Antiretroviral drug concentrations in the male and female genital tract: implications for the sexual transmission of HIV.

Department of Sexual Health and HIV Medicine, Directorate of Infection, Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, University of Birmingham, Birmingham, UK.
Current opinion in HIV and AIDS (Impact Factor: 4.39). 07/2010; 5(4):335-43. DOI: 10.1097/COH.0b013e32833a0b69
Source: PubMed

ABSTRACT To summarize the recent literature (2008-2010) on antiretroviral (ARV) drug disposition into the male and female genital tract.
Recent studies have confirmed that penetration of antiretroviral agents into the male and female genital tracts are both drug and sex specific. Concentrations achieved vary considerably depending on the class of drug studied, the sampling techniques used and the times samples are obtained.
There appear to be several patterns of drug penetration into the male and female genital tract. In addition there appear to be different patterns of genital shedding under the influence of antiretroviral therapy. What effect these factors will have on the sexual transmission of HIV or the evolution and transmission of resistant HIV remains to be seen.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The absorption and emission properties of five Pt(ii) planar complexes with bidentate ligands, namely [Pt(bpy)Cl2] (bpy = 2,2'-bipyridine) and [Pt(ppy)Cl2](-) (ppy = 2-phenylpyridine) , and terdentate ligands, namely [Pt(tpy)Cl](+) (tpy = 2,2':6',2''-terpyridine) , [Pt(phbpyR)Cl] (phbpy = 6-phenyl-2,2'-bipyridine; R = H) and [Pt(dpybR)Cl] (dpyb = 2,6-di(2-pyridyl)benzene; R = CH3) were investigated by means of density functional theory (DFT) and time-dependent DFT (TD-DFT) methods including solvent correction and spin-orbit coupling (SOC). The DFT optimized structures of the five complexes in the electronic ground state are in agreement with the experimental X-ray data and the theoretical absorption spectra reproduce quantitatively the main features of the experimental spectra. It is shown that the structures remain nearly planar in the low-lying singlet and triplet excited states of charge transfer character, metal-to-ligand (MLCT) or halide (Cl) to ligand (XLCT) whereas a significant distortion corresponding to the out-of-plane-bending of the Pt-Cl bond characterizes the geometry of the metal-centered (MC) states. In cyclometalated complexes , and this distortion is energetically unfavorable and not competitive with radiative decay via the low-lying MLCT and XLCT excited states. The absorption spectra of all complexes are significantly affected by spin-orbit coupling (red-shift and broadening), especially in the non-cyclometalated complexes and characterized by the presence of pure low-lying (3)MC states. The SOC effects are less important in the terpyridine complex the lowest part of its spectrum being contaminated by mixed (3)MLCT/(3)XLCT states. In the cyclometalated complexes and the presence of several LC states in the lowest part of the spectra is responsible for a small shift to the red as compared to the other complexes. The solvatochromism that characterizes the absorption of this class of molecules in the visible region is interpreted by the MLCT/XLCT mixed character of the excited states in this energy domain (400-450 nm). Indeed the solvent dependent XLCT contribution will control the magnitude of SOC in these excited states and will move the band to the red region when diminishing and to the blue region when increasing. As far as emission is concerned it is shown that strongly distorted non-radiative MC state's minima, situated below the charge transfer state's minima (ΔE = -0.3 eV to -0.8 eV) are easily accessible upon irradiation in the visible region in complexes and , and in to a lesser extent, leading to no or low luminescence at room temperature. In contrast, the minima of the emissive states of mixed MLCT/XLCT/LC character are efficiently populated in and . The luminescence of complex , cyclometalated in the axial position, is particularly efficient because the minimum of the lowest emissive state is well separated from those of the MC states (ΔE = +0.23 eV) in contrast to its analog, complex , cyclometalated in the lateral position where the emissive MLCT/LC state minimum is nearly degenerate with the lowest MC state minimum (ΔE = +0.01 eV).
    Dalton Transactions 08/2014; · 4.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antiretroviral drug absorption and disposition in cervicovaginal tissue is important for the effectiveness of vaginally or orally administered drug products in pre-exposure prophylaxis (PrEP) of HIV-1 sexual transmission to women. Therefore, it is imperative to understand critical determinants of cervicovaginal tissue pharmacokinetics. This study aimed to examine the mRNA expression and protein localization of three efflux transporters, P-glycoprotein (P-gp), multidrug resistance associated protein 4 (MRP4) and breast cancer resistance protein (BCRP), in the lower genital tract of premenopausal women and pigtailed macaques. Along the human lower genital tract, the three transporters were moderately to highly expressed compared to colorectal tissue and liver, as revealed by real-time RT-PCR. In a given genital tract segment, the transporter with highest expression level was either BCRP or P-gp, while MRP4 was always expressed at the lowest level among the three transporters tested. The immunohistochemical staining showed that P-gp and MRP4 were localized in multiple cell types including epithelial cells, and vascular endothelial cells. BCRP was predominantly localized in the vascular endothelial cells. Differences in transporter mRNA level and localization were observed among endocervix, ectocervix and vagina. Compared to human tissues, the macaque cervicovaginal tissues displayed comparable expression and localization pattern of the three transporters, although subtle differences were observed between the two species. The role of these cervicovaginal transporters in the drug absorption and disposition warrants further studies. The resemblance between human and pigtailed macaque in transporter expression and localization suggests the utility of the macaque model in the studies of human cervicovaginal transporters. Key words: Transporter, PrEP, P-gp, BCRP, MRP4, Cervix, Vagina.
    AIDS research and human retroviruses 05/2014; · 2.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The spectrum of HIV-1 cellular reservoirs is highly diversified, and their role varies according to the milieu of the anatomical sites in which the virus replicates. In this light, mechanisms underlying HIV-1 persistence in anatomical compartments may be profoundly different from what is observed in peripheral blood. This scenario is further complicated by sub-optimal drug penetration in tissues allowing persistent and cryptic HIV-1 replication in body districts despite undetectable viremia. On this basis, this review aims at providing recent insights regarding the critical role of HIV-1 cellular reservoirs in different anatomical compartments, and their relationship with the pathogenesis of HIV-1 infection. A comprehensive definition of the complex interplay between the virus and its reservoir is critical in order to set up prophylactic and therapeutic strategies aimed at achieving the maximal virological suppression and hopefully in the near future the cure of HIV-1 infection (either functional or biological).
    Current HIV/AIDS Reports 04/2014;