Objective-To compare single-and multiple-dose maraviroc exposures in cervicovaginal fluid (CVF) and vaginal tissue (VT) with blood plasma (BP) and quantify maraviroc protein binding in CVF.Design-Open-label pharmacokinetic study.Methods-In 12 HIV-negative women, 7 paired CVF and BP samples were collected over 12 hours after 1 maraviroc dose. Subjects then received maraviroc twice daily for 7 days. After the last dose, subjects underwent CVF and BP sampling as on day 1, with additional sampling during terminal elimination. VT biopsies were obtained at steady state.Results-Day 1 and day 7 median maraviroc CVF AUC τ were 1.9-and 2.7-fold higher, respectively, than BP. On day 1, 6 of 12 subjects had detectable maraviroc CVF concentrations within 1 hour; 12 of 12 were detectable within 2 hours, and all exceeded the protein-free IC 90 . On day 7, maraviroc CVF protein binding was 7.6% and the VT AUC τ was 1.9-fold higher than BP. Maraviroc CVF concentrations 72 hours after dose and BP concentrations 12 hours after dose were similar.Conclusions-Higher maraviroc exposure in the female genital tract provides a pharmacologic basis for further evaluation of chemokine receptor 5 antagonists in HIV infection prophylaxis. This is the first study to report antiretroviral VT concentrations, CVF protein binding, and CVF terminal elimination.

Aims-To evaluate variability in cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, Nacetyltransferase 2 (NAT2), and xanthine oxidase (XO) activity in HIV-infected patients and compare this with data from uninfected, healthy volunteers.Methods-Ten HIV-infected men and seven women on medication affecting CYP enzyme activity were phenotyped four times over 2 months using caffeine, dextromethorphan, and midazolam. Urinary caffeine and dextromethorphan metabolite ratios were used to phenotype CYP1A2, NAT2, XO, and CYP2D6 activity and midazolam plasma clearance was used to phenotype CYP3A activity. Plasma and urine samples were analyzed by validated LC/UV or LC/MS methods for midazolam, caffeine, and dextromethorphan. Noncompartmental pharmacokinetics and nonparametric statistical analyses were performed, and the data compared with those of healthy volunteer historic controls.Results-Compared with age and sex-matched healthy volunteers, HIV-infected subjects had 18% lower hepatic CYP3A4 activity, 90% lower CYP2D6 activity, 53% lower NAT2 activity, and 22% higher XO activity. No significant difference was found in CYP1A2 activity. Additionally, 25% genotype-phenotype discordance in CYP2D6 activity was noted in HIV-infected subjects. Intraindividual variability in enzyme activity increased by 42-62% in HIV-infected patients for CYP1A2, NAT2, and XO, and decreased by 33% for CYP2D6. Interindividual variability in enzyme activity increased by 27-63% in HIV-infected subjects for CYP2D6, CYP1A2, and XO, and decreased by 38% for NAT2. Higher plasma TNFα concentrations correlated with lower CYP2D6 and CYP3A4 activity.Conclusions-Infection with HIV or stage of HIV infection may alter Phase I and II drug metabolizing enzyme activity. HIV infection was related to an increase in variability of these drugmetabolizing enzymes. Altered metabolism may be a consequence of immune activation and cytokine exposure.

IntroductionChanges in the food environment in the United States during the past few decades have contributed to increased rates of obesity, diabetes, and heart disease. Improving the food environment may be an effective primary prevention strategy to address these rising disease rates. The purpose of this study was to assess the consumer food environment of a rural community with high rates of obesity and low levels of fruit and vegetable consumption. Findings were used to identify food environment intervention strategies to be implemented as part of a larger community-based heart disease prevention program.MethodsWe used the Nutrition Environment Measures Survey for Restaurants (NEMS-R) and Stores (NEMS-S) to assess 34 restaurants, 3 grocery stores, and 5 convenience stores in New Ulm, Minnesota.ResultsAt least half of the restaurants offered nonfried vegetables and 100% fruit juice. Only 32% had at least 1 entrée or 1 main dish salad that met standards for “healthy.” Fewer than half (41%) had fruit available and under one-third offered reduced-size portions (29%) or whole-grain bread (26%). Grocery stores had more healthful items available, but findings were mixed on whether these items were made available at a lower price than less healthful items. Convenience stores were less likely to have fruits and vegetables and less likely to carry more healthful products (except milk) than grocery stores.ConclusionBaseline findings indicated opportunities to improve availability, quality, and price of foods to support more healthful eating. A community-wide food environment assessment can be used to strategically plan targeted interventions.

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