Despite the success of highly active antiretroviral therapy (HAART) regimens in reducing HIV morbidity and mortality on the population level, individual responses and adverse effects are variable. Many factors influence the outcome of HAART, including the amount of drug that reaches the site of activity (treatment exposure). Behavioral factors and pharmacological parameters (bioavailability, clearance, distribution) influence exposure. Since antiretroviral drugs must be present in adequate quantities for long periods to be effective, measures of long-term exposure are needed. Stimulated by the finding that indinavir (an HIV protease inhibitor) levels in hair were highly correlated with viral load responses and resistance, we initiated preliminary work to develop methods for quantifying the amount of antiretroviral protease inhibitors and non-nucleoside reverse transcriptase inhibitors in small samples of hair. We found a strong correlation between lopinavir levels in hair and initial virologic response to lopinavir-based therapy;lopinavir concentrations in hair were significantly higher in responders versus nonresponders (Mann-Whitney exact test, p <0.0001). Hair levels of antiretrovirals may correlate more closely with long-term outcomes than single blood levels. We use another chronic illness, diabetes mellitus, to compare the value of short term and longer-term measures of disease control (blood glucose and hemoglobin Ale, respectively) as an analogy for the comparison of antiretroviral levels in blood and in hair. The overarching goals of the proposed research are to develop and evaluate methods for determining long-term exposure to antiretroviral drugs in hair samples and to test the predictive value of the hair measures for virologic and immunologic responses, as well as the incidence of adverse effects and resistance mutations. We also propose to assess the value of correcting drug levels in hair by eumelanin content (a measure of the binding capacity for drug). Measuring drug levels in hair has been successfully applied to determination of exposure to a broad array of therapeutic and recreational drugs. This work may provide an inexpensive, noninvasive, field-friendly method for determination of the level of antiretroviral exposure, which could be applied in domestic and international AIDS treatment and research settings. We therefore propose a series of studies of the value of antiretroviral drug measurement using hair specimens based in the Women's Interagency HIV Study (WIHS) cohort, the largest longitudinal cohort study of HIV infection in women in the U.S.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065233-05
Application #
7615657
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Sharp, Gerald B
Project Start
2005-07-05
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2009
Total Cost
$494,056
Indirect Cost
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
Baxi, Sanjiv M; Scherzer, Rebecca; Greenblatt, Ruth M et al. (2016) Higher tenofovir exposure is associated with longitudinal declines in kidney function in women living with HIV. AIDS 30:609-18
Röhrich, Carola R; Drögemöller, Britt I; Ikediobi, Ogechi et al. (2016) CYP2B6*6 and CYP2B6*18 Predict Long-Term Efavirenz Exposure Measured in Hair Samples in HIV-Positive South African Women. AIDS Res Hum Retroviruses 32:529-38
Mave, V; Chandanwale, A; Kinikar, A et al. (2016) Isoniazid hair concentrations in children with tuberculosis: a proof of concept study. Int J Tuberc Lung Dis 20:844-7
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
Baxi, Sanjiv M; Liu, Albert; Bacchetti, Peter et al. (2015) Comparing the novel method of assessing PrEP adherence/exposure using hair samples to other pharmacologic and traditional measures. J Acquir Immune Defic Syndr 68:13-20
Baxi, Sanjiv M; Greenblatt, Ruth M; Bacchetti, Peter et al. (2015) Nevirapine Concentration in Hair Samples Is a Strong Predictor of Virologic Suppression in a Prospective Cohort of HIV-Infected Patients. PLoS One 10:e0129100
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
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
Coetzee, Bronwyne; Kagee, Ashraf; Tomlinson, Mark et al. (2012) Reactions, beliefs and concerns associated with providing hair specimens for medical research among a South African sample: a qualitative approach. Future Virol 7:1135-1142
Gandhi, Monica; Greenblatt, Ruth M; Bacchetti, Peter et al. (2012) A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women. J Infect Dis 206:1453-61

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