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Berlin Brandenburg

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  • 1
    Language: English
    In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 01 August 2009, Vol.49(3), pp.473-6
    Description: Menopause may affect antiretroviral treatment (ART) response. Immunologic and virologic responses to ART were compared in 220 premenopausal and 47 postmenopausal women enrolled in 2 studies involving ART-naive persons. Changes in CD4 counts or human immunodeficiency virus type 1 RNA levels were similar at 24, 48, and 96 weeks after treatment initiation. ART-naive women should respond to ART regardless of menopausal status.
    Keywords: Acquired Immunodeficiency Syndrome -- Drug Therapy ; Antiretroviral Therapy, Highly Active -- Methods ; HIV-1 -- Drug Effects
    ISSN: 10584838
    E-ISSN: 1537-6591
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  • 2
    Language: English
    In: The Lancet, 30 June 2012, Vol.379(9835), pp.2409-2411
    Description: HIV acquisition is more efficient after anal intercourse,8 and more HIV variants are acquired during anal intercourse than cervicovaginal exposure.9 We have reported substantial differences in antiretroviral drug concentrations in mucosal tissues.10–12 After oral administration of co-formulated TDF and FTC, there were 100-fold higher concentrations of tenofovir in rectal tissue compared with cervicovaginal tissue.12 Intracellularly phosphorylated tenofovir (TFV-DP) and emtricitabine (FTC-TP) are required to inhibit HIV replication.12 100-fold higher concentrations of TFV-DP were detected in the rectum as compared with cervix and vagina.12 Conversely, FTC-TP concentrations were 10–15 fold higher in vaginal and cervical tissue than in rectal tissue. Powerful antiviral agents limited in their tissue penetration, intracellular metabolism, or tissue half-life are not appropriate for pre-exposure prophylaxis. [...]adherence must be measured prospectively in future trials.14,15 Under these conditions trial participants who do not adhere to treatment can be counselled or the study analysis designed to incorporate these most rigorous measures of adherence. Study population Location Route of HIV transmission Intervention Outcome Comments CAPRISA 0042 889 heterosexual women at high risk of infection, aged 18–40 years South Africa Vaginal Coitally-dependent TFV 1% gel (two doses up to 12 h precoitus and postcoitus) 39% protection; 54% protection calculated in participants using 〉80% of doses High TFV-DP concentration in vaginal and cervical tissue critical for efficacy iPrEX4 2499 MSM at high risk of infection; approximately 70% of mixed ethnicity; mean age in TDF/FTC group 27·5 years North and South America, Thailand, South Africa Rectal/penile Daily oral TDF/FTC 44% protection; 92% protection calculated for subjects with detectable drug concentrations High TFV-DP concentrations in rectal tissue might be critical for efficacy TDF25 1200 sexually active adults; 55% male, 45% female; 94% unmarried; approximately 90% age 21–29 years Botswana Vaginal/penile Daily oral TDF/FTC 63% protection 〉30% did not complete study; cannot draw definitive conclusions for women and men separately PIP6 4747 heterosexual serodiscordant couples; 38% negative-female, 68% negative-male partner; 98% married; median age 33 years Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, Zambia Vaginal Daily oral TDF or TDF/FTC 62% protection with TDF alone; 73% protection with TDF/FTC Discordant couples may be a distinct, unique population FEM-PrEP7 1951 heterosexual women at high risk of infection aged 18–35 years Kenya, South Africa, Tanzania Vaginal Daily oral TDF/FTC Trial discontinued for futility in April, 2011 Adherence assessment with monthly clinical samples to measure drug concentration is pending VOICE (MTN-003)3 5029 heterosexual women aged 18–45 years in high-prevalence areas Uganda, South Africa, Zimbabwe Vaginal Daily oral TDF or daily oral TDF/FTC or daily topical TFV gel Oral TDF group discontinued for futility in September, 2011; TFV 1% gel and placebo gel groups discontinued for futility in November, 2011; oral TDF/FTC group continues For TDF, the tissue concentration may be critical; for TFV 1% gel, adherence analysis is pending HPTN 0521 1763 heterosexual serodiscordant couples; 50% negative-female, 50% negative-male partner; 94% married; 61% aged 26–40 years Botswana, Kenya, Malawi, South Africa, Zimbabwe, Brazil, India, Thailand Vaginal/penile Immediate or delayed ART in HIV-infected partner 96% protection Suppression of viraemia on therapy assured by routine monitoring Table Antiretroviral-based HIV prevention studies
    Keywords: Medicine
    ISSN: 0140-6736
    E-ISSN: 1474-547X
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  • 3
    Language: English
    In: The Journal of infectious diseases, 15 May 2011, Vol.203(10), pp.1484-90
    Description: Antiretroviral pharmacology in seminal plasma (SP) and rectal tissue (RT) may provide insight into antiretroviral resistance and the prevention of sexual transmission of human immunodeficiency virus (HIV). Saliva may be of utility for noninvasively measuring adherence. A pharmacokinetic study was performed in 12 HIV-negative men receiving maraviroc 300 mg twice daily for 8 days. Seven time-matched pairs of blood plasma (BP) and saliva samples were collected over 12 h on day 1 (PK1) and days 7 and 8 (PK2). One RT sample from each subject was collected during PK1 and PK2. Two SP samples were collected from each subject during PK1, and 6 SP samples were collected from each subject during PK2. SP AUCs were ∼50% lower than BP. However, protein binding in SP ranged from 4% to 25%, resulting in protein-free concentrations 〉2-fold higher than BP. RT AUCs were 7.5- to 26-fold higher than BP. Maraviroc saliva AUCs were ∼70% lower than BP, but saliva concentrations correlated with BP (r(2) = 0.58). More pharmacologically available maraviroc was found in SP than BP. High RT concentrations are promising for preventing rectal HIV acquisition. Saliva correlation with BP suggests that this may be useful for monitoring adherence. NCT00775294.
    Keywords: Anti-HIV Agents -- Pharmacokinetics ; Cyclohexanes -- Pharmacokinetics ; Rectum -- Metabolism ; Saliva -- Chemistry ; Semen -- Chemistry ; Triazoles -- Pharmacokinetics
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 4
    In: AIDS, 2013, Vol.27(9), pp.1413-1419
    Description: OBJECTIVE:: To investigate the concentration of the integrase strand inhibitor raltegravir (RAL) throughout gastrointestinal (GI) tissue, especially gut-associated lymphoid tissue (GALT), as an adjunct to current prevention and cure strategies. DESIGN:: Open-label pharmacokinetic (PK) study. METHODS:: HIV-negative men received RAL 400 mg twice daily for 7 days. Seven blood plasma specimens were collected over 12-h intervals; timed tissue specimens from terminal ileum, splenic flexure, and rectum were also obtained by colonoscopy following the first dose and on day 7 [multiple dose (MD)]. RAL concentrations were measured by validated LC–MS assay with 1 ng/ml lower limit of detection. Data were analyzed by noncompartmental methods (WinNonlin 6). Tissue exposures are reported as composite medians and tissue density of 1.04 g/ml is assumed for comparisons. RESULTS:: Fourteen men completed evaluations. Median (range) age was 24 (19–49) years and BMI 25 (19–31) kg/m. After the first dose, area under the time-concentration curve (AUC)0-12h was highest in the terminal ileum (594 μg*h/ml). Exposures were 160, 68 and 39-fold greater than blood plasma at the terminal ileum, splenic flexure and rectum, respectively. After multiple doses, exposure was highest at the splenic flexure (2240 μg*h/ml); exposure at the terminal ileum and rectum were equivalent (both 788 μg*h/ml). Following multiple doses, exposures were 160 to 650-fold greater than blood plasma throughout the colon. CONCLUSION:: RAL rapidly disseminates into GI tissue and concentrations remain significantly higher than blood plasma. RAL exposure in GI tissue remains higher than any antiretroviral investigated to date. These data suggest that RAL should result in full suppression of viral replication in GI tissue and GALT.
    Keywords: Blood ; Human Immunodeficiency Virus ; Age ; Microorganisms & Parasites ; AIDS and HIV;
    ISSN: 0269-9370
    E-ISSN: 14735571
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  • 5
    Language: English
    In: Antimicrobial agents and chemotherapy, January 2016, Vol.60(1), pp.400-8
    Description: Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0-12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0-12 or Cpredose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy.
    Keywords: Anti-HIV Agents -- Pharmacokinetics ; HIV Infections -- Drug Therapy ; HIV-1 -- Drug Effects ; Lopinavir -- Pharmacokinetics ; Ritonavir -- Pharmacokinetics ; Viral Load -- Drug Effects
    E-ISSN: 1098-6596
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  • 6
    In: The Journal of Infectious Diseases, 2016, Vol. 214(1), pp.55-64
    Description: Background.  A novel translational pharmacology investigation was conducted by combining an in vitro efficacy target with mucosal tissue pharmacokinetic (PK) data and mathematical modeling to determine the number of doses required for effective human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP). Methods.  A PK/pharmacodynamic (PD) model was developed by measuring mucosal tissue concentrations of tenofovir, emtricitabine, their active metabolites (tenofovir diphosphate [TFVdp] and emtricitabine triphosphate [FTCtp], respectively), and competing endogenous nucleotides (dATP and dCTP) in 47 healthy women. TZM-bl and CD4 + T cells were used to identify 90% effective concentration (EC 90 ) ratios of TFVdp to dATP and FTCtp to dCTP (alone and in combination) for protection against HIV. Monte-Carlo simulations were then performed to identify minimally effective dosing strategies to protect lower female genital tract and colorectal tissues. Results.  The colorectal TFVdp concentration was 10 times higher than that in the lower female genital tract, whereas concentrations of endogenous nucleotides were 7–11 times lower. Our model predicted that ≥98% of the population achieved protective mucosal tissue exposure by the third daily dose of tenofovir disoproxil fumarate plus emtricitabine. However, a minimum adherence to 6 of 7 doses/week (85%) was required to protect lower female genital tract tissue from HIV, while adherence to 2 of 7 doses/week (28%) was required to protect colorectal tissue. Conclusions.  This model is predictive of recent PrEP trial results in which 2–3 doses/week was 75%–90% effective in men but ineffective in women. These data provide a novel approach for future PrEP investigations that can optimize clinical trial dosing strategies.
    Keywords: Hiv ; Antiretroviral ; Translational Medicine ; Dose Response ; Population Pharmacokinetics - Pharmacodynamics ; Quantitative Pharmacology ; Preexposure Prophylaxis
    ISSN: 0022-1899
    E-ISSN: 1537-6613
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  • 7
    In: Journal of Clinical Pharmacology, 2014, Vol.54(5), pp.574-583
    Description: ABSTRACT: Effective antiretroviral (ARV)-based HIV prevention strategies require optimizing drug exposure in mucosal tissues; yet factors influencing mucosal tissue disposition remain unknown. We hypothesized drug transporter expression in vaginal, cervical, and colorectal tissues is a contributing factor and selected 3 efflux (ABCB1/MDR1, ABCC2/MRP2, ABCC4/MRP4) and 3 uptake (SLC22A6/OAT1, SLC22A8/OAT3, SLCO1B1/OATP1B1) transporters to further investigate based on their affinity for 2 ARVs central to prevention (tenofovir, maraviroc). Tissue was collected from 98 donors. mRNA and protein expression were quantified using qPCR and immunohistochemistry (IHC). Hundred percent of tissues expressed efflux transporter mRNA. IHC localized them to the epithelium and/or submucosa. Multivariable analysis adjusted for age, smoking, and co-medications revealed significant (P 〈 0.05) differences in efflux transporter mRNA between tissue types (vaginal ABCB1 3.9-fold 〉 colorectal; vaginal ABCC2 2.9-fold 〉 colorectal; colorectal ABCC4 2.0-fold 〉 cervical). In contrast, uptake transporter mRNA was expressed in 〈25% of tissues. OAT1 protein was detected in 0% of female genital tissues and in 100% of colorectal tissues, but only in rare epithelial cells. These data support clinical findings of higher maraviroc and tenofovir concentrations in rectal tissue compared to vaginal or cervical tissue after oral dosing. Quantifying mucosal transporter expression and localization can facilitate ARV selection to target these tissues.
    Keywords: Pharmacy, Therapeutics, & Pharmacology;
    ISSN: 0091-2700
    E-ISSN: 15524604
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  • 8
    Language: English
    In: Clinical Infectious Diseases, June 15, 2015, Vol.60(12), p.1842(10)
    Description: Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C...). Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C... and lipid changes at week 48 were evaluated via linear regression. Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C... was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P 〉 .1). Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C... was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation. (ProQuest: ... denotes formulae/symbols omitted.)
    Keywords: Ritonavir – Dosage and Administration ; HIV Infections – Care and Treatment ; Clinical Trials – Usage ; Lipids – Analysis
    ISSN: 1058-4838
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  • 9
    Language: English
    In: Annals of internal medicine, 07 October 2014, Vol.161(7), pp.461-71
    Description: Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). 57 sites in the United States and Puerto Rico. Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. The trial was open-label, and ritonavir was not provided. Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. National Institute of Allergy and Infectious Diseases.
    Keywords: HIV-1 ; HIV Infections -- Drug Therapy ; HIV Protease Inhibitors -- Therapeutic Use
    ISSN: 00034819
    E-ISSN: 1539-3704
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  • 10
    Language: English
    In: Clinical Pharmacokinetics, 2012, Vol.51(12), pp.809-822
    Description: BACKGROUND AND OBJECTIVES: A previously published study of antiretroviral pharmacokinetics in the female genital tract of HIV-infected women demonstrated differing degrees of female genital tract penetration among antiretrovirals. These blood plasma (BP) and cervicovaginal fluid (CVF) data were co-modelled for four antiretrovirals with varying CVF exposures.METHODS: Six paired BP and CVF samples were collected over 24 h, and antiretroviral concentrations determined using validated liquid chromatography (LC) with UV detection or LC-mass spectrometry analytical methods. For each antiretroviral, a BP model was fit using Bayesian estimation (ADAPT5), followed by addition of a CVF model. The final model was chosen based on graphical and statistical output, and then non-linear mixed-effects modelling using S-ADAPT was performed. Population mean parameters and their variability are reported. Model-predicated area under the concentration-time curve during the dosing interval (AUC(τ)) and exposure ratios of CVF AUC(τ):BP AUC(τ) were calculated for each drug.RESULTS: The base model uses first-order absorption with a lag time, a two-compartment model, and a series of transit compartments that transfer the drug from BP to CVF. Protein-unbound drug transfers into CVF for efavirenz and atazanavir; total drug transfers for lamivudine and tenofovir. CVF follows a one-compartment model for efavirenz and atazanavir, and a two-compartment model for lamivudine and tenofovir. As expected, inter-individual variability was high. Model-predicted CVF AUC(τ):BP AUC(τ) ratios are consistent with published results.CONCLUSIONS: This is the first pharmacokinetic modelling of antiretroviral disposition in BP and CVF. These models will be further refined with tissue data, and used in clinical trials simulations to inform future studies of HIV pre-exposure prophylaxis in women.
    Keywords: Pharmacy, Therapeutics, & Pharmacology;
    ISSN: 0312-5963
    E-ISSN: 1179-1926
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