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.
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.
|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|
|Cottrell, Mackenzie L; Kashuba, Angela D M (2014) Topical microbicides and HIV prevention in the female genital tract. J Clin Pharmacol 54:603-15|
|Barry, Jeremy A; Robichaud, Guillaume; Bokhart, Mark T et al. (2014) Mapping antiretroviral drugs in tissue by IR-MALDESI MSI coupled to the Q Exactive and comparison with LC-MS/MS SRM assay. J Am Soc Mass Spectrom 25:2038-47|
|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|
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