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.

Download full-text


Available from: Kristine B Patterson, Sep 28, 2014
32 Reads
    • "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. "
    [Show abstract] [Hide abstract]
    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. MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. NCT00592124.
    PLoS ONE 01/2013; 8(1):e55013. DOI:10.1371/journal.pone.0055013 · 3.23 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: HIV reservoirs are rapidly established after infection, and the effect of HAART initiated very early during acute infection on HIV reservoirs remains poorly documented, particularly in tissue known to actively replicate the virus. In this context, we used the model of experimental infection of macaques with pathogenic SIV to assess in different tissues: (i) the effect of a short term HAART initiated at different stages during acute infection on viral dissemination and replication, and (ii) the local concentration of antiviral drugs. Here, we show that early treatment with AZT/3TC/IDV initiated either within 4 hours after intravenous infection of macaques with SIVmac251 (as a post exposure prophylaxis) or before viremia peak (7 days post-infection [pi]), had a strong impact on SIV production and dissemination in all tissues but did not prevent infection. When treatment was initiated after the viremia peak (14 days pi) or during early chronic infection (150 days pi), significant viral replication persists in the peripheral lymph nodes and the spleen of treated macaques despite a strong effect of treatment on viremia and gut associated lymphoid tissues. In these animals, the level of virus persistence in tissues was inversely correlated with local concentrations of 3TC: high concentrations of 3TC were measured in the gut whereas low concentrations were observed in the secondary lymphoid tissues. IDV, like 3TC, showed much higher concentration in the colon than in the spleen. AZT concentration was below the quantification threshold in all tissues studied. Our results suggest that limited antiviral drug diffusion in secondary lymphoid tissues may allow persistent viral replication in these tissues and could represent an obstacle to HIV prevention and eradication.
    Retrovirology 09/2010; 7(1):78. DOI:10.1186/1742-4690-7-78 · 4.19 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Journal of the International AIDS Society 02/2008; 11(1):4. DOI:10.1186/1758-2652-11-4 · 5.09 Impact Factor
Show more