HIV Pre-exposure prophylaxis (PrEP) with co-formulated emtricitabine tenofovir (FTC/TDF) in HIV negative persons is a powerful strategy for preventing HIV infection. While FTC/TDF has an excellent overall safety profile, it does produce subtle decreases in bone mineral density (BMD). Men who have sex with men (MSM) bear a major burden of HIV infection worldwide and have been shown to have low bone mineral density even in the absence of FTC/TDF treatment. Hence, understanding the nature of BMD effects of FTC/TDF is important optimizing the risk benefit ratio of PrEP. The investigators have conducted a NIH-funded project that included a randomized placebo controlled trial of FTC/TDF v. placebo for PrEP in a global sample of HIV- MSM at risk of acquiring HIV infection and an open label extension to that trial. As a part of that study, we conducted a substudy of bone and body composition effects in approximately 20% of the study participants who underwent dual x-ray absorptiometry (DEXA) scans. We recently concluded an open-label extension to the original trial. The trial found that PrEP was effective in preventing HIV infection with intent-to-treat effects of a 42% reduction in HIV infection. Comparing the randomization arm in the DEXA substudy found a mean decrease in BMD of 0.6% in the hip and 0.9% in the spine on FTC/TDF compared to placebo. The study had low overall adherence (55% at week 8) and so biological effects of FTC/TDF on bone may be underestimated. Preliminary indications are this decrement is stronger among US-enrolled participants and those with higher bone mineral density but it unclear if this is a differential response to FTC/TDF or merely a surrogate for higher adherence. There is an indication that the decrement in BMD, begins to rebound after FTC/TDF is stopped; however, we have only examined this in the first 6 months after stopping drug. An additional follow-up one year of off-drug follow-up is now available as a part of the open-label extension. We propose to combine data for our randomized study and open label extension to examine changes in BMD after discontinuation of FTC/TDF, explore subgroups most vulnerable to BMD loss from FTC/TDF and attempting to estimate the mean BMD changes expected under perfect adherence. The project concluded in late 2014. Funding this proposal will allow us to pursue important outstanding questions from an available data source.

Public Health Relevance

This project will add to understand of the effects of truvada(r)-based therapy to prevent HIV infection in HIV- persons in general and among men who have sex with men in particular. It will clarify the extent to which bone toxicity of truvada(r) is resoves after it is stopped. Secondly, it will estimate the expected bone loss associated with perfect adherence to truvada(r). Finally, it examine if there are a subgroups of potential PrEP users that are more vulnerable to bone loss from truvada(r).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI120819-02
Application #
9094441
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Mathias, Cherlynn
Project Start
2015-06-19
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Glidden, David V; Mulligan, Kathleen; McMahan, Vanessa et al. (2018) Metabolic Effects of Preexposure Prophylaxis With Coformulated Tenofovir Disoproxil Fumarate and Emtricitabine. Clin Infect Dis 67:411-419
Dunn, David T; Glidden, David V; Stirrup, Oliver T et al. (2018) The averted infections ratio: a novel measure of effectiveness of experimental HIV pre-exposure prophylaxis agents. Lancet HIV 5:e329-e334
Meyers, Kathrine; Wu, Yumeng; Qian, Haoyu et al. (2018) Interest in Long-Acting Injectable PrEP in a Cohort of Men Who have Sex with Men in China. AIDS Behav 22:1217-1227
Glidden, David V; Mayer, Kenneth; Grant, Robert M (2017) Response to: A double-edged sword: does highly active antiretroviral therapy contribute to syphilis incidence by impairing immunity to Treponema pallidum? Sex Transm Infect 93:313
Glidden, David V; Mulligan, Kathleen; McMahan, Vanessa et al. (2017) Brief Report: Recovery of Bone Mineral Density After Discontinuation of Tenofovir-Based HIV Pre-exposure Prophylaxis. J Acquir Immune Defic Syndr 76:177-182
Glidden, David V; Anderson, Peter L; Grant, Robert M (2016) Pharmacology supports on-demand PrEP. Lancet HIV 3:e405-e406
Gandhi, Monica; Glidden, David V; Mayer, Kenneth et al. (2016) Association of age, baseline kidney function, and medication exposure with declines in creatinine clearance on pre-exposure prophylaxis: an observational cohort study. Lancet HIV 3:e521-e528
Dunn, David T; Glidden, David V (2016) Statistical issues in trials of preexposure prophylaxis. Curr Opin HIV AIDS 11:116-21
Glidden, David V; Amico, K Rivet; Liu, Albert Y et al. (2016) Symptoms, Side Effects and Adherence in the iPrEx Open-Label Extension. Clin Infect Dis 62:1172-7
Gandhi, Monica; Glidden, David V; Liu, Albert et al. (2015) Strong Correlation Between Concentrations of Tenofovir (TFV) Emtricitabine (FTC) in Hair and TFV Diphosphate and FTC Triphosphate in Dried Blood Spots in the iPrEx Open Label Extension: Implications for Pre-exposure Prophylaxis Adherence Monitoring. J Infect Dis 212:1402-6

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