Dumond JB, Yeh RF, Patterson KB, et al. Antiretroviral drug exposure in the female genital tract: implications for oral pre and postexposure prophylaxis

School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina, USA.
AIDS (Impact Factor: 5.55). 10/2007; 21(14):1899-907. DOI: 10.1097/QAD.0b013e328270385a
Source: PubMed


To describe first dose and steady state antiretroviral drug exposure in the female genital tract.
Non-blinded, single center, open-label pharmacokinetic study in HIV-infected women.
Twenty-seven women initiating combination antiretroviral therapy underwent comprehensive blood plasma and cervicovaginal fluid sampling for drug concentrations during the first dose of antiretroviral therapy and at steady-state. Drug concentrations were measured by validated HPLC/UV or HPLC-MS/MS methods. Pharmacokinetic parameters were estimated for 11 drugs by non-compartmental analysis. Descriptive statistics and 95% confidence intervals were generated using Intercooled STATA Release 8.0 (Stata Corporation, College Station, Texas, USA).
For all antiretroviral drugs, genital tract concentrations were detected rapidly after the first dose. Drugs were stratified according to the genital tract concentrations achieved relative to blood plasma. Median rank order of highest to lowest genital tract concentrations relative to blood plasma at steady state were: lamivudine (concentrations achieved were 411% greater than blood plasma), emtricitabine (395%), zidovudine (235%) tenofovir (75%), ritonavir (26%), didanosine (21%), atazanavir (18%), lopinavir (8%), abacavir (8%), stavudine (5%), and efavirenz (0.4%).
This is the first study to comprehensively evaluate antiretroviral drug exposure in the female genital tract. These findings support the use of lamivudine, zidovudine, tenofovir and emtricitabine as excellent pre-exposure/post-exposure prophylaxis (PrEP/PEP) candidates. Atazanavir and lopinavir might be useful agents for these applications due to favorable therapeutic indices, despite lower genital tract concentrations. Agents such as stavudine, abacavir, and efavirenz that achieve genital tract exposures less than 10% of blood plasma are less attractive PrEP/PEP candidates.

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Available from: Kristine B Patterson, Sep 28, 2014
    • "The most notable result of the study is the 100-fold greater TFV-DP concentrations in vaginal tissue associated with vaginal dosing. This more precise estimate from our cross-over design confirms what can be inferred from combining results of separate oral dosing studies [24] with vaginal dosing studies [25]. Related to this, combination dosing conferred no concentration benefits in vaginal tissues. "
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    ABSTRACT: Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development.
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    • "After intravenous inoculation of SIVmac251, infection could not be prevented even if AZT/3TC/IDV combination was initiated within a few hours, confirming our previous results [9,28]. Recently [11] we have shown that the same regimen prevents vaginal transmission of the same virus, probably because of initial viral compartmentalization and low dissemination [29] in association with good diffusion of NRTI in the female genital tract [30]. Our results thus demonstrate the need to improve antiretroviral biodistribution for better efficacy and limitation of the pharmacological sanctuaries that allow residual viral replication. "
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    • "Recent findings on the pharmacology of antiretrovirals in the genital tract suggest that certain antiretroviral agents may be preferable for the prevention of HIV following sexual exposure (Figure 4). Lamivudine, emtricitabine, zidovudine, tenofovir and maraviroc concentrations in the female genital tract were higher than blood plasma, and lopinavir and atazanavir achieved low to moderate genital tract concentrations [88]. Efavirenz achieved female genital secretion concentrations <1% blood plasma. "
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    ABSTRACT: There are four opportunities for HIV prevention: before exposure, at the moment of exposure, immediately after exposure, and as secondary prevention focused on infected subjects. Until recently, most resources have been directed toward behavioral strategies aimed at preventing exposure entirely. Recognizing that these strategies are not enough to contain the epidemic, investigators are turning their attention to post-exposure prevention opportunities. There is increasing focus on the use of ART-either systemic or topical (microbicides)-to prevent infection at the moment of exposure. Likewise, there is growing evidence that ART treatment of infected people could serve as prevention as well. A number of ongoing clinical trials will shed some light on the potential of these approaches. Above all, prevention of HIV requires decision-makers to focus resources on strategies that are most effective. Finally, treatment of HIV and prevention of HIV must be considered and deployed together.
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