The 2007 UNAIDS report estimated that for each person treated with potent antiretroviral therapy, 4-6 new individuals became infected. Without a foreseeable cure for HIV, prevention measures must control the HIV epidemic and structural/barrier/behavioral methods simply have limited efficacy or applicability. There is a critical need, for coitally-independent dosing strategies which women can initiate and are imperceptible to their partners. It is increasingly clear that antiretroviral pharmacokinetics predict efficacy: using samples from the CAPRISA 004 study, our laboratory demonstrated that subjects who maintained the highest tenofovir concentrations in cervicovaginal fluid (and thus in genital tract tissues) were the least likely to become infected with HIV-1 and HSV2. Although topical formulations such as gels and vaginal rings are being investigated, oral antiretroviral drugs also hold significant promise for prevention. Currently, antiretroviral doses used in prevention studies are those that are FDA-approved for treatment of HIV infection. However, there are no data to confirm that exposures with these standard treatment doses will protect mucosal cells from HIV acquisition, or to inform alternative dosing strategies. We propose a highly significant plan to develop a model for oral antiretroviral prevention strategies. In healthy women volunteers, we will determine the ability of 3 doses of 4 antiretroviral drugs to concentrate in 3 at-risk mucosal surfaces. In explant tissue cultures, the concentration of these drugs, alone and in combination, required to protect tissues exposed to multiple infectious molecular clones will be identified. A new approach to normalizing tissue responses to cell numbers and composition will also be implemented. Once the in vivo tissue pharmacokinetic results and ex vivo target concentration results are known, a mathematical model will be developed to predict the antiretroviral doses/regimen maximally protective at all mucosal surfaces. Finally, a second proof-of-concept study is proposed to dose women with the final antiretroviral regimen and challenge tissue biopsies with HIV to determine risk of infection.

Public Health Relevance

There is a critical need for HIV prevention strategies which women control and are imperceptible to their partners. We propose a highly significant plan to develop a model for oral antiretroviral (ARV) prevention strategies. We will determine how 4 selected ARVs concentrate in 3 mucosal surfaces at risk for HIV infection. In tissue culture, ARV concentrations that protect tissues from HIV infection under multiple conditions will be identified. We will combine the aforementioned data in a mathematical model that will identify the most protective drug regimen to investigate in further clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI095031-01
Application #
8143809
Study Section
Special Emphasis Panel (ZAI1-QV-M (J1))
Program Officer
Veronese, Fulvia D
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$731,273
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Garrett, Katy L; Chen, Jingxian; Maas, Brian M et al. (2018) A Pharmacokinetic/Pharmacodynamic Model to Predict Effective HIV Prophylaxis Dosing Strategies for People Who Inject Drugs. J Pharmacol Exp Ther 367:245-251
Cottrell, Mackenzie L; Prince, Heather M A; Allmon, Andrew et al. (2016) Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design. J Acquir Immune Defic Syndr 72:498-506
Cottrell, Mackenzie L; Yang, Kuo H; Prince, Heather M A et al. (2016) A Translational Pharmacology Approach to Predicting Outcomes of Preexposure Prophylaxis Against HIV in Men and Women Using Tenofovir Disoproxil Fumarate With or Without Emtricitabine. J Infect Dis 214:55-64
Kashuba, Angela D M; Gengiah, Tanuja N; Werner, Lise et al. (2015) Genital Tenofovir Concentrations Correlate With Protection Against HIV Infection in the CAPRISA 004 Trial: Importance of Adherence for Microbicide Effectiveness. J Acquir Immune Defic Syndr 69:264-9
Thompson, Corbin G; Bokhart, Mark T; Sykes, Craig et al. (2015) Mass spectrometry imaging reveals heterogeneous efavirenz distribution within putative HIV reservoirs. Antimicrob Agents Chemother 59:2944-8
Nicol, Melanie R; Emerson, Cindi W; Prince, Heather M A et al. (2015) Models for predicting effective HIV chemoprevention in women. J Acquir Immune Defic Syndr 68:369-76
Cottrell, Mackenzie L; Patterson, Kristine B; Prince, Heather M A et al. (2015) Effect of HIV infection and menopause status on raltegravir pharmacokinetics in the blood and genital tract. Antivir Ther 20:795-803
Nicol, Melanie R; Fedoriw, Yuri; Mathews, Michelle et al. (2014) Expression of six drug transporters in vaginal, cervical, and colorectal tissues: Implications for drug disposition in HIV prevention. J Clin Pharmacol 54:574-83
Trezza, Christine R; Kashuba, Angela D M (2014) Pharmacokinetics of antiretrovirals in genital secretions and anatomic sites of HIV transmission: implications for HIV prevention. Clin Pharmacokinet 53:611-24
Thompson, Corbin G; Sedykh, Alexander; Nicol, Melanie R et al. (2014) Short communication: cheminformatics analysis to identify predictors of antiviral drug penetration into the female genital tract. AIDS Res Hum Retroviruses 30:1058-64

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