Antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy.
ABSTRACT Our objective was to determine antiretroviral drug concentrations and human immunodeficiency virus (HIV) RNA rebound in cervicovaginal fluid (CVF) in relation to blood plasma (BP) in women receiving suppressive highly active antiretroviral therapy (HAART).
Thirty-four HIV-infected women who had plasma HIV RNA levels < or =80 copies/mL for at least 6 months were enrolled. Sixty-eight paired CVF and BP drug concentrations and HIV RNA levels were determined before and 3-4 h after drug administration. For each woman and antiretroviral drug, the CVF:BP drug concentration ratios before and after drug administration were calculated. The nonparametric Wilcoxon rank sum test was used to determine if these ratios were different from 1.0.
Lamivudine (administered to 20 patients) and tenofovir (administered to 16) had significantly higher concentrations in CVF than in BP before drug administration, with mean CVF:BP concentration ratios of 3.19 (95% confidence interval, 1.2-8.5) and 5.2 (95% confidence interval, 1.2-22.6), respectively. Efavirenz (administered to 13 patients) and lopinavir (administered to 6) had significantly lower concentrations in CVF, with mean CVF:BP concentration ratios of 0.01 (95% confidence interval, 0.00-0.03) and 0.03 (0.01-0.11), respectively. During the study visit (median time after enrollment, 6 months), BP and CVF detectable HIV RNA levels were observed 7 patients (20.6%) and 1 patient (2.9%), respectively.
Despite lower CVF concentrations of key HAART components, such as efavirenz and lopinavir, virologic rebound was rare. The high concentrations of tenofovir and lamivudine in CVF may have implications for the prevention of sexual transmission during HAART and for pre-exposure or postexposure prophylaxis.
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ABSTRACT: Background. It is not known if fluctuations in genital tract antiretroviral drug concentrations correlate with genital virus shedding in HIV-infected women on suppressive antiretroviral therapy (ART).Methods. Among 20 HIV-infected women on ART (tenofovir- TFV, emtricitabine- FTC, and ritonavir-boosted atazanavir- ATV) with suppressed plasma virus loads, blood and cervicovaginal samples collected twice weekly for three weeks were tested for antiretroviral drug concentrations, HIV-1 RNA, and proviral DNA.Results. Cervicovaginal:plasma antiretroviral concentration ratios were highest for FTC (11.9, 95%CI 8.66-16.3), then TFV (3.52, 95%CI 2.27-5.48), and ATV (2.39, 95%CI 1.69-3.38). Within- and between-person variations in plasma and genital antiretroviral concentrations were observed. Low amounts of genital HIV-1 RNA (<50 copies/mL) were detected in 45% of women at 16% of visits. Genital HIV-1 DNA was detected in 70% of women at 35% of visits. Genital virus detection was associated with higher concentrations of mucosal leukocytes but not with genital antiretroviral concentrations, menstrual cycle phase, bacterial vaginosis, genital bleeding, or plasma virus detection.Conclusions. Standard doses of ART achieved higher genital tract than plasma concentrations across the menstrual cycle. Therapeutic ART suppresses genital virus shedding throughout the menstrual cycle, even in the presence of factors reported to increase virus shedding.The Journal of Infectious Diseases 03/2014; · 5.85 Impact Factor
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ABSTRACT: Alcohol abuse is a widespread problem among those at risk for and living with HIV and can impact transmission and disease progression. In this study we sought to use the SIV-macaque model to evaluate the immunological and virological changes in the genital microenvironment of females exposed to chronic alcohol. Female rhesus macaques were treated with alcohol (n=6) or isocaloric sucrose (n=6) for three months and then inoculated with SIVmac251. To assess the effects of chronic alcohol on SIV disease and the genital microenvironment, we quantified plasma and genital SIV levels, measured inflammatory cells in genital fluids, and characterized microbial flora by Gram stains over 10-weeks post-SIV infection. Following three months of alcohol/sucrose treatment, significant differences were observed in the vaginal microenvironment of alcohol treated animals as compared to controls. Microbial flora of alcohol-treated animals had decreased levels of lactobacillus morphotypes and increased levels of gram-positive cocci relative to sucrose-controls. Alcohol-treated animals were also more likely to have white blood cells in vaginal fluids prior to SIV-inoculation, which persisted through viral set-point. Similar levels of cell-free SIV were observed in plasma and vaginal fluids of both groups, but alcohol-treated animals had higher incidence and levels of cell-associated SIV shed in vaginal secretions. Chronic alcohol treatment negatively impacts the genital microenvironment prior to and over the course of SIV infection and may increase the risk of genital virus shedding and transmission.AIDS Research and Human Retroviruses 06/2014; · 2.46 Impact Factor
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ABSTRACT: Pre-exposure prophylaxis (PrEP) strategies utilizing anti-retroviral drugs show considerable promise for HIV prevention. However there is insufficient pharmacokinetic (PK) data on drug concentrations required for protection at the relevant mucosal tissues where the infection is initiated. Here we evaluated the utility of a humanized mouse model to derive PK data on two leading drugs, the RT inhibitor Tenofovir (TFV) and CCR5 inhibitor Maraviroc (MVC). Following oral dosing, both the drugs and the intracellular active TFV-diphosphate could be detected in vaginal, rectal and intestinal tissues. The drug exposures (AUC24h) were found to be higher in vaginal tissue compared to plasma with even higher levels detected in rectal and intestinal tissues. The overall trends of drug concentrations seen in humanized mice reflect those seen in the human thus establishing the utility of this model complementing the present non-human primate (NHP) models for future pre-clinical evaluations of promising HIV PrEP drug candidates.Virology 08/2014; 464-465C:253-263. · 3.28 Impact Factor