Comparing pharmacologic measures of tenofovir exposure in a U.S. pre-exposure prophylaxis randomized trial.
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ABSTRACT:
SUBMITTER: Baxi SM
PROVIDER: S-EPMC5760024 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Comparing pharmacologic measures of tenofovir exposure in a U.S. pre-exposure prophylaxis randomized trial.
Baxi Sanjiv M SM Vittinghoff Eric E Bacchetti Peter P Huang Yong Y Chillag Kata K Wiegand Ryan R Anderson Peter L PL Grant Robert R Greenblatt Ruth M RM Buchbinder Susan S Gandhi Monica M Liu Albert Y AY
PloS one 20180109 1
<h4>Clinical trial registration</h4>Clinical Trials.gov NCT00131677. ...[more]
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Project description:As pre-exposure prophylaxis (PrEP) effectiveness is strongly linked to adherence, we sought to determine if certain self-report measures could be used to inform objective PrEP adherence. We studied participants from the TAPIR study (a multicenter randomized study of daily text messages to support adherence to PrEP In At-Risk), a 48-week randomized controlled trial of HIV-uninfected men who have sex with men (MSM) randomized to receive text message to support adherence versus standard of care. Self-reported medication adherence was assessed using several validated measures modified for PrEP. Objective PrEP adherence was determined through dried blood spot (DBS) measurement of intracellular tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP). A summary of adherence was estimated using responses to the seven adherence items at weeks 12 and 48 using confirmatory factor analysis. Correlations between self-report questions and drug concentrations were estimated with Pearson's correlations for continuous outcomes and point-biserial correlations for dichotomous outcomes. Receiver operating characteristic (ROC) analyses were conducted to assess the performance of self-report measures in predicting protective or perfect TFV-DP concentrations. Of the 369 participants who completed week 12 or 48 visits, the mean age was 35 (standard deviation 9 years), with 79% White, 12% Black, and 29% Hispanic. Correlations between self-report measures of adherence (both individual items and the adherence factor) and quantifiable FTC-TP and continuous TFV-DP concentrations showed that all self-report measures were significantly associated with these objective measures. Compared to a summary measure of self-reported adherence, the 4-week percent taken question medication recall was the only self-report item similarly or more strongly associated with recent adherence and long-term protective and perfect adherence at weeks 12 and 48. ROC analysis also showed that 4-week percent taken question had a reasonable AUC (0.798 at week 12 and 0.758 at week 48) in predicting protective TFV-DP concentrations. All single-item self-report questions assessing PrEP adherence were significantly associated with biomarker quantification, with the 4-week percent taken question performing best. Therefore, in the absence of drug concentration measurements, a 4-week self-report percent taken question may be a good single-item measure of PrEP adherence.
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Project description:Pre-exposure prophylaxis (PrEP) trials are evaluating regimens containing tenofovir-disoproxil fumarate (TDF) for HIV prevention. We determined the baseline prevalence of low bone mineral density (BMD) and the effect of TDF on BMD in men who have sex with men (MSM) in a PrEP trial in San Francisco.We evaluated 1) the prevalence of low BMD using Dual Energy X-ray Absorptiometry (DEXA) in a baseline cohort of 210 HIV-uninfected MSM who screened for a randomized clinical trial of daily TDF vs. placebo, and 2) the effects of TDF on BMD in a longitudinal cohort of 184 enrolled men. Half began study drug after a 9-month delay to evaluate changes in risk behavior associated with pill-use. At baseline, 20 participants (10%) had low BMD (Z score?-2.0 at the L2-L4 spine, total hip, or femoral neck). Low BMD was associated with amphetamine (OR?=?5.86, 95% CI 1.70-20.20) and inhalant (OR?=?4.57, 95% CI 1.32-15.81) use; men taking multivitamins, calcium, or vitamin D were less likely to have low BMD at baseline (OR?=?0.26, 95% CI 0.10-0.71). In the longitudinal analysis, there was a 1.1% net decrease in mean BMD in the TDF vs. the pre-treatment/placebo group at the femoral neck (95% CI 0.4-1.9%), 0.8% net decline at the total hip (95% CI 0.3-1.3%), and 0.7% at the L2-L4 spine (95% CI -0.1-1.5%). At 24 months, 13% vs. 6% of participants experienced >5% BMD loss at the femoral neck in the TDF vs. placebo groups (p?=?0.13).Ten percent of HIV-negative MSM had low BMD at baseline. TDF use resulted in a small but statistically significant decline in BMD at the total hip and femoral neck. Larger studies with longer follow-up are needed to determine the trajectory of BMD changes and any association with clinical fractures.ClinicalTrials.gov: NCT00131677.
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Project description:BACKGROUND:Although antiretroviral pre-exposure prophylaxis prevents HIV acquisition, it is not known if it alters HIV disease progression. This study assesses whether tenofovir gel impacted on disease progression among CAPRISA 004 microbicide trial seroconvertors. METHODS:Eighty-three seroconvertors from the tenofovir and placebo gel arms of the CAPRISA 004 trial were monitored prospectively for a minimum of 2 years by CD4 count and viral load (VL). Linear mixed models were fitted to HIV VL, and log rank test was used to compare time to reach CD4 counts of <350 cells per microliter. RESULTS:Median 2-week postinfection VL was 4.74 and 4.45 log copies per milliliter in women assigned to tenofovir gel (n = 32) and placebo gel (n = 51) (P = 0.189). Corresponding 12-month postinfection VLs were 4.24 and 3.70 log copies per milliliter (P = 0.016). After adjusting for clinical and behavioral characteristics and protective HLA alleles, mean VLs within the first 2 years were 4.51 and 4.02 log copies per milliliter in women from the tenofovir and placebo arms (P = 0.013). Among women with vaginal tenofovir measurements, mean VLs were 4.53 and 4.60 log copies per milliliter in those with detectable versus undetectable levels (P = 0.840). Overall mean CD4 counts were 463 and 514 cells per microliter in women assigned to tenofovir and placebo (P = 0.290). Thirty-two women (38.6%) reached CD4 counts of <350 cells per microliter at median 9.4 months postinfection, 13 (40.6%) from the tenofovir and 19 (37.3%) from the placebo arms (P = 0.786). CONCLUSIONS:Tenofovir gel had no impact on postinfection CD4 counts or the rate of CD4 decline. Although seroconvertors from the tenofovir arm experienced higher VLs, this did not result in a need for earlier antiretroviral therapy.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2020-07-07 | GSE139611 | GEO
Project description:Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults.A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ?3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs).Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60-93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair.This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs.ClinicalTrials.gov NCT00903084.
| S-EPMC3885443 | biostudies-literature
Project description:Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) effectively prevents infection with HIV-1. We sought to determine how use of these medications affects gene expression. We performed a small, prospective trial (https://clinicaltrials.gov/ct2/show/NCT02621242) of eight men initiating PrEP with TDF/FTC. We obtained blood before treatment initiation and after two months of daily use. We isolated RNA from cryopreserved peripheral blood mononuclear cells (PBMC). Gene expression was measured from all eight men at both time points.
2020-07-07 | GSE139609 | GEO
Project description:INTRODUCTION:Although pre-exposure prophylaxis (PrEP) greatly reduces risk of HIV infection in HIV-negative individuals, use is not widespread enough to impact HIV incidence. Involvement of primary care physicians (PCPs) in PrEP prescription is essential, but previous research has shown low rates of prescription among PCPs. To identify targets for interventions, the information-motivation-behavioral skills model for PrEP discussion and prescription was tested in a ten-city sample of PCPs. METHODS:PCPs from ZIP codes with high HIV incidence in ten U.S. cities (N=280, 52% male, 56% white) completed a survey online between July 2014 and May 2015. Information items assessed knowledge, motivation items evaluated attitudes, and behavioral skills items measured comfort with behaviors involved in prescribing PrEP. Providers indicated whether they had discussed PrEP with or prescribed PrEP to patients. Data were analyzed in 2015 and 2016. RESULTS:One third of PCPs had discussed and 17% had prescribed PrEP. A structural equation model with good fit supported the information-motivation-behavioral skills model. Information and motivation predicted behavioral skills (b=0.35, 95% CI=0.13, 0.57; and b=0.31, 95% CI=0.14, 0.47, respectively). Behavioral skills predicted prescription (b=0.27, 95% CI=0.12, 0.42). Furthermore, behavioral skills mediated effects of information and motivation on prescription (b=0.10, 95% CI=0.03, 0.19; and b=0.08, 95% CI=0.03, 0.16, respectively). CONCLUSIONS:The information-motivation-behavioral skills model can be applied to PCPs' PrEP discussion and prescription. Its constructs represent potential targets for PCP-directed interventions to increase PrEP use in high-risk populations.
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Project description:BACKGROUND:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing Covid-19 pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS CoV-2 in healthcare workers at high-risk of exposure. METHODS:We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with Covid-19, including those working in emergency departments, intensive care units, Covid-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine 400mg once weekly or twice weekly for 12 weeks. The primary endpoint was confirmed or probable Covid-19-compatible illness. We measured hydroxychloroquine whole blood concentrations. RESULTS:We enrolled 1483 healthcare workers, of which 79% reported performing aerosol-generating procedures. The incidence of Covid-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo. For once weekly hydroxychloroquine prophylaxis, the hazard ratio was 0.72 (95%CI 0.44 to 1.16; P=0.18) and for twice weekly was 0.74 (95%CI 0.46 to 1.19; P=0.22) as compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with once-weekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed Covid-19 (154 ng/mL) versus participants without Covid-19 (133 ng/mL; P=0.08). CONCLUSIONS:Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed Covid-19 or Covid-19-compatible illness among healthcare workers.
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Project description:Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) effectively prevents infection with HIV-1. We sought to determine how use of these medications affects gene expression. We performed a small, prospective trial (https://clinicaltrials.gov/ct2/show/NCT02621242) of eight men initiating PrEP with TDF/FTC. We obtained duodenal biopsies before treatment initiation and after two months of daily use. We isolated RNA from duodenal biopsies preserved with RNAlater. Gene expression was measured from all eight men at both time points.
2020-07-07 | GSE139608 | GEO
Project description:Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) effectively prevents infection with HIV-1. We sought to determine how use of these medications affects gene expression. We performed a small, prospective trial (https://clinicaltrials.gov/ct2/show/NCT02621242) of eight men initiating PrEP with TDF/FTC. We obtained blood before treatment initiation and after two months of daily use. We isolated RNA from whole blood (PAXgene tubes). Gene expression was measured from all eight men at both time points.
2020-07-07 | GSE139607 | GEO