A Translational Pharmacology Approach to Predicting Outcomes of Preexposure Prophylaxis Against HIV in Men and Women Using Tenofovir Disoproxil Fumarate With or Without Emtricitabine

Cottrell, Mackenzie L.; Yang, Kuo-Hsiung; Prince, Heather M. A.; Sykes, Craig; White, Nicole; Malone, Stephanie; Dellon, Evan S.; Madanick, Ryan D.; Shaheen, Nicholas J.; Hudgens, Michael G.; Wulff, Jacob; Patterson, Kristine B.; Nelson, Julie A.; Kashuba, Angela D. M.

doi:10.1093/infdis/jiw077

Cited by 246 publications

(308 citation statements)

References 39 publications

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“…Pharmacokinetic data suggest that individuals should take several daily doses upon PrEP initiation to achieve steady-state tenofovir levels in blood and longer in tissue compartments, ranging from a few days for men who have sex with men to 1–3 weeks in women(18, 19). Additionally, risk for HIV acquisition may be difficult to anticipate(20).…”

Section: Discussionmentioning

confidence: 99%

Brief Report: Context Matters: PrEP Adherence is Associated With Sexual Behavior Among HIV Serodiscordant Couples in East Africa

Haberer¹,

Ngure

Muwonge

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background Short message service (SMS) surveys are a promising tool for understanding whether pre-exposure prophylaxis (PrEP) adherence aligns with risk for HIV acquisition— a concept known as prevention-effective adherence. Methods The Partners Demonstration Project was an open-label study of integrated PrEP and antiretroviral therapy (ART) delivery among high-risk HIV serodiscordant couples in East Africa. HIV-uninfected partners were offered PrEP until their HIV-infected partner had taken ART for ≥6 months. At 2 study sites, HIV-uninfected partners were offered enrollment into the Partners Mobile Adherence to PrEP (PMAP) sub-study based on ongoing PrEP use, personal cell phone ownership, and ability to use SMS. SMS surveys asked about PrEP adherence and sexual activity in the prior 24 hours; these surveys were sent daily for the 7 days prior and 7 days after routine study visits in the Partners Demonstration Project. Results The PMAP sub-study enrolled 373 HIV-uninfected partners; 69% were male and mean age was 31 years. Participants completed 17,030 of 23,056 SMS surveys sent (74%) with a mean of 47 surveys per participant over 9.8 months of follow-up. While HIV-infected partner use of ART was <6 months, mean reported PrEP adherence was 92% on surveys concurrently reporting sex within the serodiscordant partnership and 84% on surveys reporting no sex (p<0.001). Discussion SMS surveys provided daily assessment of concurrent PrEP adherence and sexual behavior. Higher PrEP adherence was temporally associated with increased risk for HIV acquisition.

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Section: Discussionmentioning

confidence: 99%

Brief Report: Context Matters: PrEP Adherence is Associated With Sexual Behavior Among HIV Serodiscordant Couples in East Africa

Haberer¹,

Ngure

Muwonge

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…TFV can be detected in plasma for about one week after oral dosing, indicating longer-term systemic availability of TFV than has been seen for gel-based PrEP but lower concentrations in vaginal tissue than gel-based dosing (32,38). Pharmacokinetic studies of oral PrEP have shown that TFV-DP has more difficulty reaching protective concentrations in the female genital tract than in colorectal tissue, and higher levels of adherence (about 6–7 doses/week) are thought to be required to provide effective HIV prevention for people having vaginal exposure to HIV (38,39 ■ ). Results from the Partners PrEP Study, VOICE, and FEM-PrEP have shown that oral FTC/TDF and TDF are efficacious with high adherence levels, but oral PrEP is not protective for women with lower adherence to the dosing regimen (7,23 ■ ,24).…”

Section: Text Of Reviewmentioning

confidence: 99%

The Vaginal Microbiome and its Potential to Impact Efficacy of HIV Pre-exposure Prophylaxis for Women

Velloza

Heffron

2017

Curr HIV/AIDS Rep

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Purpose of review This review describes existing evidence addressing the potential modulation of PrEP products, specifically 1% tenofovir (TFV) gel and oral tenofovir-based PrEP, by vaginal dysbiosis and discusses future considerations for delivering novel, long-acting PrEP products to women at high-risk for vaginal dysbiosis and HIV. Recent findings We describe results from analyses investigating the modification of PrEP efficacy by vaginal dysbiosis and studies of biological mechanisms that could render PrEP ineffective in the presence of specific microbiota. A secondary analysis from the CAPRISA-004 cohort demonstrated that there is no effect of the 1% TFV gel in the presence of non-Lactobacillus dominant microbiota. Another recent analysis comparing oral tenofovir-based PrEP efficacy among women with and without bacterial vaginosis in the Partners PrEP Study found that oral PrEP efficacy is not modified by bacterial vaginosis. Gardnerella vaginalis, commonly present in women with vaginal dysbiosis, can rapidly metabolize TFV particularly when it is locally applied and thereby prevent TFV integration into cells. Given that vaginal dysbiosis appears to modulate efficacy for 1% TFV gel but not for oral tenofovir-based PrEP, vaginal dysbiosis is potentially less consequential to HIV protection from TFV in the context of systemic drug delivery and high product adherence. Summary Vaginal dysbiosis may undermine the efficacy of 1% TFV gel to protect women from HIV but not the efficacy of oral PrEP. Ongoing development of novel ring, injectable, and film-based PrEP products should investigate whether vaginal dysbiosis can reduce efficacy of these products, even in the presence of high adherence.

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“…Tenofovir plasma parameters are consistent with the literature (22, 23), which generally describes tenofovir disposition as a two-compartment model. For tissue parameters, no direct comparators are available in the literature, though estimates are similar in magnitude to those of Cottrell et al(21) Standard diagnostic plots are included in the Supplement.…”

Section: Methodsmentioning

confidence: 89%

“…This “true” model was built by fitting data from the terminal tissue and plasma compartments from the Patterson et al study (20) and plasma data from Cottrell et al study. (21) This model consisted of a four compartment model, as seen in Figure 1. A standard two-compartment model described the plasma concentrations, with an additional compartment to describe drug transfer from plasma to tissue and a compartment to describe drug transfer from the rectal tissue to a transit compartment (tissue compartment 2) then back to the plasma (central compartment).…”

Section: Methodsmentioning

confidence: 99%

Comparison of tenofovir plasma and tissue exposure using a population pharmacokinetic model and bootstrap: a simulation study from observed data

Collins

Dumond

2017

J Pharmacokinet Pharmacodyn

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Sparse tissue sampling with intensive plasma sampling creates a unique data analysis problem in determining drug exposure in clinically relevant tissues. Tissue exposure may govern drug efficacy, as many drugs exert their actions in tissues. We compared tissue area-under-the-curve (AUC) generated from bootstrapped noncompartmental analysis (NCA) methods and compartmental nonlinear mixed effect (NLME) modeling. A model of observed data after single-dose tenofovir disoproxil fumarate was used to simulate plasma and tissue concentrations for two destructive tissue sampling schemes. Two groups of 100 data sets with densely-sampled plasma and one tissue sample per individual were created. The bootstrapped NCA (SAS 9.3) used a trapezoidal method to calculate geometric mean tissue AUC per dataset. For NLME, individual post-hoc estimates of tissue AUC were determined, and the geometric mean from each dataset calculated. Median normalized prediction error (NPE) and absolute normalized prediction error (ANPE) were calculated for each method from the true values of the modeled concentrations. Both methods produced similar tissue AUC estimates close to true values. Although the NLME-generated AUC estimates had larger NPEs, it had smaller ANPEs. Overall, NLME NPEs showed AUC under-prediction but improved precision and fewer outliers. The bootstrapped NCA method produced more accurate estimates but with some NPEs >100%. In general, NLME is preferred, as it accommodates less intensive tissue sampling with reasonable results, and provides simulation capabilities for optimizing tissue distribution. However, if the main goal is an accurate AUC for the studied scenario, and relatively intense tissue sampling is feasible, the NCA bootstrap method is a reasonable, and potentially less time-intensive solution.

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A Translational Pharmacology Approach to Predicting Outcomes of Preexposure Prophylaxis Against HIV in Men and Women Using Tenofovir Disoproxil Fumarate With or Without Emtricitabine

Abstract: This model is predictive of recent PrEP trial results in which 2-3 doses/week was 75%-90% effective in men but ineffective in women. These data provide a novel approach for future PrEP investigations that can optimize clinical trial dosing strategies.

Cited by 246 publications

References 39 publications

Brief Report: Context Matters: PrEP Adherence is Associated With Sexual Behavior Among HIV Serodiscordant Couples in East Africa

Brief Report: Context Matters: PrEP Adherence is Associated With Sexual Behavior Among HIV Serodiscordant Couples in East Africa

The Vaginal Microbiome and its Potential to Impact Efficacy of HIV Pre-exposure Prophylaxis for Women

Comparison of tenofovir plasma and tissue exposure using a population pharmacokinetic model and bootstrap: a simulation study from observed data

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