Our group has pioneered the use of small hair samples to monitor adherence to antiretroviral (ARV) therapy in HIV infection. We have demonstrated that hair concentrations of ARVs, which monitor long-term exposure, are stronger predictors of treatment success than self-reported adherence or plasma ARV levels in large cohorts of HIV-infected patients. Moreover, we have shown high sensitivity and specificity for tenofovir (TFV) detection in hair in a PrEP trial and have demonstrated a strong correlation between TFV dosing and TFV concentrations in hair. Recent data from HIV pre-exposure prophylaxis (PrEP) trials and prevention of mother to child transmission (PMTCT) settings indicate that adherence to prophylactic ARVs when assessed by more objective biomarkers of adherence (e.g. drug levels in plasma, peripheral blood mononuclear cells (PBMCs), breast milk, cord blood) is not always concordant with self report or other more traditional adherence measures, such as pill counts. Hair specimens are easy to collect, store and analyze, providing substantial feasibility, safety and accuracy advantages over other objective methods to monitor adherence, especially in resource-limited settings. This proposal seeks to extend our approach of using hair ARV levels to monitor adherence from the HIV treatment to the prevention setting, partnering with two large, ongoing NIH-funded global HIV prevention trials to further test our methodology in a cost-effective manner.
Aim 1 adds hair measures for TFV and emtricitabine (FTC) adherence monitoring into the active oral arms of VOICE (Vaginal and Oral Interventions to Control the Epidemic), an ongoing MTN-sponsored PrEP trial in African women to assess the effectiveness and safety of oral TFV-based products or vaginal TFV gel in preventing HIV acquisition.
Aim 2 adds hair measures for nevirapine (NVP) monitoring into the daily infant NVP prophylaxis arm of PROMISE BF (Promoting Maternal and Infant Survival Everywhere), a recently- launched IMPAACT-sponsored PMTCT trial in breastfeeding (BF) infants. We will analyze the relevant prophylactic ARV level(s) in hair in each trial once outcomes are available and analyze these hair levels as predictors for HIV seroconversion (aims 1A, 2A) and ARV toxicity (aims 1B, 2B) in multivariate models, comparing hair levels to self-report, pill counts and plasma ARV levels. We will also monitor hair TFV levels in women receiving vaginal TFV gel product to assess for systemic absorption (aim 1C) in VOICE and assess correlations between hair and breast milk ARV levels in the pharmacology sub-study of PROMISE BF (aim 2C). Finally, for Aim 3, we will develop a low-cost point-of care testing method to analyze ARV levels in hair and compare this assay to our validated and sensitive method using liquid chromatography/tandem mass spectrometry. At study completion, we expect to have validated hair levels of ARVs as a novel and practical biomarker of adherence which can easily be implemented into public health programs geared towards HIV prevention and prevention of maternal to child transmission.

Public Health Relevance

HIV medications (antiretrovirals) taken by HIV-negative people can reduce the risk of getting HIV through sex in adults and through breastfeeding in infants. However, HIV-uninfected individuals may not be motivated to take medications every day. Recent clinical trials in HIV prevention have shown that HIV-negative people don't always tell investigators when they don't take the medications as prescribed, so ongoing prevention trials need more objective ways to measure adherence, such as measuring drug levels. We have proven that measuring antiretroviral levels in small cut pieces of scalp hair are excellent measures of drug adherence. Hair samples are easy to collect, store and analyze. Cutting small hair samples is painless and avoids drawing blood, a particular advantage in babies. This project will plug our hair measures into two ongoing large HIV prevention trials in Africa and India (one in women and one in infants) to more accurately measure adherence in these trials and in real-world HIV prevention programs. Our innovative way of monitoring medication levels in hair has public health relevance not only for HIV, but for many chronic disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI098472-03
Application #
8588786
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Zhang, Hao
Project Start
2011-12-15
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$350,225
Indirect Cost
$67,521
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Olds, Peter K; Kiwanuka, Julius P; Nansera, Denis et al. (2015) Assessment of HIV antiretroviral therapy adherence by measuring drug concentrations in hair among children in rural Uganda. AIDS Care 27:327-32
Hickey, Matthew D; Salmen, Charles R; Tessler, Robert A et al. (2014) Antiretroviral concentrations in small hair samples as a feasible marker of adherence in rural Kenya. J Acquir Immune Defic Syndr 66:311-5
Scherzer, Rebecca; Gandhi, Monica; Estrella, Michelle M et al. (2014) A chronic kidney disease risk score to determine tenofovir safety in a prospective cohort of HIV-positive male veterans. AIDS 28:1289-95
Bartelink, Imke H; Savic, Rada M; Mwesigwa, Julia et al. (2014) Pharmacokinetics of lopinavir/ritonavir and efavirenz in food insecure HIV-infected pregnant and breastfeeding women in Tororo, Uganda. J Clin Pharmacol 54:121-32
Gandhi, Monica; Yang, Qiyun; Bacchetti, Peter et al. (2014) Short communication: A low-cost method for analyzing nevirapine levels in hair as a marker of adherence in resource-limited settings. AIDS Res Hum Retroviruses 30:25-8
Baxi, Sanjiv M; Greenblatt, Ruth M; Bacchetti, Peter et al. (2014) Common clinical conditions - age, low BMI, ritonavir use, mild renal impairment - affect tenofovir pharmacokinetics in a large cohort of HIV-infected women. AIDS 28:59-66
Liu, Albert Y; Yang, Qiyun; Huang, Yong et al. (2014) Strong relationship between oral dose and tenofovir hair levels in a randomized trial: hair as a potential adherence measure for pre-exposure prophylaxis (PrEP). PLoS One 9:e83736
Gandhi, Monica; Mwesigwa, Julia; Aweeka, Francesca et al. (2013) Hair and plasma data show that lopinavir, ritonavir, and efavirenz all transfer from mother to infant in utero, but only efavirenz transfers via breastfeeding. J Acquir Immune Defic Syndr 63:578-84