281 results on '"Angela D. M. Kashuba"'
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2. Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection
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Isabella C. Young, Ivana Massud, Mackenzie L. Cottrell, Roopali Shrivastava, Panita Maturavongsadit, Alka Prasher, Andres Wong-Sam, Chuong Dinh, Tiancheng Edwards, Victoria Mrotz, James Mitchell, Josilene Nascimento Seixas, Aryani Pallerla, Allison Thorson, Amanda Schauer, Craig Sykes, Gabriela De la Cruz, Stephanie A. Montgomery, Angela D. M. Kashuba, Walid Heneine, Charles W. Dobard, Martina Kovarova, J. Victor Garcia, J. Gerardo Garcίa-Lerma, and S. Rahima Benhabbour
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
Ultra-long-acting delivery platforms for HIV pre-exposure prophylaxis (PrEP) may increase adherence and maximize public health benefit. We report on an injectable, biodegradable, and removable in-situ forming implant (ISFI) that is administered subcutaneously and can release the integrase inhibitor cabotegravir (CAB) above protective benchmarks for more than 6 months. CAB ISFIs are well-tolerated in female mice and female macaques showing no signs of toxicity or chronic inflammation. In macaques, median plasma CAB concentrations exceed established PrEP protection benchmarks within 3 weeks and confer complete protection against repeated rectal SHIV challenges. Implant removal via a small incision in 2 macaques at week 12 results in a 7- to 48-fold decrease in plasma CAB levels within 72 hours. Modeling to translate CAB ISFI dosing suggests that a 3 mL injection would exceed protective benchmarks in humans for over 5 months post administration. Our results support the clinical advancement of CAB ISFIs for ultra-long-acting PrEP in humans.
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- 2023
3. Feasibility, Acceptability, and Preliminary Efficacy of a Gamified Mobile Health Contingency Management Intervention for PrEP Adherence Among Black MSM
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John T. Mitchell, Charles M. Burns, Breyah Atkinson, Mackenzie Cottrell, Justin K. Frye, Mehri S. McKellar, Angela D. M. Kashuba, F. Joseph McClernon, and Nwora Lance Okeke
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Infectious Diseases ,Social Psychology ,Public Health, Environmental and Occupational Health - Published
- 2022
4. Quantitative Imaging Analysis of the Spatial Relationship between Antiretrovirals, Reverse Transcriptase Simian-Human Immunodeficiency Virus RNA, and Fibrosis in the Spleens of Nonhuman Primates
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Aaron S. Devanathan, Nicole R. White, Yury Desyaterik, Gabriela De la Cruz, Michael Nekorchuk, Margaret Terry, Kathleen Busman-Sahay, Lourdes Adamson, Paul Luciw, Yuri Fedoriw, Jacob D. Estes, Elias P. Rosen, and Angela D. M. Kashuba
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Pharmacology ,Simian Acquired Immunodeficiency Syndrome ,HIV ,HIV Infections ,Viral Load ,Fibrosis ,Macaca mulatta ,HIV Reverse Transcriptase ,Maraviroc ,Infectious Diseases ,Anti-Retroviral Agents ,Animals ,Humans ,RNA, Viral ,Pharmacology (medical) ,Simian Immunodeficiency Virus ,Spleen - Abstract
Although current antiretroviral therapy (ART) has increased life expectancy, a cure for human immunodeficiency virus (HIV) remains elusive due to the persistence of the virus in tissue reservoirs. In the present study, we sought to elucidate the relationship between antiretrovirals (ARVs) and viral expression in the spleen. We performed mass spectrometry imaging (MSI) of 6 different ARVs, RNAscope in situ hybridization of viral RNA, and immunohistochemistry of three different fibrosis markers in the spleens of 8 uninfected and 10 reverse transcriptase simian-human immunodeficiency virus (RT-SHIV)-infected rhesus macaques (infected for 6 weeks) that had been dosed for 10 days with combination ART. Using MATLAB, computational quantitative imaging analysis was performed to evaluate the spatial and pharmacological relationships between the 6 ARVs, viral RNA, and fibrotic deposition. In these spleens, >50% of the spleen tissue area was not covered by any detectable ARV response (any concentration above the limits of detection for individual ARVs). The median spatial ARV coverage across all tissues was driven by maraviroc followed by efavirenz. Yet >50% of RNA-positive cells were not exposed to any detectable ARV. Quantifiable maraviroc and efavirenz colocalization with RNA-positive cells was usually greater than the in vitro concentration inhibiting 50% replication (IC(50)). Fibrosis markers covered more than 50% of the spleen tissue area and had negative relationships with cumulative ARV coverages. Our findings suggest that a heterogeneous ARV spatial distribution must be considered when evaluating viral persistence in lymphoid tissue reservoirs.
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- 2023
5. Dose-Ranging Plasma and Genital Tissue Pharmacokinetics and Biodegradation of Ultra-Long-Acting Cabotegravir In Situ Forming Implant
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Isabella C. Young, Allison L. Thorson, Roopali Shrivastava, Craig Sykes, Amanda P. Schauer, Mackenzie L. Cottrell, Angela D. M. Kashuba, and Soumya Rahima Benhabbour
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biodegradable ,long acting ,HIV ,injectable ,pharmacokinetics ,polymer ,Pharmaceutical Science - Abstract
HIV continues to affect millions of men and women worldwide. The development of long-acting injectables for HIV prevention can overcome adherence challenges with daily oral prevention regimens by reducing dosing frequency and stigma. We previously developed an ultra-long-acting injectable, biodegradable, and removeable in situ forming implant (ISFI) with cabotegravir (CAB) that demonstrated protection after multiple rectal SHIV challenges in female macaques. Here, we sought to further characterize CAB ISFI pharmacokinetics (PK) in mice by assessing the effect of dose and number of injections on CAB PK, time to completion of CAB release and polymer degradation, long-term genital tissue PK, and CAB PK tail after implant removal. CAB concentrations in plasma were above the benchmark for protection for 11–12 months with proportionality between dose and drug exposure. CAB ISFI exhibited high concentrations in vaginal, cervical, and rectal tissues for up to 180 days. Furthermore, depots were easily retrievable up to 180 days post-administration with up to 34% residual CAB and near complete (85%) polymer degradation quantified in depots ex vivo. After depot removal, results demonstrated a median 11-fold decline in CAB plasma concentrations across all doses. Ultimately, this study provided critical PK information for the CAB ISFI formulation that could aid in its future translation to clinical studies.
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- 2023
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6. Human Immunodeficiency Virus Persistence in the Spleen: Opportunities for Pharmacologic Intervention
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Aaron S. Devanathan and Angela D. M. Kashuba
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Immune recovery ,animal diseases ,Immunology ,Cell ,Human immunodeficiency virus (HIV) ,Reviews ,HIV Infections ,chemical and pharmacologic phenomena ,Spleen ,medicine.disease_cause ,Pharmacologic intervention ,Persistence (computer science) ,Immune system ,Virology ,medicine ,Humans ,business.industry ,HIV ,biochemical phenomena, metabolism, and nutrition ,Immune dysregulation ,Virus Latency ,Infectious Diseases ,medicine.anatomical_structure ,Anti-Retroviral Agents ,bacteria ,business - Abstract
The persistence of HIV in the spleen, despite combination antiretroviral therapy, is not well understood. Sustained immune dysregulation and delayed immune recovery, in addition to immune cell exhaustion, may contribute to persistence of infection in the spleen. Eliminating HIV from this secondary lymphoid organ will require a thorough understanding of antiretroviral (ARV) pharmacology in the spleen, which has been minimally investigated. Low ARV exposure within the spleen may hinder the achievement of a functional or sterilizing cure if cells are not protected from HIV infection. In this study, we provide an overview of the anatomy and physiology of the spleen, review the evidence of the spleen as a site for persistence of HIV, discuss the consequences of persistence of HIV in the spleen, address challenges to eradicating HIV in the spleen, and examine opportunities for future curative efforts.
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- 2021
7. S-warfarin limited sampling strategy with a population pharmacokinetic approach to estimate exposure and cytochrome P450 (CYP) 2C9 activity in healthy adults
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Sandrine Turpault, Joseph D. Ma, Edmund V. Capparelli, Lana Tran, Joseph S. Bertino, Angela D. M. Kashuba, Anne N. Nafziger, and Mina Nikanjam
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Pharmacology ,Volume of distribution ,medicine.medical_specialty ,education.field_of_study ,Correlation coefficient ,business.industry ,Population ,Sampling (statistics) ,Lopinavir ,General Medicine ,030226 pharmacology & pharmacy ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,Medicine ,Pharmacology (medical) ,Ritonavir ,030212 general & internal medicine ,business ,education ,CYP2C9 ,medicine.drug - Abstract
S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults. In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient (R2) >0.9, relative percent mean prediction error (%MPE) >−5 to
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- 2021
8. A mechanism‐based pharmacokinetic model of remdesivir leveraging interspecies scaling to simulate COVID‐19 treatment in humans
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Anthony J. Hickey, Angela D. M. Kashuba, Alexander V. Kabanov, Timothy P. Sheahan, Patrick O. Hanafin, Gauri G. Rao, and Brian Jermain
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viruses ,Respiratory Mucosa ,Pharmacology ,Antiviral Agents ,Loading dose ,Article ,Mice ,chemistry.chemical_compound ,Species Specificity ,Pharmacokinetics ,In vivo ,Modelling and Simulation ,Animals ,Humans ,Distribution (pharmacology) ,Pharmacology (medical) ,Cells, Cultured ,Active metabolite ,Mice, Knockout ,Alanine ,Research ,lcsh:RM1-950 ,COVID-19 ,Articles ,Prodrug ,Adenosine Monophosphate ,COVID-19 Drug Treatment ,Mice, Inbred C57BL ,lcsh:Therapeutics. Pharmacology ,chemistry ,Modeling and Simulation ,Models, Animal ,Nucleoside triphosphate ,Female ,Nucleoside - Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) outbreak initiated the global coronavirus disease 2019 (COVID‐19) pandemic resulting in 42.9 million confirmed infections and > 1.1 million deaths worldwide as of October 26, 2020. Remdesivir is a broad‐spectrum nucleotide prodrug shown to be effective against enzootic coronaviruses. The pharmacokinetics (PKs) of remdesivir in plasma have recently been described. However, the distribution of its active metabolite nucleoside triphosphate (NTP) to the site of pulmonary infection is unknown in humans. Our objective was to use existing in vivo mouse PK data for remdesivir and its metabolites to develop a mechanism‐based model to allometrically scale and simulate the human PK of remdesivir in plasma and NTP in lung homogenate. Remdesivir and GS‐441524 concentrations in plasma and total phosphorylated nucleoside concentrations in lung homogenate from Ces1c −/− mice administered 25 or 50 mg/kg of remdesivir subcutaneously were simultaneously fit to estimate PK parameters. The mouse PK model was allometrically scaled to predict human PK parameters to simulate the clinically recommended 200 mg loading dose followed by 100 mg daily maintenance doses administered as 30‐minute intravenous infusions. Simulations of unbound remdesivir concentrations in human plasma were below 2.48 μM, the 90% maximal inhibitory concentration for SARS‐CoV‐2 inhibition in vitro. Simulations of NTP in the lungs were below high efficacy in vitro thresholds. We have identified a need for alternative dosing strategies to achieve more efficacious concentrations of NTP in human lungs, perhaps by reformulating remdesivir for direct pulmonary delivery.
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- 2021
9. Pregnancy-Related Hormones Increase Nifedipine Metabolism in Human Hepatocytes by Inducing CYP3A4 Expression
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Craig R. Lee, Craig Sykes, Angela D. M. Kashuba, John K. Fallon, Rebecca J.B. Rementer, Melina M. Malinen, Kim L. R. Brouwer, Amanda P. Schauer, Merrie Mosedale, Paul B. Watkins, Philip C. Smith, Natasha Kulick, Raju Khatri, and Kim A. Boggess
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medicine.medical_specialty ,Nifedipine ,CYP2B6 ,Pharmaceutical Science ,02 engineering and technology ,030226 pharmacology & pharmacy ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pregnancy ,Tandem Mass Spectrometry ,Internal medicine ,medicine ,Cytochrome P-450 CYP3A ,Humans ,CYP2A6 ,Progesterone ,CYP3A4 ,biology ,Cytochrome P450 ,021001 nanoscience & nanotechnology ,Endocrinology ,Estetrol ,chemistry ,Hepatocytes ,biology.protein ,Female ,0210 nano-technology ,Drug metabolism ,medicine.drug ,Hormone - Abstract
Pregnancy-related hormones (PRH) have emerged as key regulators of hepatic cytochrome P450 (CYP) enzyme expression and function. The impact of PRH on protein levels of CYP3A4 and other key CYP enzymes, and the metabolism of nifedipine (a CYP3A4 substrate commonly prescribed during pregnancy), was evaluated in primary human hepatocytes. Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to PRH (estradiol, estriol, estetrol, progesterone, and cortisol), individually or in combination as a cocktail. Absolute protein concentrations of twelve CYP isoforms in SCHH membrane fractions were quantified by nanoLC-MS/MS, and metabolism of nifedipine to dehydronifedipine in SCHH was evaluated. PRH significantly increased CYP3A4 protein concentrations and nifedipine metabolism to dehydronifedipine in a concentration-dependent manner. CYP3A4 mRNA levels in hepatocyte-derived exosomes positively correlated with CYP3A4 protein levels and dehydronifedipine formation in SCHH. PRH also increased CYP2B6, CYP2C8 and CYP2A6 levels. Our findings demonstrate that PRH increase nifedipine metabolism in SCHH by inducing CYP3A4 expression and alter expression of other key CYP proteins in an isoform-specific manner, and suggest that hepatocyte-derived exosomes warrant further investigation as biomarkers of hepatic CYP3A4 metabolism. Together, these results offer mechanistic insight into the increases in nifedipine metabolism and clearance observed in pregnant women.
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- 2021
10. Antiretroviral drug exposure in lymph nodes is heterogeneous and drug dependent
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Elias P, Rosen, Claire, Deleage, Nicole, White, Craig, Sykes, Catherine, Brands, Lourdes, Adamson, Paul, Luciw, Jacob D, Estes, and Angela D M, Kashuba
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Male ,Infectious Diseases ,Anti-Retroviral Agents ,Simian Acquired Immunodeficiency Syndrome ,Public Health, Environmental and Occupational Health ,Animals ,Humans ,RNA, Viral ,HIV Infections ,Simian Immunodeficiency Virus ,Collagen ,Lymph Nodes ,Macaca mulatta - Abstract
HIV reservoirs and infected cells may persist in tissues with low concentrations of antiretrovirals (ARVs). Traditional pharmacology methods cannot assess variability in ARV concentrations within morphologically complex tissues, such as lymph nodes (LNs). We evaluated the distribution of six ARVs into LNs and the proximity of these ARVs to CD4Between December 2014 and April 2017, RT-SHIV infected (SHIV+; N = 6) and healthy (SHIV-; N = 6) male rhesus macaques received two selected four-drug combinations of six ARVs over 10 days to attain steady-state conditions. Serial cryosections of axillary LN were analysed by a multimodal imaging approach that combined mass spectrometry imaging (MSI) for ARV disposition, RNAscope in situ hybridization for viral RNA (vRNA) and immunohistochemistry for CD4Through MSI, ARV-dependent, heterogeneous concentrations were observed in different morphological LN regions, such as the follicles and medullary sinuses. After 5-6 weeks of infection, more limited ARV penetration into LN tissue relative to the blood marker heme was found in SHIV+ animals (SHIV+: 0.7 [0.2-1.4] mm; SHIV-: 1.3 [0.5-1.7] mm), suggesting alterations in the microcirculation. However, we found no detectable increase in collagen deposition. Regimen-wide maps of composite ARV distribution indicated that up to 27% of SHIV+ LN tissue area was not exposed to detectable ARVs. Regions associated with B cell follicles had median 1.15 [0.94-2.69] -fold reduction in areas with measurable drug, though differences were only statistically significant for tenofovir (p = 0.03). Median co-localization of drug with CD4Our investigation of the spatial distributions of drug, virus and target cells underscores the influence of location and microenvironment within LN, where a small population of T cells may remain vulnerable to infection and low-level viral replication during suppressive ART.
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- 2022
11. Feasibility, Acceptability, and Preliminary Efficacy of a Gamified Mobile Health Contingency Management Intervention for PrEP Adherence Among Black MSM
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John T, Mitchell, Charles M, Burns, Breyah, Atkinson, Mackenzie, Cottrell, Justin K, Frye, Mehri S, McKellar, Angela D M, Kashuba, F Joseph, McClernon, and Nwora Lance, Okeke
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Male ,Sexual and Gender Minorities ,Anti-HIV Agents ,Feasibility Studies ,Humans ,HIV Infections ,Pre-Exposure Prophylaxis ,Homosexuality, Male ,Telemedicine ,Medication Adherence - Abstract
Oral HIV pre-exposure prophylaxis (PrEP) is effective at preventing HIV. However, low adherence is common and undermines these protective effects. This is particularly relevant for groups with disproportionately higher rates of HIV, including Black men who have sex with men (MSM). The current study tested the feasibility, acceptability, and preliminary efficacy of a gamified mobile health contingency management intervention for PrEP adherence-called mSMART (Mobile App-Based Personalized Solutions for Medication Adherence of Rx Pill Tool). Fifteen Black MSM already prescribed PrEP in the community completed baseline and follow-up assessments separated by 8 weeks of using mSMART. Regarding feasibility, there was no study attrition, no mSMART functional difficulties that significantly interfered with use, and a mean rate of 82% daily mSMART use. Acceptability ratings were in the moderately to extremely satisfied range for factors such as willingness to recommend mSMART to others and user-friendliness, and in the low range for ratings on difficulty learning how to use mSMART. Scores on a system usability measure were in the acceptable range for 73% of the sample. Qualitative analysis of follow-up interviews identified individual components of mSMART that could be modified in future iterations to make it more engaging. PrEP composite adherence scores from biomarkers indicated an improvement from baseline to follow-up with a medium effect size, as well as a decrease in the number of perceived barriers to medication adherence. Findings indicate a future efficacy trial is needed to examine the effects of this gamified mobile health contingency management intervention on PrEP adherence.
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- 2022
12. Mass Spectroscopy Imaging of Hair Strands Captures Short-Term and Long-Term Changes in Emtricitabine Adherence
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Joseph N. Mwangi, William M. Gilliland, Nicole White, Craig Sykes, Amanda Poliseno, Kelly A. Knudtson, Lisa Hightow-Weidman, Angela D. M. Kashuba, and Elias P. Rosen
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Pharmacology ,Male ,Anti-HIV Agents ,HIV Infections ,Antiviral Agents ,Mass Spectrometry ,Medication Adherence ,Sexual and Gender Minorities ,Infectious Diseases ,Emtricitabine ,Humans ,Pharmacology (medical) ,Pre-Exposure Prophylaxis ,Homosexuality, Male ,Tenofovir ,Hair ,Retrospective Studies - Abstract
Most measures of adherence to antiretroviral therapy require a blood sample, and none capture longitudinal daily adherence. A new noninvasive method for measuring daily adherence to antiretroviral regimens containing emtricitabine (FTC) was developed for intact hair strands using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging (MSI). A directly observed therapy study of daily and intermittent (3, 1, and 0 doses/week) FTC dosing (n = 12) benchmarked adherence in hair, revealing distinct accumulation patterns and median FTC signal abundance (1,702, 495, 352, and 0, respectively) with each dosing frequency. A threshold value of FTC(signal abundance) of 500 differentiated daily dosing from 3 or fewer doses/week (specificity, 100%; sensitivity, 100% over 30 days and 80% over 60 days). Using these criteria, daily FTC hair adherence was classified in young men (n = 8) who have sex with men (YMSM) engaged in or initiating preexposure prophylaxis (PrEP). Four types of adherence profiles were observed in sequential 30-day periods: consistently high, occasional missed doses, improvement following study initiation, and intermittent. Discrete days of nonadherence were identified across the 60-day window, with the average number of consecutive days classified as nonadherent increasing across the four profile types (1, 2, 19, and 58 days, respectively). Additionally, cumulative FTC response in hair (60-day average) significantly correlated with dried blood spot tenofovir diphosphate concentrations collected simultaneously (r(s) = 0.79, P = 0.03). Based on these data, IR-MALDESI FTC adherence classification in hair strands can better delineate short-term changes in adherence behaviors over a long retrospective window, offering great potential for noninvasive adherence monitoring and quick supportive interventions.
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- 2022
13. Leveraging physiologically based pharmacokinetic modeling to optimize dosing for lopinavir/ritonavir with rifampin in pediatric patients
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Sara N. Salerno, Edmund V. Capparelli, Helen McIlleron, Jacqueline G. Gerhart, Julie B. Dumond, Angela D. M. Kashuba, Paolo Denti, and Daniel Gonzalez
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Pharmacology (medical) - Abstract
Treatment of HIV and tuberculosis co-infection leads to significant mortality in pediatric patients, and treatment can be challenging due to the clinically significant drug-drug interaction (DDI) between lopinavir/ritonavir (LPV/RTV) and rifampin. Doubling LPV/RTV results in insufficient lopinavir trough concentrations in pediatric patients. The objective of this study was to leverage physiologically based pharmacokinetic (PBPK) modeling to optimize the adjusted doses of LPV/RTV in children receiving the WHO-revised doses of rifampin (15 mg/kg daily).Adult and pediatric PBPK models for LPV/RTV with rifampin were developed, including CYP3A and P-glycoprotein inhibition and induction.Data for LPV/RTV model development and evaluation were available from the pediatric AIDS Clinical Trials Group.Dosing simulations were next performed to optimize dosing in children (2 months to 8 years of age).Exposure following super-boosted LPV/RTV with 10 and 15 mg/kg PO daily rifampin was simulated.Simulated parameters were within twofold observations for LPV, RTV, and rifampin in adults and children ≥2 weeks old. The model predicted that, in healthy adults receiving 400/100 mg oral LPV/RTV twice daily (BID), co-treatment with 600 mg oral rifampin daily decreased the steady-state area under the concentration vs. time curve of LPV by 79%, in line with the observed change of 75%. Simulated and observed concentration profiles were comparable for LPV/RTV (230/57.5 mg/mSuper-boosted LPV/RTV with 15 mg/kg rifampin achieves therapeutic LPV troughs in HIV/TB-infected simulated children.
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- 2022
14. Dynamics of the Decay of Human Immunodeficiency Virus (HIV) RNA and Distribution of Bictegravir in the Genital Tract and Rectum in Antiretroviral-naive Adults Living With HIV–1 Treated With Bictegravir/Emtricitabine/Tenofovir Alafenamide (Spanish HIV/AIDS Research Network, PreEC/RIS 58)
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Daniel Podzamczer, Sandra Morenilla, Brian Van Horne, Sofía Scévola, Amanda P. Schauer, Victor Urrea, Pere Domingo, Javier Martinez-Picado, Ana C Silva-Klug, Angela D. M. Kashuba, Eugenia Negredo, Mackenzie L. Cottrell, Benito Garcia, Jordi Niubó, Juan Tiraboschi, Arkaitz Imaz, and Ivan Chivite
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Adult ,Male ,0301 basic medicine ,Microbiology (medical) ,Anti-HIV Agents ,Pyridones ,030106 microbiology ,HIV Infections ,Emtricitabine ,Tenofovir alafenamide ,Piperazines ,Andrology ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Blood plasma ,Humans ,Medicine ,Genitalia ,Prospective Studies ,030212 general & internal medicine ,Tenofovir ,Online Only Articles ,Alanine ,Bictegravir ,business.industry ,HIV/AIDS research ,Rectum ,RNA ,Amides ,Infectious Diseases ,HIV-1 ,Population study ,Female ,business ,Heterocyclic Compounds, 3-Ring ,medicine.drug - Abstract
BackgroundThe pharmacokinetics of bictegravir (BIC) and its association with the decay of human immunodeficiency virus (HIV)–1 RNA in genital fluids and the rectum have not yet been addressed.MethodsWe conducted a prospective, multicenter study of antiretroviral-naive people living with HIV-1 and initiating BIC/emtricitabine (FTC)/tenofovir alafenamide (TAF). HIV-1 RNA was measured (limit of quantification, 40 copies/mL) in blood plasma (BP), seminal plasma (SP), rectal fluid (RF), and cervicovaginal fluid (CVF) at baseline; Days 3, 7, 14, and 28; and Weeks 12 and 24. Total and protein-unbound BIC concentrations at 24 hours postdose (C24h) were quantified in BP, SP, CVF and rectal tissue (RT) on Day 28 and Week 12 using a validated liquid chromatography-tandem mass spectrometry assay.ResultsThe study population comprised 15 males and 8 females. In SP, RF, and CVF, the baseline HIV-1 RNA was >40 copies/mL in 12/15, 13/15, and 4/8 individuals, respectively, with medians of 3.54 (2.41–3.79), 4.19 (2.98–4.70), and 2.56 (1.61–3.56) log10 copies/mL, respectively. The initial decay slope was significantly lower in SP than in RF and BP. The time to undetectable HIV-1 RNA was significantly shorter in SP and RF than in BP. All women achieved undetectable HIV-1 RNA in CVF at Day 14. The median total BIC concentrations in SP, RT, and CVF were 65.5 (20.1–923) ng/mL, 74.1 (6.0–478.5) ng/g, and 61.6 (14.4–1760.2) ng/mL, respectively, representing 2.7%, 2.6%, and 2.8% of the BP concentration, respectively, while the protein-unbound fractions were 51.1%, 44.6%, and 42.6%, respectively.ConclusionsBIC/FTC/TAF led to rapid decay of HIV-1 RNA in genital and rectal fluids. Protein-unbound BIC concentrations in SP, RT, and CVF highly exceeded the half-maximal effective concentration (EC50) value (1.1 ng/mL).Clinical Trials RegistrationEudraCT 2018-002310-12.
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- 2020
15. Efficacy, pharmacokinetics and neurocognitive performance of dual, NRTI-sparing antiretroviral therapy in acute HIV-infection
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Angela D. M. Kashuba, Guido Ferrari, Kara S. McGee, Susan A. Fiscus, Nicholas J. Shaheen, Aaron S. Devanathan, Kevin Robertson, Joe Sebastian, Joseph J. Eron, Joann D. Kuruc, John L. Schmitz, Charles B. Hicks, David M. Margolis, Dayna T Neo, and Mehri S McKellar
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Anti-HIV Agents ,Gut-associated lymphoid tissue ,Immunology ,Etravirine ,HIV Infections ,Pilot Projects ,Article ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Antiretroviral Therapy, Highly Active ,Internal medicine ,Drug Resistance, Viral ,medicine ,Humans ,Immunology and Allergy ,Sex organ ,030212 general & internal medicine ,Darunavir ,Ritonavir ,business.industry ,Neuropsychology ,HIV ,Middle Aged ,Viral Load ,CD4 Lymphocyte Count ,Regimen ,Treatment Outcome ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,HIV-1 ,Drug Therapy, Combination ,Female ,business ,Neurocognitive ,medicine.drug - Abstract
OBJECTIVES The aim of this study was to evaluate penetration of antiretrovirals into compartments and efficacy of a dual, NRTI-sparing regimen in acute HIV infection (AHI). DESIGN Single-arm, open-label pilot study of participants with AHI initiating ritonavir-boosted darunavir 800 mg once daily and etravirine 400 mg once daily or 200 mg twice daily within 30 days of AHI diagnosis. METHODS Efficacy was defined as HIV RNA less than 200 copies/ml by week 24. Optional sub-studies included pharmacokinetics analysis from genital fluids (weeks 0-4, 12, 48), cerebrospinal fluid (CSF) (weeks 2-4, 24 and 48) and endoscopic biopsies (weeks 4-12 and 36-48). Neuropsychological performance was assessed at weeks 0, 24 and 48. RESULTS Fifteen AHI participants were enrolled. Twelve (80%) participants achieved HIV RNA less than 200 copies/ml by week 24. Among 12 participants retained through week 48, nine (75%) remained suppressed to less than 50 copies/ml. The median time from ART initiation to suppression less than 200 and less than 50 copies/ml was 59 and 86 days, respectively. The penetration ratios for etravirine and darunavir in gut associated lymphoid tissue were 19.2 and 3.05, respectively. Most AHI participants achieving viral suppression experienced neurocognitive improvement. Of the three participants without overall improvement in neurocognitive functioning as measured by impairment ratings (more than two tests below 1 SD), two had virologic failure. CONCLUSION NRTI-sparing ART started during AHI resulted in rapid viral suppression similar to NRTI-based regimens. More novel and compact two-drug treatments for AHI should be considered. Early institution of ART during AHI appears to improve overall neurocognitive function and may reduce the risk of subsequent neurocognitive impairment. CLINICALTRIALS.GOV:: NCT00855413.
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- 2020
16. Rivaroxaban Precision Dosing Strategy for Real‐World Atrial Fibrillation Patients
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Daniel Gonzalez, J. Robert Powell, Daniel Weiner, Yanguang Carter Cao, Paul B. Watkins, Angela D. M. Kashuba, J. Herbert Patterson, Anil K. Gehi, and Robyn Konicki
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Male ,030213 general clinical medicine ,Population ,Administration, Oral ,Phases of clinical research ,Renal function ,Models, Biological ,030226 pharmacology & pharmacy ,Drug Administration Schedule ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Rivaroxaban ,Pharmacokinetics ,Atrial Fibrillation ,medicine ,Humans ,Computer Simulation ,Drug Dosage Calculations ,In patient ,Dosing ,General Pharmacology, Toxicology and Pharmaceutics ,education ,Aged ,education.field_of_study ,Dose-Response Relationship, Drug ,business.industry ,lcsh:Public aspects of medicine ,Research ,General Neuroscience ,lcsh:RM1-950 ,lcsh:RA1-1270 ,Atrial fibrillation ,Articles ,General Medicine ,medicine.disease ,lcsh:Therapeutics. Pharmacology ,Area Under Curve ,Anesthesia ,business ,Factor Xa Inhibitors ,medicine.drug - Abstract
Rivaroxaban is a direct‐acting oral anticoagulant approved to prevent strokes in patients with atrial fibrillation. Dosage recommendations are approved for all adult patients to receive either 15 mg or 20 mg once daily depending upon renal function. There are a number of reasons to believe rivaroxaban dosing could be more effective and/or safer for more patients if increased dosing precision is available. Because real‐world patients are more diverse than those studied in phase III clinical trials, we evaluated the extremes of creatinine clearance (CrCl) on rivaroxaban clearance using a published population pharmacokinetic model and applying exposure variation limits (±20%) based on published literature. The proposed dosing recommendations are 10 mg once daily (CrCl 15–29 ml/min), 15 mg once daily (CrCl 30–69 ml/min), 10 mg twice daily (CrCl 70–159 ml/min), and 15 mg twice daily (CrCl 160–250 ml/min). These new dosing recommendations should be prospectively tested for predictive accuracy and to assess the impact on AF patient efficacy and safety.
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- 2020
17. CCR5 inhibitor as novel acute graft versus host disease prophylaxis in children and young adults undergoing allogeneic stem cell transplant: results of the phase II study
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J.J. Bleesing, Adam Lane, Michael B. Jordan, Pooja Khandelwal, Mary Christa Krupski, Tsuyoshi Fukuda, Adam S. Nelson, Parinda A. Mehta, Ashley Teusink-Cross, Angela D. M. Kashuba, Kasiani C. Myers, Javier El-Bietar, Sharat Chandra, Michael Grimley, Rebecca A. Marsh, and Stella M. Davies
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Transplantation ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,Hematology ,CCR5 receptor antagonist ,Gastroenterology ,Calcineurin ,03 medical and health sciences ,chemistry.chemical_compound ,surgical procedures, operative ,0302 clinical medicine ,chemistry ,immune system diseases ,030220 oncology & carcinogenesis ,Internal medicine ,Pharmacodynamics ,medicine ,Methotrexate ,Young adult ,Adverse effect ,business ,030215 immunology ,medicine.drug ,Maraviroc - Abstract
We report results of a phase II study of maraviroc to prevent acute graft versus host disease (GVHD) in children undergoing allogeneic hematopoietic stem cell transplant (HSCT). Oral maraviroc was added to standard GVHD prophylaxis of a calcineurin inhibitor with either mycophenolate mofetil, methotrexate or steroids from day −3 until day +30 after HSCT. Maraviroc trough levels were analyzed on day 0, +7, 14, and 21. We assessed functional CCR5 blockade by our previously described pharmacodynamic assay. In total, 17 patients were enrolled prospectively. No patient had liver GVHD by day +100. Four patients developed gastrointestinal (GI) GVHD (Grade II upper GI GVHD n = 2, grade III lower GI GVHD n = 2). No adverse effects of maraviroc were observed. Seven patients discontinued maraviroc at a median of day +14 (range day +1–day +29) due to study rules regarding hepatotoxicity (n = 5), renal function decline (n = 1) and withdrawal from study (n = 1). Maraviroc administration led to CCR5 inhibition but was limited by study rules defining hepatotoxicity, leading to frequent drug discontinuation. We cannot comment on the efficacy of maraviroc with our data but speculate that it could have a role in prevention of acute GI GVHD, with adequate compliance.
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- 2020
18. Influence of hair treatments on detection of antiretrovirals by mass spectrometry imaging
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Angela D. M. Kashuba, William M Gilliland, Elias P. Rosen, Heather M.A. Prince, Ann Marie Weideman, Nicole White, Bryan H Yam, and Joseph N. Mwangi
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Spectrometry, Mass, Electrospray Ionization ,Efavirenz ,Hair Dyes ,Pharmacology ,Emtricitabine ,Antiviral Agents ,01 natural sciences ,Biochemistry ,Article ,Analytical Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,Abacavir ,otorhinolaryngologic diseases ,Electrochemistry ,medicine ,Humans ,Environmental Chemistry ,030212 general & internal medicine ,Spectroscopy ,Darunavir ,Maraviroc ,Hair Bleaching Agents ,integumentary system ,business.industry ,Cobicistat ,010401 analytical chemistry ,virus diseases ,Relaxer ,0104 chemical sciences ,Hair Analysis ,chemistry ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Dolutegravir ,sense organs ,business ,Hair ,medicine.drug - Abstract
Analysis of drugs in hair by mass spectrometry imaging (MSI) has great potential as an objective, long-term measure of medication adherence. However, the fidelity of the chemical record in hair may be compromised by any cosmetic hair treatments. Here, we investigate infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) MSI response to multiple antiretrovirals (ARVs) in cosmetically treated hair. Hair strands from patients on different ARV regimens were mechanically treated with dye, bleach, and relaxer. The treatments had little or no effect relative to untreated controls for cobicistat, abacavir, dolutegravir, maraviroc, efavirenz, and darunavir, but all three treatments removed emtricitabine (FTC) to undetectable levels from patient hair strands. We also evaluated hair strands by IR-MALDESI MSI from 8 patients on FTC-based regimens who reported a range of hair treatments at varying recency prior to hair collection. While FTC was undetectable in the treated portion of these hair strands, ARVs coadministered with FTC remained detectable in hair strands after treatment. We conclude that IR-MALDESI MSI can be used when measuring adherence to ARV therapy, provided that ARVs other than FTC are targeted in people using hair treatments.
- Published
- 2020
19. The
- Author
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Carolina, Herrera, Mackenzie L, Cottrell, John, Prybylski, Angela D M, Kashuba, Ronald S, Veazey, Javier, García-Pérez, Natalia, Olejniczak, Clare F, McCoy, Paul, Ziprin, Nicola, Richardson-Harman, José, Alcami, Karl R, Malcolm, and Robin J, Shattock
- Abstract
Non-human primates (NHP) are widely used for the pre-clinical assessment of antiretrovirals (ARVs) for HIV treatment and prevention. However, the utility of these models is questionable given the differences in ARV pharmacology between humans and macaques. Here, we report a model based on
- Published
- 2021
20. Correction to: Feasibility, Acceptability, and Preliminary Efficacy of a Gamified Mobile Health Contingency Management Intervention for PrEP Adherence Among Black MSM
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John T. Mitchell, Charles M. Burns, Breyah Atkinson, Mackenzie Cottrell, Justin K. Frye, Mehri S. McKellar, Angela D. M. Kashuba, F. Joseph McClernon, and Nwora Lance Okeke
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Infectious Diseases ,Social Psychology ,Public Health, Environmental and Occupational Health - Published
- 2022
21. Intracellular islatravir pharmacology differs between species in an in vitro model: implications for preclinical study design
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Craig Sykes, Brian Van Horne, Justin Jones, Angela D. M. Kashuba, Gregory Gatto, Ariane Van Der Straten, Leah Johnson, and Mackenzie L. Cottrell
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Pharmacology ,Microbiology (medical) ,Deoxyadenosines ,Anti-HIV Agents ,Swine ,HIV Infections ,Macaca mulatta ,Models, Biological ,Rats ,Infectious Diseases ,Dogs ,Species Specificity ,Research Design ,Tandem Mass Spectrometry ,Animals ,Reverse Transcriptase Inhibitors ,Swine, Miniature ,Pharmacology (medical) ,Rabbits ,Original Research - Abstract
Background Islatravir (4′-ethynyl-2-fluoro-2′-deoxyadenosine; EFdA) is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI) being investigated for HIV treatment and prevention. EFdA is intracellularly phosphorylated to EFdA-triphosphate (EFdA-tp), a competitive substrate of deoxyadenosine-triphosphate (dATP). Thus, translating safety and efficacy findings from preclinical studies relies on the assumption that EFdA’s intracellular pharmacology can be extrapolated across species. Objectives We investigated how EFdA is phosphorylated across animal species commonly used for preclinical models in drug development to identify those that most closely matched humans. Methods PBMCs were isolated from whole blood of six species (human, rhesus macaque non-human primate (rmNHP), rat, minipig, dog, and rabbit) using Ficoll separation and counted on a haemocytometer by Trypan blue staining. One million live cells were cultured in media supplemented with 10 U/mL human IL-2, 10% FBS and 1% antibiotics and treated with 0, 17, 170, and 1700 nM EFdA (n = 3 replicates per concentration). After 24 h, representative cell counts were derived from untreated control wells (as above), cells were washed in PBS, and lysed with 70:30 methanol:water. EFdA-tp and dATP concentrations were quantified by HPLC-MS/MS and normalized to the representative live cell counts for each species. Results When compared to human values, EFdA-tp concentrations for each EFdA treatment concentration were lower in all species (rmNHP 1.5–2.1-fold, rat 4.5–15-fold, minipig 37–71-fold, dog and rabbit >100-fold). Additionally, rmNHP and dog PBMCs exhibited significantly higher (7–10-fold; P < 0.001) dATP when compared with human PBMCs. Conclusions Given intracellular pharmacology differences, these preclinical models may be a conservative estimate of EFdA’s intracellular pharmacokinetics and efficacy in humans.
- Published
- 2021
22. Biodegradable Polymeric Solid Implants for Ultra-Long-Acting Delivery of Single or Multiple Antiretroviral Drugs
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Craig Sykes, S. Rahima Benhabbour, Mackenzie L. Cottrell, Angela D. M. Kashuba, Stephanie A. Montgomery, Panita Maturavongsadit, and Roopali Shrivastava
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Drug ,Materials science ,Polymers ,media_common.quotation_subject ,Pharmaceutical Science ,HIV Infections ,02 engineering and technology ,030226 pharmacology & pharmacy ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Humans ,Micronization ,media_common ,Rilpivirine ,021001 nanoscience & nanotechnology ,PLGA ,chemistry ,Anti-Retroviral Agents ,Pharmaceutical Preparations ,Dolutegravir ,Drug delivery ,Implant ,0210 nano-technology ,Phase inversion ,Biomedical engineering - Abstract
Lack of adherence is a key barrier to a successful human immunodeficiency virus (HIV) treatment and prevention. We report on an ultra-long-acting (ULA) biodegradable polymeric solid implant (PSI) that can accommodate one or more antiretrovirals (e.g., dolutegravir (DTG) and rilpivirine (RPV)) at translatable human doses (65% wt.) in a single implant. PSIs are fabricated using a three-step process: (a) phase inversion of a drug/polymer solution to form an initial in-situ forming solid implant, (b) micronization of dried drug-loaded solid implants, and (c) compression of the micronized drug-loaded solid powder to generate the PSI. DTG and RPV can be pre-combined in a single PLGA-based solution to make dual-drug PSI; or formulated individually in PLGA-based solutions to generate separate micronized powders and form a bilayer dual-drug PSI. Results showed that in a single or bilayer dual-drug PSI, DTG and RPV exhibited physicochemical properties similar to their pure drug analogues. PSIs were well tolerated in vivo and effectively delivered drug(s) over 180 days with concentrations above 4 × PA-IC90 after a single subcutaneous administration. While biodegradable and do not require removal, these PSIs can safely be removed to terminate the treatment if required. The versatility of this technology makes it attractive as an ULA drug delivery platform for HIV and various therapeutic applications.
- Published
- 2021
23. Food Insecurity Is Associated With Lower Levels of Antiretroviral Drug Concentrations in Hair Among a Cohort of Women Living With Human Immunodeficiency Virus in the United States
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Angela D. M. Kashuba, Peter Bacchetti, Anna M. Leddy, Craig Sykes, Mardge H. Cohen, Lisa R. Metsch, Adaora A. Adimora, Bani Tamraz, Ighovwerha Ofotokun, Tracey E. Wilson, Lila A. Sheira, Janet M. Turan, Eryka L. Wentz, Daniel Merenstein, Sheri D. Weiser, and Adebola Adedimeji
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Microbiology (medical) ,Anti-HIV Agents ,antiretroviral therapy ,HIV Infections ,Medical and Health Sciences ,Microbiology ,Food Supply ,Medication Adherence ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,7.1 Individual care needs ,Clinical Research ,food insecurity ,Environmental health ,medicine ,Humans ,Prospective Studies ,adherence ,women living with HIV ,030212 general & internal medicine ,Articles and Commentaries ,Darunavir ,ART concentrations in hair ,030505 public health ,Food security ,business.industry ,HIV ,Repeated measures design ,Biological Sciences ,Raltegravir ,United States ,Atazanavir ,Food Insecurity ,Infectious Diseases ,Pharmaceutical Preparations ,chemistry ,Dolutegravir ,Cohort ,HIV/AIDS ,Female ,Zero Hunger ,Management of diseases and conditions ,0305 other medical science ,business ,medicine.drug ,Cohort study - Abstract
Background Food insecurity is a well-established determinant of suboptimal, self-reported antiretroviral therapy (ART) adherence, but few studies have investigated this association using objective adherence measures. We examined the association of food insecurity with levels of ART concentrations in hair among women living with human immunodeficiency virus (WLHIV) in the United States. Methods We analyzed longitudinal data collected semiannually from 2013 through 2015 from the Women’s Interagency HIV Study, a multisite, prospective, cohort study of WLHIV and controls not living with HIV. Our sample comprised 1944 person-visits from 677 WLHIV. Food insecurity was measured using the US Household Food Security Survey Module. ART concentrations in hair, an objective and validated measure of drug adherence and exposure, were measured using high-performance liquid chromatography with mass spectrometry detection for regimens that included darunavir, atazanavir, raltegravir, or dolutegravir. We conducted multiple 3-level linear regressions that accounted for repeated measures and the ART medication(s) taken at each visit, adjusting for sociodemographic and clinical characteristics. Results At baseline, 67% of participants were virally suppressed and 35% reported food insecurity. In the base multivariable model, each 3-point increase in food insecurity was associated with 0.94-fold lower ART concentration in hair (95% confidence interval, 0.89 to 0.99). This effect remained unchanged after adjusting for self-reported adherence. Conclusions Food insecurity was associated with lower ART concentrations in hair, suggesting that food insecurity may be associated with suboptimal ART adherence and/or drug absorption. Interventions seeking to improve ART adherence among WLHIV should consider and address the role of food insecurity.
- Published
- 2019
24. Association between Use of Methadone, Other Central Nervous System Depressants, and<scp>QT</scp>c Interval–Prolonging Medications and Risk of Mortality in a Large Cohort of Women Living with or at Risk for Human Immunodeficiency Virus Infection
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Joel Milam, Bani Tamraz, Bradley E. Aouizerat, Jennifer Cocohoba, Kerry Murphy, Stephen J. Gange, Ruth M. Greenblatt, Patrick R. Finley, Angela D. M. Kashuba, Chenglong Liu, Igho Ofotokun, Peter Bacchetti, Samuel T. King, Michael Augenbraun, Audrey L. French, Margaret A. Fischl, and Lori Reisner
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0301 basic medicine ,HIV Infections ,030204 cardiovascular system & hematology ,Kidney Function Tests ,Benzodiazepines ,Electrocardiography ,Hemoglobins ,0302 clinical medicine ,Risk Factors ,Cause of Death ,Risk of mortality ,Medicine ,Pharmacology (medical) ,Prospective Studies ,Substance Abuse, Intravenous ,Depression ,Hazard ratio ,Middle Aged ,Viral Load ,Long QT Syndrome ,Cohort ,Female ,medicine.drug ,Cohort study ,Adult ,medicine.medical_specialty ,Adolescent ,Sexual Behavior ,030106 microbiology ,National Death Index ,Article ,Young Adult ,03 medical and health sciences ,Acquired immunodeficiency syndrome (AIDS) ,Internal medicine ,Tobacco Smoking ,Humans ,Mortality ,Serum Albumin ,Aged ,Proportional Hazards Models ,Acquired Immunodeficiency Syndrome ,business.industry ,Proportional hazards model ,Central Nervous System Depressants ,medicine.disease ,CD4 Lymphocyte Count ,Socioeconomic Factors ,business ,Methadone - Abstract
STUDY OBJECTIVE: To evaluate the association between use of methadone, other central nervous system (CNS) depressants, and QTc interval–prolonging medications and risk of mortality among human immunodeficiency virus (HIV)-infected and at-risk HIV-uninfected women. DESIGN: Multicenter, prospective, observational cohort study (Women’s Interagency HIV Study [WIHS]). PARTICIPANTS: A total of 4150 women enrolled in the WIHS study between 1994 and 2014 who were infected (3119 women) or not infected (1031 women) with HIV. MEASUREMENTS AND MAIN RESULTS: Data on medication utilization were collected from all study participants via interviewer-administered surveys at 6-month intervals (1994–2014). Mortality was confirmed by National Death Index data. With age defining the time scale for the analysis, Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause mortality in HIV-infected and -uninfected women and non–acquired immunodeficiency syndrome (AIDS) deaths in HIV-infected women. A total of 1046 deaths were identified, of which 429 were considered non-AIDS deaths. Use of benzodiazepines, CNS depressants (excluding methadone), and number of medications with conditional QTc interval–prolonging effects were each associated with all-cause mortality in multivariate models of HIV-infected women: hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.01–1.60, p=0.037; HR 1.61, 95% CI 1.35–1.92, p0.05). CONCLUSION: In this cohort of HIV-infected and at-risk HIV-uninfected women, use of benzodiazepines, CNS depressants, and conditional QTc interval–prolonging medications were associated with a higher risk of mortality independent of methadone and other well-recognized mortality risk factors. Care must be taken to assess risk when prescribing these medications in this underserved and at-risk patient population.
- Published
- 2019
25. Infrared Matrix-Assisted Laser Desorption Electrospray Ionization Mass Spectrometry Imaging of Human Hair to Characterize Longitudinal Profiles of the Antiretroviral Maraviroc for Adherence Monitoring
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Heather M.A. Prince, Elias P. Rosen, Amanda Poliseno, William M. Gilliland, and Angela D. M. Kashuba
- Subjects
Spectrometry, Mass, Electrospray Ionization ,Matrix-assisted laser desorption electrospray ionization ,Infrared Rays ,Chemistry ,Electrospray ionization ,010401 analytical chemistry ,Medication adherence ,010402 general chemistry ,Mass spectrometry ,01 natural sciences ,Healthy Volunteers ,Article ,Mass spectrometry imaging ,Medication Adherence ,0104 chemical sciences ,Analytical Chemistry ,Hair growth ,chemistry.chemical_compound ,Anti-Retroviral Agents ,Adherence monitoring ,Humans ,Hair ,Biomedical engineering ,Maraviroc - Abstract
Here, we assess infrared matrix assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging (MSI) analysis of hair as a clinical tool for monitoring patient adherence to the antiretroviral maraviroc (MVC). A custom MATLAB-based algorithm has been developed to streamline data analysis and generate longitudinal profiles of drug incorporation along the length of hair strands. Hair strands from volunteers enrolled in a directly observed therapy study were analyzed by IR-MALDESI MSI and processed using this tool to characterize the profiles of single doses and a daily dose regimen of MVC. Single dose responses were 1.7 [1.1, 2.5] mm (median [range]) wide along the length of the hair and were detected in 8 out of 12 volunteers. Daily dose profiles capturing 28 days of continuous dosing were approximately 5 times the intensity of single dose profiles and 10.5 [7.0, 13] mm wide, corresponding to 1 month of hair growth. MVC ion abundance was observed in all 12 volunteers for the daily dosing period. Daily dosing profiles were consistent with a model of MVC accumulation in hair based on linear superposition of a single dose response, indicating the potential for prediction of daily drug-taking behavior based on deconvolution of a complex longitudinal profile in hair.
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- 2019
26. Patient and clinician perspectives on optimizing graphical displays of longitudinal medication adherence data
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Jessica Carda-Auten, Angela D. M. Kashuba, Deshira D. Wallace, Elias P. Rosen, Monica Gandhi, Carol E. Golin, Claire E Farel, Heather M.A. Prince, Sruthi Cherkur, Lauren M. Hill, and Allison P. Pack
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Adult ,Male ,medicine.medical_specialty ,Anti-HIV Agents ,Bar chart ,Decision Making ,Medication adherence ,HIV Infections ,Health literacy ,Article ,Medication Adherence ,law.invention ,Drug levels ,03 medical and health sciences ,0302 clinical medicine ,Patient Education as Topic ,law ,medicine ,Humans ,030212 general & internal medicine ,Health communication ,Audiovisual Aids ,business.industry ,030503 health policy & services ,General Medicine ,Graphical display ,Health Literacy ,Cross-Sectional Studies ,Drug concentration ,Adherence monitoring ,Data Display ,Physical therapy ,Female ,0305 other medical science ,business ,Hair - Abstract
Objective New pharmacological measures assessing medication adherence, including longitudinal drug levels in hair, are emerging. Little is known, however, about how best to present results from such measures to patients and clinicians in comprehensive, easy-to-understand, acceptable formats. We, therefore, developed three graphical display prototypes of hypothetical daily drug concentrations measured in hair, and assessed their acceptability among participants. Methods We interviewed 30 HIV-positive patients and 29 clinicians to examine perceived acceptability for each graphical display prototype. Results Patients and clinicians generally found the prototypes acceptable for facilitating understanding of patient adherence; however, areas for optimization were identified. For patients with lower health literacy, prototypes did not provide sufficient understanding of the link between medication-taking and drug concentrations in hair. These patients also preferred pictographs over bar or line graphs. Clinicians largely preferred daily drug concentration data in bar graphs with information included about the measure’s accuracy. Participants questioned the utility of showing drug concentrations above a therapeutic range, though they found color-coding results acceptable. Conclusions Assessing prototype versions of graphical displays of hypothetical longitudinal adherence data indicated ways to optimize their acceptability. Practice implications Acceptable prototype-tested graphical displays of longitudinal patient-specific drug concentrations may enhance adherence monitoring in clinical settings.
- Published
- 2019
27. HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood–brain barrier integrity
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Pamela E. Knapp, Jason J. Paris, Matthew S. Halquist, Woong-Ki Kim, Quamrun N. Masuda, Austin M Jones, Kurt F. Hauser, Angela D. M. Kashuba, Crystal R. Leibrand, and MaryPeace McRae
- Subjects
0301 basic medicine ,HIV Infections ,Striatum ,Pharmacology ,Hippocampus ,Piperazines ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Abacavir ,Medicine ,P-glycoprotein ,Morphine ,biology ,Lamivudine ,Dextrans ,medicine.anatomical_structure ,Neurology ,Blood-Brain Barrier ,Dolutegravir ,Female ,tat Gene Products, Human Immunodeficiency Virus ,Opiate ,Heterocyclic Compounds, 3-Ring ,Fluorescein-5-isothiocyanate ,medicine.drug ,Anti-HIV Agents ,Pyridones ,Neurocognitive Disorders ,Mice, Transgenic ,Blood–brain barrier ,Models, Biological ,Article ,Capillary Permeability ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Virology ,Oxazines ,Animals ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,business.industry ,Biological Transport ,Corpus Striatum ,Dideoxynucleosides ,030104 developmental biology ,chemistry ,HIV-1 ,biology.protein ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Poor antiretroviral penetration may contribute to human immunodeficiency virus (HIV) persistence within the brain and to neurocognitive deficits in opiate abusers. To investigate this problem, HIV-1 Tat protein and morphine effects on blood-brain barrier (BBB) permeability and drug brain penetration were explored using a conditional HIV-1 Tat transgenic mouse model. METHODS. Tat and morphine effects on the leakage of fluorescently-labeled dextrans (10-, 40- and 70- kDa) into the brain were assessed. To evaluate effects on antiretroviral brain penetration, Tat+ and Tat− mice received three antiretroviral drugs (dolutegravir, abacavir, and lamivudine) with or without concurrent morphine exposure. Antiretroviral and morphine brain and plasma concentrations were determined by LC-MS/MS. FINDINGS. Morphine exposure, and to a lesser extent, Tat, significantly increased tracer leakage from the vasculature into the brain. Despite enhanced BBB breakdown evidenced by increased tracer leakiness, morphine exposure led to significantly lower abacavir concentrations within striatum and significantly less dolutegravir within hippocampus and striatum (normalized to plasma). P-glycoprotein, an efflux transporter for which these drugs are substrates, expression and function were significantly increased in the brains of morphine-exposed mice compared to mice not exposed to morphine. These findings were consistent with lower antiretroviral concentrations in brain tissues examined. Lamivudine concentrations were unaffected by Tat or morphine exposure. CONCLUSIONS. Collectively, our investigations indicate that Tat and morphine differentially alter BBB integrity. Morphine decreased brain concentrations of specific antiretroviral drugs, perhaps via increased expression of the drug efflux transporter, P-glycoprotein.
- Published
- 2019
28. Decreased Tenofovir Diphosphate Concentrations in a Transgender Female Cohort: Implications for Human Immunodeficiency Virus Preexposure Prophylaxis
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Angela D. M. Kashuba, Amanda Poliseno, Tae-Wook Chun, Amanda P. Schauer, Anne F. Peery, Mackenzie L. Cottrell, Evan S. Dellon, Jessica L. Adams, Erin D Huiting, Kaitlyn A. Maffuid, Heather M.A. Prince, Craig Sykes, and Frank Z. Stanczyk
- Subjects
Adult ,0301 basic medicine ,Microbiology (medical) ,Adolescent ,Tenofovir diphosphate ,Anti-HIV Agents ,medicine.medical_treatment ,030106 microbiology ,Human immunodeficiency virus (HIV) ,Brief Reports and Commentary ,Physiology ,HIV Infections ,medicine.disease_cause ,Transgender Persons ,Young Adult ,03 medical and health sciences ,Pre-exposure prophylaxis ,0302 clinical medicine ,Hormone replacement therapy (female-to-male) ,Transgender ,medicine ,Humans ,Tissue Distribution ,030212 general & internal medicine ,Aged ,business.industry ,Adenine ,HIV ,Middle Aged ,Organophosphates ,Clinical trial ,Treatment Outcome ,Infectious Diseases ,Cohort ,Female ,Pre-Exposure Prophylaxis ,Hormone therapy ,Drug Monitoring ,business - Abstract
Feminizing hormone therapy (FHT) may interact with human immunodeficiency virus preexposure prophylaxis (PrEP). We found that transgender women who took FHT exhibited a 7-fold lower rectal tissue ratio of PrEP’s active metabolites vs competing deoxynucleotides compared to cisgender women and men (P = .03) that inversely correlated with estradiol (ρ = –0.79; P < .05). Thus, FHT may negatively impact PrEP efficacy. Clinical Trials Registration . NCT02983110.
- Published
- 2019
29. Contemporary Drug–Drug Interactions in <scp>HIV</scp> Treatment
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Ashley C. Saunders, Angela D. M. Kashuba, Mackenzie L. Cottrell, Aaron S. Devanathan, Erin M. Burgunder, and Daijha J.C. Anderson
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Drug ,medicine.medical_specialty ,Anti-HIV Agents ,media_common.quotation_subject ,Human immunodeficiency virus (HIV) ,Antineoplastic Agents ,HIV Infections ,medicine.disease_cause ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,medicine ,Humans ,Distribution (pharmacology) ,Drug Interactions ,Pharmacology (medical) ,Hiv treatment ,Intensive care medicine ,Antihypertensive Agents ,media_common ,Pharmacology ,business.industry ,Standard treatment ,Drug interaction ,Anti-Retroviral Agents ,030220 oncology & carcinogenesis ,business ,Drug metabolism - Abstract
Despite development of modern antiretrovirals with lower drug interaction potential than their predecessors, drug interaction challenges remain. Standard treatment regimens still require multiple antiretrovirals that may cause, or may be the target of, drug interactions. Additionally, people living with HIV are living longer and often present with comorbid conditions that require concomitant long-term drug therapy. Also, treatment of infectious diseases in resource-limited settings can result in significant interactions. In this review, we describe absorption, distribution, metabolism, and excretion pathways as they relate to relevant drug interactions with antiretrovirals along with the potential clinical consequences of these interactions. We highlight clinical data that illustrate pertinent interactions and provide tools to assist in predicting drug interactions in the absence of clinical data. Given these tools and thoughtful consideration of drug combinations, drug therapy in people living with HIV can be safely and effectively managed throughout their lifetime.
- Published
- 2019
30. Effect of Hormonal Contraception on Pharmacokinetics of Vaginal Tenofovir in Healthy Women: Increased Tenofovir Diphosphate in Injectable Depot Medroxyprogesterone Acetate Users
- Author
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Jill L. Schwartz, Andrea R. Thurman, Gustavo F. Doncel, Debra H. Weiner, Angela D. M. Kashuba, Neelima Chandra, Vivian Brache, Beatrice A. Chen, and Christine K. Mauck
- Subjects
Adult ,Oral contraceptive pill ,Anti-HIV Agents ,media_common.quotation_subject ,Medroxyprogesterone ,Physiology ,HIV Infections ,Medroxyprogesterone Acetate ,030312 virology ,Luteal phase ,Young Adult ,03 medical and health sciences ,Pharmacokinetics ,immune system diseases ,Contraceptive Agents, Female ,Humans ,Medicine ,Medroxyprogesterone acetate ,Drug Interactions ,Pharmacology (medical) ,Prospective Studies ,Tenofovir ,Menstrual Cycle ,Menstrual cycle ,media_common ,0303 health sciences ,business.industry ,virus diseases ,Middle Aged ,Healthy Volunteers ,Menstrual cycle phase ,Administration, Intravaginal ,Treatment Outcome ,Infectious Diseases ,Hormonal contraception ,Vaginal Creams, Foams, and Jellies ,Female ,business ,medicine.drug - Abstract
Endogenous and exogenous contraceptive hormones may affect mucosal pharmacokinetics (PKs) of topical antiretrovirals such as tenofovir. We present PK data from healthy women using tenofovir vaginal gel, at baseline (follicular and luteal phases) and after oral contraceptive pill (OCP) or depot medroxyprogesterone acetate (DMPA) use.CONRAD A10-114 was a prospective, interventional, open-label, parallel study. We enrolled 74 women and 60 completed the study (32 and 28 who selected OCPs or DMPA, respectively). Participants used 2 doses of tenofovir gel separated by 2 hours, without intercourse, and were examined 3 or 11 hours after the last dose. We assessed pharmacokinetics in plasma, cervicovaginal (CV) aspirate, and vaginal tissue.In general, there were no significant differences in mucosal tenofovir and tenofovir diphosphate concentrations (P0.23) in the follicular and luteal phases, except for lower mean tenofovir tissue concentrations (P0.01) in the follicular phase. Tenofovir concentrations significantly decreased in CV aspirate (P0.01) after contraceptive use, but overall remained very high (10 ng/mL). Mean tissue tenofovir diphosphate increased to 6229 fmol/mg after DMPA use compared with 3693 and 1460 fmol/mg in the follicular and luteal phases, respectively (P0.01). The molecular conversion of tenofovir into tenofovir diphosphate was more effective in DMPA users (molecular ratio of 2.02 versus 0.65 luteal phase, P0.01).Both menstrual cycle phase and exogenous hormones affect topical tenofovir mucosal and systemic PKs. However, high levels of tenofovir and tenofovir diphosphate were observed in the CV mucosa in the presence or absence of OCPs and DMPA, with tissue levels exceeding benchmarks of predicted mucosal anti-HIV efficacy (tenofovir1.00 ng/mL in CV aspirate and tenofovir diphosphate1000 fmol/mg).
- Published
- 2019
31. Human Immunodeficiency Virus Type 1 RNA Detected in the Central Nervous System (CNS) After Years of Suppressive Antiretroviral Therapy Can Originate from a Replicating CNS Reservoir or Clonally Expanded Cells
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Magnus Gisslén, Prema Menezes, Christopher K Lippincott, Laura P. Kincer, Richard W. Price, Michael J. Vinikoor, Serena Spudich, Sarah B. Joseph, Joseph J. Eron, Natalie M. Bowman, Christopher S. Evans, Kevin Robertson, Nancie M. Archin, Angela D. M. Kashuba, and Ronald Swanstrom
- Subjects
Central Nervous System ,Male ,0301 basic medicine ,T-Lymphocytes ,Drug Resistance ,HIV Infections ,Drug resistance ,Medical and Health Sciences ,CSF escape ,Cohort Studies ,Plasma ,0302 clinical medicine ,Cerebrospinal fluid ,2.2 Factors relating to the physical environment ,Viral ,Longitudinal Studies ,030212 general & internal medicine ,Aetiology ,Articles and Commentaries ,Cerebrospinal Fluid ,education.field_of_study ,Microglia ,persistence ,Viral Load ,Middle Aged ,Biological Sciences ,Mental Health ,Infectious Diseases ,medicine.anatomical_structure ,Anti-Retroviral Agents ,RNA, Viral ,HIV/AIDS ,Female ,CNS ,Infection ,Adult ,Microbiology (medical) ,Lineage (genetic) ,030106 microbiology ,Population ,Central nervous system ,HIV reservoirs ,Microbiology ,03 medical and health sciences ,Viral envelope ,Drug Resistance, Viral ,medicine ,Humans ,education ,business.industry ,Neurosciences ,RNA ,Virology ,Cross-Sectional Studies ,Asymptomatic Diseases ,HIV-1 ,business - Abstract
Background Human immunodeficiency virus type 1 (HIV-1) populations are detected in cerebrospinal fluid (CSF) of some people on suppressive antiretroviral therapy (ART). Detailed analysis of these populations may reveal whether they are produced by central nervous system (CNS) reservoirs. Methods We performed a study of 101 asymptomatic participants on stable ART. HIV-1 RNA concentrations were cross-sectionally measured in CSF and plasma. In participants with CSF HIV-1 RNA concentrations sufficient for analysis, viral populations were genetically and phenotypically characterized over multiple time points. Results For 6% of participants (6 of 101), the concentration of HIV-1 RNA in their CSF was ≥0.5 log copies/mL above that of plasma (ie, CSF escape). We generated viral envelope sequences from CSF of 3 participants. One had a persistent CSF escape population that was macrophage-tropic, partially drug resistant, genetically diverse, and closely related to a minor macrophage-tropic lineage present in the blood prior to viral suppression and enriched for after ART. Two participants (1 suppressed and 1 not) had transient CSF escape populations that were R5 T cell-tropic with little genetic diversity. Conclusions Extensive analysis of viral populations in 1 participant revealed that CSF escape was from a persistently replicating population, likely in macrophages/microglia, present in the CNS over 3 years of ART. CSF escape in 2 other participants was likely produced by trafficking and transient expansion of infected T cells in the CNS. Our results show that CNS reservoirs can persist during ART and that CSF escape is not exclusively produced by replicating CNS reservoirs.
- Published
- 2018
32. Seminal Tenofovir Concentrations, Viral Suppression, and Semen Quality With Tenofovir Alafenamide, Compared With Tenofovir Disoproxil Fumarate (Spanish HIV/AIDS Research Network, PreEC/RIS 40)
- Author
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Emilia Perez, Angela D. M. Kashuba, Sandra Morenilla, Benito Garcia, Jordi Niubó, Juan Tiraboschi, Arkaitz Imaz, Mackenzie L. Cottrell, and Daniel Podzamczer
- Subjects
Adult ,Male ,0301 basic medicine ,Microbiology (medical) ,030106 microbiology ,HIV Infections ,Semen ,Quinolones ,Emtricitabine ,Tenofovir alafenamide ,Peripheral blood mononuclear cell ,Andrology ,03 medical and health sciences ,Semen quality ,0302 clinical medicine ,Blood plasma ,medicine ,Humans ,Prospective Studies ,030212 general & internal medicine ,Tenofovir ,Articles and Commentaries ,Alanine ,Elvitegravir ,business.industry ,Adenine ,Cobicistat ,Middle Aged ,Semen Analysis ,Infectious Diseases ,Anti-Retroviral Agents ,HIV-1 ,RNA, Viral ,business ,medicine.drug - Abstract
Background This study assessed the penetration and efficacy of tenofovir alafenamide (TAF) in the male genital tract (MGT) and the semen quality of individuals infected with human immunodeficiency virus (HIV)-1 who were treated with a TAF-containing regimen. Methods This was a prospective, open-label, single-arm study of 14 virologically-suppressed, HIV-1–infected men on stable antiretroviral therapy with elvitegravir, cobicistat, emtricitabine (E/C/F) and tenofovir disoproxil fumarate (TDF) who switched to E/C/F and TAF. At baseline (pre-switch) and at 12 weeks post-switch, we measured HIV-1 RNA in seminal plasma (SP) and blood plasma (BP), tenofovir (TFV) in SP and BP, and TFV-diphosphate (dp) in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells (SMCs) at the end of the dosing interval (C24h). Semen quality was assessed before switching and after 12 weeks on TAF. Results With TAF, TFV C24 was 11.9-fold higher in SP than in BP. This concentration was significantly lower than TFV C24 in SP with TDF, but 9.6-fold higher than the 50% inhibitory concentration (IC50) (11.5 ng/mL). By contrast, the median TFV-dp concentration achieved with TAF in SMCs was 6% that of TFV-dp in PBMCs. The TFV-dp SMC:PBMC ratio was also significantly lower with TAF. Nonetheless, TFV-dp C24 in SMC was comparable with TAF and TDF. All the patients had HIV-1 RNA Conclusions Extracellular and intracellular seminal TFV distribution differs between TAF and TDF. Nevertheless, both formulations, combined with elvitegravir/cobicistat/emtricitabine, maintained HIV-1 RNA suppression in semen. Differences in MGT distribution were not associated with differences in semen quality. Clinical Trials Registration EudraCT: 2016-001371-69
- Published
- 2018
33. Pregnancy-Related Hormones Increase UGT1A1-Mediated Labetalol Metabolism in Human Hepatocytes
- Author
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Raju Khatri, John K. Fallon, Amanda P. Schauer, Kim A. Boggess, Craig Sykes, Natasha Kulick, Angela D. M. Kashuba, Craig R. Lee, Philip C. Smith, Rebecca J.B. Rementer, Taryn A. Miner, and Kim L. R. Brouwer
- Subjects
targeted proteomics ,medicine.medical_specialty ,hypertension ,Metabolite ,RM1-950 ,progesterone ,digestive system ,030226 pharmacology & pharmacy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,estradiol ,Internal medicine ,medicine ,Pharmacology (medical) ,Labetalol ,Original Research ,Pharmacology ,hepatic metabolism ,Metabolism ,labetalol ,UGT2B7 ,Estetrol ,Endocrinology ,chemistry ,030220 oncology & carcinogenesis ,Therapeutics. Pharmacology ,pregnancy ,uridine diphosphate glucuronosyltransferases ,Glucuronide ,Drug metabolism ,medicine.drug ,Hormone - Abstract
Pregnancy-related hormones (PRH) are recognized as important regulators of hepatic cytochrome P450 enzyme expression and function. However, the impact of PRH on the hepatic expression and function of uridine diphosphate glucuronosyltransferases (UGTs) remains unclear. Using primary human hepatocytes, we evaluated the effect of PRH exposure on mRNA levels and protein concentrations of UGT1A1, UGT2B7, and other key UGT enzymes, and on the metabolism of labetalol (a UGT1A1 and UGT2B7 substrate commonly prescribed to treat hypertensive disorders of pregnancy). Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to the PRH estradiol, estriol, estetrol, progesterone, and cortisol individually or in combination. We quantified protein concentrations of UGT1A1, UGT2B7, and four additional UGT1A isoforms in SCHH membrane fractions and evaluated the metabolism of labetalol to its glucuronide metabolites in SCHH. PRH exposure increased mRNA levels and protein concentrations of UGT1A1 and UGT1A4 in SCHH. PRH exposure also significantly increased labetalol metabolism to its UGT1A1-derived glucuronide metabolite in a concentration-dependent manner, which positively correlated with PRH-induced changes in UGT1A1 protein concentrations. In contrast, PRH did not alter UGT2B7 mRNA levels or protein concentrations in SCHH, and formation of the UGT2B7-derived labetalol glucuronide metabolite was decreased following PRH exposure. Our findings demonstrate that PRH alter expression and function of UGT proteins in an isoform-specific manner and increase UGT1A1-mediated labetalol metabolism in human hepatocytes by inducing UGT1A1 protein concentrations. These results provide mechanistic insight into the increases in labetalol clearance observed in pregnant individuals.
- Published
- 2021
34. A cross-species comparison of antiretroviral penetration into lymph nodes using novel physiologically based pharmacokinetic models
- Author
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Yanguang Cao, Erin M. B. Scholz, and Angela D. M. Kashuba
- Subjects
Microbiology (medical) ,Oncology ,medicine.medical_specialty ,Physiologically based pharmacokinetic modelling ,Efavirenz ,Population ,Cmax ,HIV Infections ,Emtricitabine ,Models, Biological ,chemistry.chemical_compound ,immune system diseases ,Internal medicine ,medicine ,Distribution (pharmacology) ,Animals ,Pharmacology (medical) ,education ,Tenofovir ,Lymph node ,Original Research ,Pharmacology ,education.field_of_study ,business.industry ,virus diseases ,Infectious Diseases ,medicine.anatomical_structure ,chemistry ,Anti-Retroviral Agents ,Lymph ,Lymph Nodes ,business ,medicine.drug - Abstract
Background Investigating antiretroviral (ARV) penetration and pharmacology in lymph nodes is crucial to understanding mechanisms of HIV persistence in tissue, but sampling these tissues in humans is invasive and costly. Physiologically based pharmacokinetic (PBPK) modelling is a non-invasive solution for understanding lymph node penetration of ARVs across multiple species. Objectives To develop customized PBPK models with a novel lymph node compartment, and use these models to describe the distribution of three ARVs—tenofovir, emtricitabine and efavirenz—into the plasma and lymph nodes of non-human primates (NHPs) and humans. Materials and methods In this analysis, we utilized standard monkey and human PBPK models in PK-Sim, and added a novel lymph node compartment using MoBi. We used these models to describe the distribution of tenofovir, emtricitabine and efavirenz into NHP and human plasma and lymph nodes, and compared model-predicted versus observed AUC and Cmax. Results For all three ARVs, population simulations using the base and final models reasonably characterized observed plasma and tissue data in NHPs and humans, with predicted/observed AUC and Cmax ratios within 0.7–2.0. Conclusions Overall, our novel PBPK model provides a framework for understanding lymph node penetration of ARVs or future HIV cure therapies.
- Published
- 2021
35. Quantitative Imaging Analysis of the Spatial Relationship between Antiretrovirals, Reverse Transcriptase Simian-Human Immunodeficiency Virus RNA, and Collagen in the Mesenteric Lymph Nodes of Nonhuman Primates
- Author
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Paul A. Luciw, Elias P. Rosen, Kathleen Busman-Sahay, Angela D. M. Kashuba, Joseph N. Mwangi, Erin M. B. Scholz, Jacob D. Estes, Michael Nekorchuk, Gabriela De la Cruz, Yuri Fedoriw, Lourdes Adamson, and Chi Ngai Chan
- Subjects
viruses ,Simian Acquired Immunodeficiency Syndrome ,Viremia ,HIV Infections ,In situ hybridization ,Biology ,Virus Replication ,Antiviral Agents ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Mesenteric lymph nodes ,Animals ,Pharmacology (medical) ,030304 developmental biology ,Maraviroc ,Pharmacology ,0303 health sciences ,Follicular dendritic cells ,030306 microbiology ,virus diseases ,HIV ,RNA-Directed DNA Polymerase ,Viral Load ,medicine.disease ,Virology ,Macaca mulatta ,Reverse transcriptase ,Infectious Diseases ,medicine.anatomical_structure ,Viral replication ,chemistry ,Simian Immunodeficiency Virus ,Lymph ,Collagen ,Lymph Nodes - Abstract
Human immunodeficiency virus (HIV) persistence in tissue reservoirs is a major barrier to HIV cure. While antiretrovirals (ARVs) suppress viral replication, antiretroviral therapy (ART) interruption results in rapid rebound viremia that may originate from lymphoid tissues. To understand the relationship between anatomic distribution of ARV exposure and viral expression in lymph nodes, we performed mass spectrometry imaging (MSI) of 6 ARVs, RNAscope in situ hybridization for viral RNA (vRNA), and immunohistochemistry of collagen in mesenteric lymph nodes from 8 uninfected and 10 reverse transcriptase simian/human immunodeficiency virus (RT-SHIV)-infected rhesus macaques dosed to steady state with combination ART. MATLAB-based quantitative imaging analysis was used to evaluate spatial and pharmacological relationships between these ARVs, viral RNA (both vRNA(+) cells and follicular dendritic cell [FDC]-bound virions), and collagen deposition. Using MSI, 31% of mesenteric lymph node tissue area was found to be not covered by any ARV. Additionally, 28% of FDC-trapped virions and 21% of infected cells were not exposed to any detected ARV. Of the 69% of tissue area that was covered by cumulative ART exposure, nearly 100% of concentrations were greater than in vitro 50% inhibitory concentration (IC(50)) values; however, 52% of total tissue coverage was from only one ARV, primarily maraviroc. Collagen covered ∼35% of tissue area but did not influence ARV distribution heterogeneity. Our findings are consistent with our hypothesis that ARV distribution, in addition to total-tissue drug concentration, must be considered when evaluating viral persistence in lymph nodes and other reservoir tissues.
- Published
- 2021
36. S-warfarin limited sampling strategy with a population pharmacokinetic approach to estimate exposure and cytochrome P450 (CYP) 2C9 activity in healthy adults
- Author
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Lana, Tran, Mina, Nikanjam, Edmund V, Capparelli, Joseph S, Bertino, Anne N, Nafziger, Angela D M, Kashuba, Sandrine, Turpault, and Joseph D, Ma
- Subjects
Male ,Ritonavir ,Dose-Response Relationship, Drug ,Genotype ,Metabolic Clearance Rate ,Age Factors ,Bayes Theorem ,Models, Biological ,Healthy Volunteers ,Lopinavir ,Drug Combinations ,Phenotype ,Sex Factors ,Area Under Curve ,Humans ,Female ,Warfarin ,Cytochrome P-450 CYP2C9 ,Cytochrome P-450 CYP2C9 Inducers - Abstract
S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults.In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient (RS-warfarin concentrations (n=2540) were well described with a two-compartment model. Mean apparent oral clearance was 0.56 L/hr and volume of distribution was 35.5 L. Clearance decreased 33% with the CYP2C9 *3 allele and increased 42% with lopinavir/ritonavir co-administration. During CYP2C9 constitutive conditions, LSMs at 48 hr and at 72 hr as well as 2-timepoint LSMs were within acceptable limits for RPhenotyping studies with S-warfarin in healthy subjects can utilize a single- and/or a 2-timepoint LSM with a population PK approach to estimate constitutive CYP2C9 activity.
- Published
- 2021
37. Effects of Injection Volume and Route of Administration on Dolutegravir In Situ Forming Implant Pharmacokinetics
- Author
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Jordan B. Joiner, Jasmine L. King, Roopali Shrivastava, Sarah Anne Howard, Mackenzie L. Cottrell, Angela D. M. Kashuba, Paul A. Dayton, and Soumya Rahima Benhabbour
- Subjects
Pharmaceutical Science ,long-acting ,in situ ,injectable ,biodegradable ,implants ,PLGA ,controlled release ,drug delivery ,ultrasound ,pharmacokinetics - Abstract
Due to the versatility of the in situ forming implant (ISFI) drug delivery system, it is crucial to understand the effects of formulation parameters for clinical translation. We utilized ultrasound imaging and pharmacokinetics (PK) in mice to understand the impact of administration route, injection volume, and drug loading on ISFI formation, degradation, and drug release in mice. Placebo ISFIs injected subcutaneously (SQ) with smaller volumes (40 μL) exhibited complete degradation within 30–45 days, compared to larger volumes (80 μL), which completely degraded within 45–60 days. However, all dolutegravir (DTG)-loaded ISFIs along the range of injection volumes tested (20–80 μL) were present at 90 days post-injection, suggesting that DTG can prolong ISFI degradation. Ultrasound imaging showed that intramuscular (IM) ISFIs flattened rapidly post administration compared to SQ, which coincides with the earlier Tmax for drug-loaded IM ISFIs. All mice exhibited DTG plasma concentrations above four times the protein-adjusted 90% inhibitory concentration (PA-IC90) throughout the entire 90 days of the study. ISFI release kinetics best fit to zero order or diffusion-controlled models. When total administered dose was held constant, there was no statistical difference in drug exposure regardless of the route of administration or number of injections.
- Published
- 2022
38. The Lymph Node Reservoir: Physiology, HIV Infection, and Antiretroviral Therapy
- Author
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Angela D. M. Kashuba and Erin M. B. Scholz
- Subjects
CD4-Positive T-Lymphocytes ,Physiology ,Inflammation ,HIV Infections ,Disease ,030226 pharmacology & pharmacy ,Article ,Lymphatic System ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Acquired immunodeficiency syndrome (AIDS) ,Medicine ,Humans ,Pharmacology (medical) ,Lymph node ,Pharmacology ,business.industry ,Immunity ,virus diseases ,Viral Load ,medicine.disease ,Lymphatic system ,medicine.anatomical_structure ,Anti-Retroviral Agents ,030220 oncology & carcinogenesis ,Lymph ,Lymph Nodes ,medicine.symptom ,business ,Viral load - Abstract
Despite advances in treatment, finding a cure for HIV remains a top priority. Chronic HIV infection is associated with increased risk of comorbidities, such as diabetes and cardiovascular disease. Additionally, people living with HIV must remain adherent to daily antiretroviral therapy, because lapses in medication adherence can lead to viral rebound and disease progression. Viral recrudescence occurs from cellular reservoirs in lymphoid tissues. In particular, lymph nodes are central to the pathology of HIV due to their unique architecture and compartmentalization of immune cells. Understanding how antiretrovirals (ARVs) penetrate lymph nodes may explain why these tissues are maintained as HIV reservoirs, and how they contribute to viral rebound upon treatment interruption. In this report, we review (i) the physiology of the lymph nodes and their function as part of the immune and lymphatic systems, (ii) the pathogenesis and outcomes of HIV infection in lymph nodes, and (iii) ARV concentrations and distribution in lymph nodes, and the relationship between ARVs and HIV in this important reservoir.
- Published
- 2020
39. Antiretroviral Penetration and Drug Transporter Concentrations in the Spleens of Three Preclinical Animal Models and Humans
- Author
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John K. Fallon, Lourdes Adamson, Angela D. M. Kashuba, Craig Sykes, Jason R. Pirone, Ramesh Akkina, Martina Kovarova, Amanda P. Schauer, Kimberly Blake, Leila Remling-Mulder, Philip C. Smith, Brian Van Horne, Paul A. Luciw, Aaron S. Devanathan, J. Victor Garcia, and Nicole White
- Subjects
Drug ,Anti-HIV Agents ,media_common.quotation_subject ,HIV Infections ,Spleen ,Pharmacology ,Mice ,03 medical and health sciences ,Pharmacokinetics ,Tandem Mass Spectrometry ,Blood plasma ,medicine ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Animals ,Humans ,Pharmacology (medical) ,Dosing ,030304 developmental biology ,media_common ,0303 health sciences ,biology ,030306 microbiology ,business.industry ,virus diseases ,Transporter ,biology.organism_classification ,Macaca mulatta ,Neoplasm Proteins ,Rhesus macaque ,Infectious Diseases ,medicine.anatomical_structure ,Pharmaceutical Preparations ,Splenic Tissue ,Models, Animal ,business ,Chromatography, Liquid - Abstract
Adequate antiretroviral (ARV) concentrations in lymphoid tissues are critical for optimal antiretroviral therapy (ART). While the spleen contains 25% of the body’s lymphocytes, there are minimal data on ARV penetration in this organ. This study quantified total and protein-unbound splenic ARV concentrations and determined whether drug transporters, sex, or infection status were modifiers of these concentrations in animal models and humans. Two humanized mice models (hu-HSC-Rag [n = 36; 18 HIV-positive (HIV(+)) and 18 HIV-negative (HIV(−))] and bone marrow-liver-thymus [n = 13; 7 HIV(+) and 6 HIV(−)]) and one nonhuman primate (NHP) model (rhesus macaque [n = 18; 10 SHIV(+) and 8 SHIV(−)]) were dosed to steady state with ARV combinations. HIV(+) human spleens (n = 14) from the National NeuroAIDS Tissue Consortium were analyzed postmortem (up to 24 h postdose). ARV concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), drug transporter concentrations were measured with LC-MS proteomics, and protein binding in NHP spleens was determined by rapid equilibrium dialysis. Mice generally had the lowest splenic concentrations of the three species. Protein binding in splenic tissue was 6 to 96%, compared to 76 to 99% in blood plasma. NHPs had quantifiable Mrp4, Bcrp, and Ent1 concentrations, and humans had quantifiable ENT1 concentrations. None significantly correlated with tissue ARV concentrations. There was also no observable influence of infection status or sex. With these dosing strategies, NHP splenic penetration most closely resembled that of humans. These data can inform tissue pharmacokinetic scaling to humans to target HIV reservoirs by identifying important species-related differences.
- Published
- 2020
40. Application of a Scavenger Receptor A1-Targeted Polymeric Prodrug Platform for Lymphatic Drug Delivery in HIV
- Author
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Kathleen Busman-Sahay, David M. Stevens, Kelsie S Snapp, Nimit L. Patel, Mackenzie L. Cottrell, Stephan T. Stern, Sarah L. Skoczen, Marina A. Dobrovolskaia, Edward Cedrone, Siva Sai Krishna Dasa, Craig Sykes, Elias P. Rosen, Pavan Adiseshaiah, Tim M Potter, Angela D. M. Kashuba, and Jacob D. Estes
- Subjects
Male ,Anti-HIV Agents ,Pharmaceutical Science ,HIV Infections ,02 engineering and technology ,Pharmacology ,030226 pharmacology & pharmacy ,Proof of Concept Study ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Pharmacokinetics ,Drug Discovery ,Animals ,Emtricitabine ,Humans ,Polylysine ,Prodrugs ,Scavenger receptor ,Active metabolite ,Drug Carriers ,Chemistry ,Scavenger Receptors, Class A ,Prodrug ,021001 nanoscience & nanotechnology ,Controlled release ,Rats ,Drug Liberation ,Lymphatic system ,RAW 264.7 Cells ,Poly I ,Drug delivery ,Molecular Medicine ,Female ,0210 nano-technology ,Ex vivo ,Half-Life - Abstract
We have developed a macromolecular prodrug platform based on poly(l-lysine succinylated) (PLS) that targets scavenger receptor A1 (SR-A1), a receptor expressed by myeloid and endothelial cells. We demonstrate the selective uptake of PLS by murine macrophage, RAW 264.7 cells, which was eliminated upon cotreatment with the SR-A inhibitor polyinosinic acid (poly I). Further, we observed no uptake of PLS in an SR-A1-deficient RAW 264.7 cell line, even after 24 h incubation. In mice, PLS distributed to lymphatic organs following i.v. injection, as observed by ex vivo fluorescent imaging, and accumulated in lymph nodes following both i.v. and i.d. administrations, based on immunohistochemical analysis with high-resolution microscopy. As a proof-of-concept, the HIV antiviral emtricitabine (FTC) was conjugated to the polymer's succinyl groups via ester bonds, with a drug loading of 14.2% (wt/wt). The prodrug (PLS-FTC) demonstrated controlled release properties in vitro with a release half-life of 15 h in human plasma and 29 h in esterase-inhibited plasma, indicating that drug release occurs through both enzymatic and nonenzymatic mechanisms. Upon incubation of PLS-FTC with human peripheral blood mononuclear cells (PBMCs), the released drug was converted to the active metabolite FTC triphosphate. In a pharmacokinetic study in rats, the prodrug achieved ∼7-19-fold higher concentrations in lymphatic tissues compared to those in FTC control, supporting lymphatic-targeted drug delivery. We believe that the SR-A1-targeted macromolecular PLS prodrug platform has extraordinary potential for the treatment of infectious diseases.
- Published
- 2020
41. Validation of an LC-MS/MS Assay for the Simultaneous Determination of Bictegravir, Doravirine, and Raltegravir in Human Plasma
- Author
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Mackenzie L. Cottrell, Craig Sykes, Angela D. M. Kashuba, and Amanda P. Schauer
- Subjects
Analyte ,Chromatography ,Bictegravir ,medicine.diagnostic_test ,Therapeutic drug monitoring ,Chemistry ,Electrospray ionization ,medicine ,Integrase inhibitor ,Protein precipitation ,Raltegravir ,medicine.drug ,Triple quadrupole mass spectrometer - Abstract
Bictegravir (BIC), an integrase inhibitor, and doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor, were recently approved by the US FDA for HIV treatment and are recommended first line treatment options. Because certain clinical scenarios warrant using them in combination, we developed a fully validated LC-MS/MS method for simultaneous measurement of BIC and DOR, along with a legacy integrase inhibitor, raltegravir (RAL), in human plasma over a clinically relevant 1000-fold range for each analyte. These analytes were extracted from the plasma by protein precipitation with their stable, isotopically labeled internal standards (BIC-d5, 13C6-DOR, and RAL-d6). Following extraction, samples were analyzed by reverse phase chromatography on a Waters Atlantis T3 C18 (50×2.1mm, 3um particle size) column with subsequent detection by electrospray ionization in positive ion mode on an AB Sciex API-5000 triple quadrupole mass spectrometer. The assay was linear (R2>0.994) over the selected calibration ranges (20.0-20,000ng/mL (BIC), 3.00-3,000ng/mL (DOR), and 10.0-10,000 (RAL)). The assay was accurate (inter-assay %Bias ≤±8.5) and precise (inter-assay %CV ≤11.4). This method was validated according to FDA guidance for industry and can be used to assess the pharmacokinetics of two newly approved antiretrovirals, or to support therapeutic drug monitoring for modern antiretroviral therapy.
- Published
- 2020
42. Antiretroviral therapy concentrations differ in gut versus lymph node tissues and are associated with HIV viral transcription by a novel RT-ddPCR assay
- Author
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Teri Liegler, Sophie Stephenson, Peter W. Hunt, Steven A. Yukl, Angela D. M. Kashuba, Radojka M. Savic, Sushama Telwatte, Sulggi A. Lee, Steven G. Deeks, Rebecca Hoh, Mackenzie L. Cottrell, Ma Somsouk, and Hiroyu Hatano
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,Anti-HIV Agents ,Biopsy ,Atazanavir Sulfate ,Rectum ,Ileum ,HIV Infections ,030312 virology ,Real-Time Polymerase Chain Reaction ,Virus Replication ,Article ,03 medical and health sciences ,Antiretroviral Therapy, Highly Active ,Raltegravir Potassium ,Medicine ,Humans ,Pharmacology (medical) ,Lymph node ,Darunavir ,0303 health sciences ,business.industry ,Raltegravir ,Virology ,Atazanavir ,Gastrointestinal Tract ,Infectious Diseases ,medicine.anatomical_structure ,Lymphatic system ,Cross-Sectional Studies ,HIV-1 ,Female ,San Francisco ,Lymph ,Lymph Nodes ,business ,medicine.drug - Abstract
BACKGROUND: The majority of HIV-infected cells during antiretroviral therapy (ART) persist in lymphoid tissues. Studies disagree on whether suboptimal tissue ART concentrations contribute to ongoing HIV replication during viral suppression. METHODS: We performed a cross-sectional study in virally-suppressed HIV+ participants measuring lymphoid tissue ART (darunavir [DRV], atazanavir [ATV], and raltegravir [RAL]) concentrations by LC-MS/MS assay. Tissue and plasma ART concentrations were used to estimate tissue:plasma penetration ratios (TPRs) as well as drug-specific tissue:inhibitory concentration ratios (TICs). HIV DNA and sequentially-produced HIV RNA transcripts were quantified from rectal biopsies using droplet digital PCR (ddPCR) assays. RESULTS: Tissue samples were collected in duplicate from 19 participants: 38 rectal, 8 ileal (4 RAL, 2 DRV, 2 ATV), and 6 lymph node (4 RAL, 2 DRV) samples. Overall, median TICs were higher for RAL than DRV or ATV (both P=0.006). Median TICs were lower in lymph nodes vs. ileum (0.49 vs. 143, P=0.028) or rectum (33, P=0.019), and all ART levels were below target concentrations. Higher rectal TICs were associated with lower HIV RNA transcripts (read-through, long LTR, and Nef, P all
- Published
- 2020
43. Long-Acting Rilpivirine (RPV) Preexposure Prophylaxis Does Not Inhibit Vaginal Transmission of RPV-Resistant HIV-1 or Select for High-Frequency Drug Resistance in Humanized Mice
- Author
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Angela D. M. Kashuba, Kevin Melody, Pleuni S. Pennings, Mackenzie L. Cottrell, Moses T. Bility, Zandrea Ambrose, Kathleen A. Shutt, Dwayne Evans, Brandon F. Keele, Christopher E. Kline, and Chandra Nath Roy
- Subjects
NNRTI ,Anti-HIV Agents ,preexposure prophylaxis ,Immunology ,Human immunodeficiency virus (HIV) ,HIV Infections ,Viremia ,Drug resistance ,Biology ,Virus Replication ,medicine.disease_cause ,gag Gene Products, Human Immunodeficiency Virus ,Microbiology ,Virus ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Virology ,Drug Resistance, Viral ,Vaccines and Antiviral Agents ,medicine ,Animals ,030212 general & internal medicine ,0303 health sciences ,drug resistance ,Reverse-transcriptase inhibitor ,030306 microbiology ,Transmission (medicine) ,animal model ,Rilpivirine ,medicine.disease ,PrEP ,3. Good health ,Disease Models, Animal ,humanized mice ,Long acting ,chemistry ,Insect Science ,Mutation ,Vagina ,HIV-1 ,Reverse Transcriptase Inhibitors ,Female ,Pre-Exposure Prophylaxis ,vaginal transmission ,medicine.drug - Abstract
The antiretroviral drug rilpivirine was developed into a long-acting formulation (RPV LA) to improve adherence for preexposure prophylaxis (PrEP) to prevent HIV-1 transmission. A concern is that RPV LA will not inhibit transmission of drug-resistant HIV-1 and may select for drug-resistant virus. In female humanized mice, we found that RPV LA inhibited vaginal transmission of WT or 3-fold RPV-resistant HIV-1 but not virus with 30-fold RPV resistance. In animals that became infected despite RPV LA PrEP, WT HIV-1 dissemination was delayed until genital and plasma RPV concentrations waned. RPV resistance was detected at similar low frequencies in untreated and PrEP-treated mice that became infected. These results indicate the importance of maintaining RPV at a sustained threshold after virus exposure to prevent dissemination of HIV-1 after vaginal infection and low-frequency resistance mutations conferred low-level resistance, suggesting that RPV resistance is difficult to develop after HIV-1 infection during RPV LA PrEP., As a long-acting formulation of the nonnucleoside reverse transcriptase inhibitor rilpivirine (RPV LA) has been proposed for use as preexposure prophylaxis (PrEP) and the prevalence of transmitted RPV-resistant viruses can be relatively high, we evaluated the efficacy of RPV LA to inhibit vaginal transmission of RPV-resistant HIV-1 in humanized mice. Vaginal challenges of wild-type (WT), Y181C, and Y181V HIV-1 were performed in mice left untreated or after RPV PrEP. Plasma viremia was measured for 7 to 10 weeks, and single-genome sequencing was performed on plasma HIV-1 RNA in mice infected during PrEP. RPV LA significantly prevented vaginal transmission of WT HIV-1 and Y181C HIV-1, which is 3-fold resistant to RPV. However, it did not prevent transmission of Y181V HIV-1, which has 30-fold RPV resistance in the viruses used for this study. RPV LA did delay WT HIV-1 dissemination in infected animals until genital and plasma RPV concentrations waned. Animals that became infected despite RPV LA PrEP did not acquire new RPV-resistant mutations above frequencies in untreated mice or untreated people living with HIV-1, and the mutations detected conferred low-level resistance. These data suggest that high, sustained concentrations of RPV were required to inhibit vaginal transmission of HIV-1 with little or no resistance to RPV but could not inhibit virus with high resistance. HIV-1 did not develop high-level or high-frequency RPV resistance in the majority of mice infected after RPV LA treatment. However, the impact of low-frequency RPV resistance on virologic outcome during subsequent antiretroviral therapy still is unclear. IMPORTANCE The antiretroviral drug rilpivirine was developed into a long-acting formulation (RPV LA) to improve adherence for preexposure prophylaxis (PrEP) to prevent HIV-1 transmission. A concern is that RPV LA will not inhibit transmission of drug-resistant HIV-1 and may select for drug-resistant virus. In female humanized mice, we found that RPV LA inhibited vaginal transmission of WT or 3-fold RPV-resistant HIV-1 but not virus with 30-fold RPV resistance. In animals that became infected despite RPV LA PrEP, WT HIV-1 dissemination was delayed until genital and plasma RPV concentrations waned. RPV resistance was detected at similar low frequencies in untreated and PrEP-treated mice that became infected. These results indicate the importance of maintaining RPV at a sustained threshold after virus exposure to prevent dissemination of HIV-1 after vaginal infection and low-frequency resistance mutations conferred low-level resistance, suggesting that RPV resistance is difficult to develop after HIV-1 infection during RPV LA PrEP.
- Published
- 2020
44. CCR5 inhibitor as novel acute graft versus host disease prophylaxis in children and young adults undergoing allogeneic stem cell transplant: results of the phase II study
- Author
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Pooja, Khandelwal, Tsuyoshi, Fukuda, Ashley, Teusink-Cross, Angela D M, Kashuba, Adam, Lane, Parinda A, Mehta, Rebecca A, Marsh, Michael B, Jordan, Michael S, Grimley, Kasiani C, Myers, Adam S, Nelson, Javier, El-Bietar, Sharat, Chandra, Jacob J, Bleesing, Mary C, Krupski, and Stella M, Davies
- Subjects
Young Adult ,Pharmaceutical Preparations ,Receptors, CCR5 ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Humans ,Mycophenolic Acid ,Child ,Stem Cell Transplantation - Abstract
We report results of a phase II study of maraviroc to prevent acute graft versus host disease (GVHD) in children undergoing allogeneic hematopoietic stem cell transplant (HSCT). Oral maraviroc was added to standard GVHD prophylaxis of a calcineurin inhibitor with either mycophenolate mofetil, methotrexate or steroids from day -3 until day +30 after HSCT. Maraviroc trough levels were analyzed on day 0, +7, 14, and 21. We assessed functional CCR5 blockade by our previously described pharmacodynamic assay. In total, 17 patients were enrolled prospectively. No patient had liver GVHD by day +100. Four patients developed gastrointestinal (GI) GVHD (Grade II upper GI GVHD n = 2, grade III lower GI GVHD n = 2). No adverse effects of maraviroc were observed. Seven patients discontinued maraviroc at a median of day +14 (range day +1-day +29) due to study rules regarding hepatotoxicity (n = 5), renal function decline (n = 1) and withdrawal from study (n = 1). Maraviroc administration led to CCR5 inhibition but was limited by study rules defining hepatotoxicity, leading to frequent drug discontinuation. We cannot comment on the efficacy of maraviroc with our data but speculate that it could have a role in prevention of acute GI GVHD, with adequate compliance.
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- 2020
45. Antiretroviral Penetration across Three Preclinical Animal Models and Humans in Eight Putative HIV Viral Reservoirs
- Author
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Erin M. Burgunder, Lourdes Adamson, Craig Sykes, Kimberly Blake, Ramesh Akkina, Martina Kovarova, Aaron S. Devanathan, Nithya Srinivas, Nicole White, J. Victor Garcia, Jason R. Pirone, Paul A. Luciw, Angela D. M. Kashuba, Leila Remling-Mulder, Amanda P. Schauer, and Elias P. Rosen
- Subjects
Tissue concentrations ,Anti-HIV Agents ,Atazanavir Sulfate ,Human immunodeficiency virus (HIV) ,HIV Infections ,In Vitro Techniques ,medicine.disease_cause ,Maraviroc ,03 medical and health sciences ,Mice ,Pharmacokinetics ,immune system diseases ,Raltegravir Potassium ,medicine ,Animals ,Emtricitabine ,Humans ,Pharmacology (medical) ,Dosing ,Hiv treatment ,Tenofovir ,030304 developmental biology ,Pharmacology ,0303 health sciences ,030306 microbiology ,business.industry ,virus diseases ,Penetration (firestop) ,Infectious Diseases ,Anti-Retroviral Agents ,Immunology ,Female ,business - Abstract
For HIV cure strategies like "kick and kill" to succeed, antiretroviral (ARV) drugs must reach effective concentrations in putative viral reservoirs. We characterize penetration of six ARVs in three preclinical animal models and humans. We found that standard dosing strategies in preclinical species closely mimicked tissue concentrations in humans for some, but not all, ARVs. These results have implications for interpreting HIV treatment, prevention, or cure interventions between preclinical and clinical models.
- Published
- 2019
46. Differences in Local and Systemic TFV PK Among Premenopausal Versus Postmenopausal Women Exposed to TFV 1% Vaginal Gel
- Author
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Angela D. M. Kashuba, Andrea R. Thurman, Jill L. Schwartz, Craig Sykes, Neelima Chandra, Sharon Anderson, Nazita Yousefieh, Mackenzie L. Cottrell, Thomas Kimble, and Gustavo F. Doncel
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0301 basic medicine ,Time Factors ,Administration, Topical ,Human immunodeficiency virus (HIV) ,menopause ,HIV Infections ,medicine.disease_cause ,Epithelium ,Pharmacology (medical) ,media_common ,Estradiol ,Clinical Science ,tenofovir pharmocokinetics ,Organophosphates ,3. Good health ,Postmenopause ,Infectious Diseases ,medicine.anatomical_structure ,Vagina ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Vaginal Creams, Foams, and Jellies ,Female ,medicine.drug ,medicine.medical_specialty ,Tenofovir ,Anti-HIV Agents ,media_common.quotation_subject ,030106 microbiology ,Urology ,03 medical and health sciences ,Pharmacokinetics ,medicine ,Humans ,Menstrual Cycle ,Menstrual cycle ,Mucous Membrane ,Postmenopausal women ,hormones ,Extramural ,business.industry ,Adenine ,Vaginal gel ,HIV ,cervicovaginal ,Administration, Intravaginal ,030104 developmental biology ,Premenopause ,business - Abstract
Supplemental Digital Content is Available in the Text., Objective: We describe and compare the local and systemic pharmacokinetics (PK) of tenofovir (TFV) and TFV-diphosphate (TFV-DP) in healthy premenopausal (PRE) and postmenopausal (POST) women using TFV 1% gel and correlate local PK with other mucosal end points. Methods: PRE (n = 20) and POST (n = 17) women used 2 doses of TFV 1% vaginal gel, separated by 2 hours. Blood and cervicovaginal samples were obtained 3 and 23 hours after the second dose. PRE women used gel in the follicular and luteal phases of the menstrual cycle. POST women used gel at baseline and again after approximately 2 months of treatment with 0.01% vaginal estradiol (E2) cream. Results: Median TFV concentrations in cervicovaginal aspirate (ng/mL) and vaginal tissue (ng/mg) were significantly higher in PRE (4.3E106, 49.8) versus POST women (2.6E106, 2.2). POST women had significantly higher median molecular ratios of TFV-DP to TFV (3.7%) compared with PRE (0.19%). After vaginal E2 treatment, the local and systemic PK end points in POST women were generally similar to PRE women (all P values > 0.05). Importantly, median vaginal tissue TFV-DP concentrations (fmol/mg) among PRE, POST, and POST women after E2 therapy were similar (292.5, 463.3, and 184.6, respectively). Vaginal tissue TFV concentrations were significantly positively correlated with vaginal epithelial thickness, whereas vaginal tissue TFV-DP concentrations were positively correlated with density of vaginal CD4+ and CD8+ immune cells. Conclusions: The state of the cervicovaginal mucosa has a significant impact on local and systemic PK of a topically applied microbicide.
- Published
- 2018
47. Disparate effects of Cytotoxic Chemotherapy on the Antiviral Activity of Antiretroviral Therapy: Implications for Treatments of HIV-Infected Cancer Patients
- Author
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Joseph Bryant, Raymond F. Schinazi, Angela D. M. Kashuba, Robert R. Redfield, Mackenzie L. Cottrell, Juan C. Zapata, Nhut Le, Alonso Heredia, Sijia Tao, Sandra Medina-Moreno, and Edward A. Sausville
- Subjects
CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Cart ,Oncology ,medicine.medical_specialty ,Combined use ,HIV Infections ,Mice, Transgenic ,Article ,Mice ,03 medical and health sciences ,immune system diseases ,Antiretroviral Therapy, Highly Active ,Neoplasms ,Internal medicine ,Hiv infected ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Drug Interactions ,Pharmacology (medical) ,Cause of death ,Pharmacology ,business.industry ,virus diseases ,Cancer ,Viral Load ,Cytotoxic chemotherapy ,medicine.disease ,030112 virology ,Antiretroviral therapy ,CD4 Lymphocyte Count ,Disease Models, Animal ,Treatment Outcome ,Infectious Diseases ,Female ,business ,Biomarkers - Abstract
Background Cancer is a leading cause of death in HIV-infected patients in the era of combination antiretroviral therapy (cART). Yet, there are no specific guidelines for the combined use of cART and chemotherapy in HIV-infected cancer patients. The cellular enzyme thymidylate synthase (TS) catalyses the conversion of dUMP to TMP, which is converted to TDP and ultimately to TTP, a building block in DNA synthesis. TS inhibitors are recommended in some cancers, particularly non-small cell lung cancer (NSCLC). Because TS inhibitors modulate intracellular concentrations of endogenous 2′-deoxynucleotides, we hypothesized that TS inhibitors could impact the anti-HIV activity of nucleoside analogue reverse transcriptase inhibitors (NRTIs). Methods We evaluated gemcitabine and pemetrexed, two approved TS inhibitors, on the anti-HIV activities of NRTIs in infectivity assays using peripheral blood mononuclear cells (PBMCs) and in humanized mice. Results Gemcitabine enhanced the anti-HIV activities of tenofovir, abacavir and emtricitabine (FTC) in PBMCs. In contrast, pemetrexed had no effect on tenofovir, enhanced abacavir and, unexpectedly, decreased FTC and lamivudine (3TC) activities. Pemetrexed inhibitory effects on FTC and 3TC may be due to lower concentrations of active metabolites (FTCtp and 3TCtp) relative to their competing endogenous nucleotide (dCTP), as shown by decreases in FTCtp/dCTP ratios. Gemcitabine enhanced tenofovir while pemetrexed abrogated FTC antiviral activity in humanized mice. Conclusions Chemotherapy with TS inhibitors can have opposing effects on cART, potentially impacting control of HIV and thereby development of viral resistance and size of the reservoir in HIV-infected cancer patients. Combinations of cART and chemotherapy should be carefully selected.
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- 2018
48. Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women
- Author
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Leila E. Mansoor, Jo-Ann S. Passmore, Quarraisha Abdool Karim, Aida Sivro, Jose Gerardo Garcia Lerma, Lyle R. McKinnon, Nico J. D. Nagelkerke, Lindi Masson, Sinaye Ngcapu, Lenine J. P. Liebenberg, Derseree Archary, Nonhlanhla Yende-Zuma, Salim S. Abdool Karim, and Angela D. M. Kashuba
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Tenofovir ,medicine.medical_treatment ,Inflammation ,HIV Infections ,General Biochemistry, Genetics and Molecular Biology ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,CAPRISA 004 ,Humans ,Sex organ ,030212 general & internal medicine ,Genitalia ,Acquired Immunodeficiency Syndrome ,business.industry ,virus diseases ,HIV ,General Medicine ,Genitalia, Female ,Confidence interval ,3. Good health ,Clinical trial ,030104 developmental biology ,Cytokine ,Treatment Outcome ,Multivariate Analysis ,Cytokines ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
Several clinical trials have demonstrated that antiretroviral (ARV) drugs taken as pre-exposure prophylaxis (PrEP) can prevent HIV infection, with the magnitude of protection ranging from -49 to 86% (refs. ). Although these divergent outcomes are thought to be due primarily to differences in product adherence, biological factors likely contribute. Despite selective recruitment of higher-risk participants for prevention trials, HIV risk is heterogeneous even within higher-risk groups. To determine whether this heterogeneity could influence patient outcomes following PrEP, we undertook a post hoc prospective analysis of results from the CAPRISA 004 trial for 1% tenofovir gel (n = 774 patients), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine proinflammatory cytokines were measured in cervicovaginal lavages at >2,000 visits, and a graduated cytokine score was used to define genital inflammation. In women without genital inflammation, tenofovir was 57% protective against HIV (95% confidence interval (CI): 7-80%) but was 3% protective (95% CI: -104-54%) if genital inflammation was present. Among women who highly adhered to the gel, tenofovir protection was 75% (95% CI: 25-92%) in women without inflammation compared to -10% (95% CI: -184-57%) in women with inflammation. Immunological predictors of HIV risk may modify the effectiveness of tools for HIV prevention; reducing genital inflammation in women may augment HIV prevention efforts.
- Published
- 2018
49. Validation of an LC–MS/MS assay to simultaneously monitor the intracellular active metabolites of tenofovir, emtricitabine, and lamivudine in dried blood spots
- Author
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Mackenzie L. Cottrell, Angela D. M. Kashuba, Amanda P. Schauer, Heather M.A. Prince, and Craig Sykes
- Subjects
0301 basic medicine ,Spectrometry, Mass, Electrospray Ionization ,Anti-HIV Agents ,Electrospray ionization ,Liquid-Liquid Extraction ,030106 microbiology ,Clinical Biochemistry ,Pharmaceutical Science ,HIV Infections ,Pharmacology ,Emtricitabine ,01 natural sciences ,Peripheral blood mononuclear cell ,Article ,Medication Adherence ,Analytical Chemistry ,03 medical and health sciences ,Tandem Mass Spectrometry ,Drug Discovery ,medicine ,Humans ,Protein precipitation ,Tenofovir ,Chromatography, High Pressure Liquid ,Spectroscopy ,Active metabolite ,Chemistry ,010401 analytical chemistry ,Reproducibility of Results ,Lamivudine ,0104 chemical sciences ,Triple quadrupole mass spectrometer ,Dried blood spot ,Leukocytes, Mononuclear ,Drug Therapy, Combination ,Dried Blood Spot Testing ,medicine.drug - Abstract
The ability to monitor adherence to antiretroviral therapy is critical for the interpretation of outcomes from clinical studies of HIV, and for optimizing patient care. The antiretrovirals tenofovir (TFV), emtricitabine (FTC), and lamivudine (3TC) are commonly included in drug regimens for HIV prevention and treatment. The active form of the drugs tenofovir diphosphate (TFVdp), emtricitabine triphosphate (FTCtp), and lamivudine triphosphate (3TCtp) are found intracellularly in erythrocytes and peripheral blood mononuclear cells (PBMCs). The ability to collect and analyze dried blood spot (DBS) samples is an attractive alternative to PBMC sampling in many resource limited settings. We developed and validated an assay to quantify all three intracellular metabolites over the range of 100–25000 fmol/sample. This assay utilizes a simple protein precipitation/liquid-liquid extraction of a single 3-mm DBS punch (from a Whatman 903 Protein Saver card) with isotopically labeled 13C5-TFVdp included as the internal standard. Following extraction, samples are analyzed by anion exchange chromatography on a Thermo Biobasic AX 5micron column with detection by electrospray ionization in the positive mode on a AB Sciex API-5000 triple quadrupole mass spectrometer with a total run time of 8 minutes. The assay was linear over the entire range (R2>0.996). The assay was accurate (inter-assay %bias within ±3.0%) and precise (inter-assay %CV ≤9.8%). The assay was also reproducible from multiple punches within a spot as well as punches from separate blood spots. Stability was established at room temperature for 3 days, and at −80°C for up to 63 days. Clinical samples were analyzed from subjects on Truvada®, Stribild®, Descovy®, and Triumeq® regimens and intracellular metabolites were detected in all samples as expected, indicating the assay performs well for all current formulations of TFV, FTC, and 3TC.
- Published
- 2018
50. The role of menopause in tenofovir diphosphate and emtricitabine triphosphate concentrations in cervical tissue
- Author
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Craig Sykes, Melanie R. Nicol, Lindsey M. Brewers, and Angela D. M. Kashuba
- Subjects
Adult ,0301 basic medicine ,Tenofovir diphosphate ,Tenofovir ,Anti-HIV Agents ,Immunology ,Cervix Uteri ,Pharmacology ,Emtricitabine ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Tandem Mass Spectrometry ,In vivo ,medicine ,Humans ,Immunology and Allergy ,030212 general & internal medicine ,Active metabolite ,Aged ,business.industry ,Adenine ,Snap ,Middle Aged ,medicine.disease ,030112 virology ,Organophosphates ,Menopause ,Infectious Diseases ,Female ,business ,Nucleoside ,Chromatography, Liquid ,medicine.drug - Abstract
OBJECTIVE: Although postmenopausal women have behavioral and biological risk factors for HIV infection, the activity of pre-exposure prophylaxis agents in older adults has not been well studied. DESIGN: We used an ex-vivo approach to compare the tissue concentrations of tenofovir diphosphate (TFVdp) and emtricitabine triphosphate (FTCtp) in cervical tissues from premenopausal and postmenopausal women. METHOD: Cervical explants from 16 premenopausal and 11 postmenopausal women were incubated in 10–300 μg/mL tenofovir or emtricitabine for 24 hours. Explants were then snap frozen in liquid nitrogen and stored until analysis. TFVdp and FTCtp were quantified using tandem liquid chromatography-mass spectrometry. RESULTS: Active metabolite concentrations of TFVdp were >9-fold lower in postmenopausal explants (p
- Published
- 2018
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