7.1% for 5,6-OQTQ at 1 ng/mL in plasma (n = 14). For urine, the inter-assay precision was 8.2% for TQ and 6.4% for 5,6-OQTQ at 10 ng/mL (n = 14). TQ and 5,6-OQTQ are stable in blood, plasma and urine for at least three months at both -80 °C and -20 °C. Once validated, the analytical methods were applied to samples collected from healthy volunteers who were experimentally infected with Plasmodium falciparum to evaluate the blood stage antimalarial activity of TQ and to determine the therapeutic dose estimates for TQ, the full details of which will be published elsewhere. In this study, the measurement of TQ and 5,6-OQTQ concentrations in samples from one of the four cohorts of participants is reported. Interestingly, TQ urine concentrations were proportional to parasite recrudescence times post dosing To our knowledge, this is the first description of a fully validated method for the measurement of TQ and 5,6-OQTQ quantification in urine.

Dataset Information

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

Publications

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

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