RESUMO
BACKGROUND: For patients with asymptomatic, severe aortic stenosis (AS) and preserved left ventricular ejection fraction, current guidelines recommend clinical surveillance every 6 to 12 months. To date, no randomized trials have examined whether an early intervention with transcatheter aortic valve replacement (TAVR) will improve outcomes among these patients. STUDY DESIGN AND OBJECTIVES: EARLY TAVR is a prospective, randomized, controlled, and multicenter trial, with an event-based design. Asymptomatic severe AS patients (n = 900) are randomized 1:1 to either clinical surveillance or TAVR with the Edwards SAPIEN 3/SAPIEN 3 Ultra transcatheter heart valve. Patients are stratified by whether they are able to perform a treadmill stress test. The primary end point is death, stroke, or unplanned cardiovascular hospitalization. Patients who are asymptomatic but have a positive stress test will be followed in a registry and undergo aortic valve replacement as per current guidelines. CONCLUSIONS: EARLY TAVR is the largest randomized trial to date assessing the role of early intervention among patients with asymptomatic severe AS compared to clinical surveillance and the first to study the role of TAVR. TRIAL REGISTRATION NUMBER: NCT03042104.
Assuntos
Estenose da Valva Aórtica , Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Substituição da Valva Aórtica Transcateter , Humanos , Estenose da Valva Aórtica/epidemiologia , Volume Sistólico , Estudos Prospectivos , Fatores de Risco , Resultado do Tratamento , Função Ventricular Esquerda , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Índice de Gravidade de DoençaRESUMO
Maraviroc-based regimens have been explored as preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV). In this study, we utilized mucosal tissue drug exposure data, combined with target concentrations generated in vitro, in a pharmacokinetic-pharmacodynamic analysis to predict the effects of drug combinations and adherence on PrEP efficacy. Mucosal tissue concentrations of maraviroc were measured in 24 healthy women. The 90% effective concentrations (EC90) of maraviroc (alone and combined with tenofovir and emtricitabine) for protection against HIV were identified in CD4+ T cells. Monte Carlo simulations were performed to identify dosing strategies to protect colorectal and female genital tract (FGT) tissues from HIV infection. Colorectal maraviroc concentrations were 350-fold higher than in the FGT. Under steady-state conditions, our model predicted that one 300-mg dose/week was sufficient to protect colorectal tissue from HIV in 99% of the population, while 300 mg daily would protect the FGT in only 63% of the population. FGT protection increased to >90% when maraviroc was used in combination with tenofovir (5 doses/week) or emtricitabine (3 doses/week). Poor adherence resulted in a drastic decrease in efficacy in the FGT but not colorectal tissue. However, greater forgiveness was seen when maraviroc was combined with tenofovir or emtricitabine, suggesting that maraviroc should not be used alone as PrEP.
Assuntos
Fármacos Anti-HIV/farmacocinética , Emtricitabina/farmacocinética , Infecções por HIV/prevenção & controle , Maraviroc/farmacocinética , Profilaxia Pré-Exposição , Infecções do Sistema Genital/tratamento farmacológico , Tenofovir/farmacologia , Fármacos Anti-HIV/administração & dosagem , Linfócitos T CD4-Positivos , Estudos de Coortes , Simulação por Computador , Demografia , Quimioterapia Combinada , Emtricitabina/administração & dosagem , Feminino , Infecções por HIV/virologia , Humanos , Maraviroc/administração & dosagem , Infecções do Sistema Genital/virologia , Tenofovir/administração & dosagem , Resultado do TratamentoRESUMO
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.
Assuntos
Antivirais/análise , Análise do Cabelo/métodos , Cabelo/química , Antivirais/química , Descolorantes de Cabelo/química , Tinturas para Cabelo/química , Humanos , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodosRESUMO
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.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Organofosfatos/farmacocinética , Profilaxia Pré-Exposição , Pessoas Transgênero , Adenina/administração & dosagem , Adenina/farmacocinética , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Monitoramento de Medicamentos , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Humanos , Pessoa de Meia-Idade , Organofosfatos/administração & dosagem , Distribuição Tecidual , Resultado do Tratamento , Adulto JovemRESUMO
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.
Assuntos
Antirretrovirais/análise , Cabelo/química , Adesão à Medicação , Voluntários Saudáveis , Humanos , Raios Infravermelhos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
The goal of this work was to evaluate dosing strategies for tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine (FTC) for pre-exposure prophylaxis (PrEP) with injection drug use with a pharmacokinetic/pharmacodynamics analysis of concentration data generated from two single-dose clinical studies conducted in healthy women. Population pharmacokinetic models were developed using measured intracellular metabolite, endogenous nucleotide competitors, and extracellular parent drug concentrations. Intracellular metabolite concentrations were normalized to endogenous competitors and compared with an EC90 target for PrEP efficacy. Monte Carlo simulations were used to select effective dose strategies of single agents (TAF, TDF, and FTC) and combinations (TDF + FTC and TAF + FTC). Daily, intermittent, and event-driven dosing regimens at varying dosage amounts were explored. When combined, TDF + FTC and TAF + FTC both provided quick (0.5 hours) and durable (up to 84 and 108 hours, respectively) protection of ≥99% after a single dose. When dosed twice per week, protection remained at 100%. Single-agent regimens provided lower estimates of protection than either combination tested. Here, the application of pharmacokinetic modeling to in vitro target concentrations demonstrates the added utility of including FTC in a successful PrEP regimen. While no TAF-based PrEP data are currently available for comparison, this analysis suggests TAF + FTC could completely protect against percutaneous exposure with as little as two doses per week.
Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/uso terapêutico , Adulto , Alanina , Emtricitabina/farmacocinética , Emtricitabina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Profilaxia Pré-Exposição/métodos , Tenofovir/farmacocinética , Tenofovir/uso terapêutico , Adulto JovemRESUMO
Objectives: Tenofovir alafenamide, a prodrug of tenofovir, produces higher PBMC concentrations of tenofovir diphosphate (tenofovir-dp) than tenofovir disoproxil fumarate. To understand tenofovir alafenamide's mucosal tissue distribution and its implications for pre-exposure prophylaxis, we characterized tenofovir-dp in female genital tract (FGT) and lower gastrointestinal (GI) tissues. Methods: Healthy seronegative women were given 5, 10 or 25 mg of tenofovir alafenamide ( n = 8/group). Each participant provided plasma, PBMC and cervical, vaginal and rectal tissue samples over 14 days. Plasma, cell lysate and tissue homogenate concentrations were analysed by LC-MS/MS. Dose proportionality was declared in plasma and PBMCs if the natural log AUC versus natural log dose regression line 90% CI was within 0.57-1.43. In vitro tenofovir-dp formation was assessed in PBMCs and ectocervical (Ect1/E6E7) and vaginal (VK2/E6E7) cells incubated in 0.5 and 10 µM tenofovir alafenamide or tenofovir. clinicaltrials.gov: NCT02357602. Results: Following single doses of 5, 10 and 25 mg, median (IQR) tenofovir plasma AUC 0-14 days was 52.8 (49.5-59.6), 78.1 (68.2-86.9) and 169.7 (131.2-211.4) ng·h/mL and tenofovir-dp PBMC AUC 0-14 days was 2268 (1519-4090), 4584 (3113-5734) and 9306 (6891-10785) fmol·h/10 6 cells, respectively. Tenofovir was quantifiable in 52% and 92% of FGT and GI tissues, whereas tenofovir-dp was quantifiable in only 5% and 19% of FGT and GI tissues, respectively. Plasma tenofovir and PBMC tenofovir-dp were dose proportional (90% CI = 0.87-1.15 and 0.62-1.02, respectively). In vitro tenofovir-dp was 1.7-17-fold higher in epithelial cells than PBMCs. Conclusions: After tenofovir alafenamide dosing in vivo , tenofovir-dp was unquantifiable in most tissues (91%) although cervical and vaginal epithelial cells efficiently formed tenofovir-dp from tenofovir alafenamide in vitro . These findings warrant further investigation of tenofovir alafenamide's pharmacology.
Assuntos
Adenina/análogos & derivados , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Mucosa/metabolismo , Organofosfatos/farmacocinética , Adenina/administração & dosagem , Adenina/sangue , Adenina/metabolismo , Adenina/farmacocinética , Adulto , Alanina , Colo do Útero/química , Colo do Útero/citologia , Colo do Útero/metabolismo , Esquema de Medicação , Células Epiteliais/química , Células Epiteliais/efeitos dos fármacos , Feminino , Trato Gastrointestinal/química , Trato Gastrointestinal/metabolismo , Humanos , Leucócitos Mononucleares/química , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , Mucosa/química , Organofosfatos/sangue , Organofosfatos/metabolismo , Profilaxia Pré-Exposição , Reto/química , Reto/citologia , Reto/metabolismo , Tenofovir/análogos & derivados , Distribuição Tecidual , Vagina/química , Vagina/metabolismo , Adulto JovemRESUMO
BACKGROUND: A novel translational pharmacology investigation was conducted by combining an in vitro efficacy target with mucosal tissue pharmacokinetic (PK) data and mathematical modeling to determine the number of doses required for effective human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP). METHODS: A PK/pharmacodynamic (PD) model was developed by measuring mucosal tissue concentrations of tenofovir, emtricitabine, their active metabolites (tenofovir diphosphate [TFVdp] and emtricitabine triphosphate [FTCtp], respectively), and competing endogenous nucleotides (dATP and dCTP) in 47 healthy women. TZM-bl and CD4(+) T cells were used to identify 90% effective concentration (EC90) ratios of TFVdp to dATP and FTCtp to dCTP (alone and in combination) for protection against HIV. Monte-Carlo simulations were then performed to identify minimally effective dosing strategies to protect lower female genital tract and colorectal tissues. RESULTS: The colorectal TFVdp concentration was 10 times higher than that in the lower female genital tract, whereas concentrations of endogenous nucleotides were 7-11 times lower. Our model predicted that ≥98% of the population achieved protective mucosal tissue exposure by the third daily dose of tenofovir disoproxil fumarate plus emtricitabine. However, a minimum adherence to 6 of 7 doses/week (85%) was required to protect lower female genital tract tissue from HIV, while adherence to 2 of 7 doses/week (28%) was required to protect colorectal tissue. CONCLUSIONS: This model is predictive of recent PrEP trial results in which 2-3 doses/week was 75%-90% effective in men but ineffective in women. These data provide a novel approach for future PrEP investigations that can optimize clinical trial dosing strategies.
Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/farmacologia , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Feminino , Previsões , Humanos , Masculino , New York , Profilaxia Pré-Exposição/tendências , Pesquisa Translacional Biomédica , Adulto JovemRESUMO
Adherence to a drug regimen can be a strong predictor of health outcomes, and validated measures of adherence are necessary at all stages of therapy from drug development to prescription. Many of the existing metrics of drug adherence (e.g., self-report, pill counts, blood monitoring) have limitations, and analysis of hair strands has recently emerged as an objective alternative. Traditional methods of hair analysis based on LC-MS/MS (segmenting strands at ≥1 cm length) are not capable of preserving a temporal record of drug intake at higher resolution than approximately 1 month. Here, we evaluated the detectability of HIV antiretrovirals (ARVs) in hair from a range of drug classes using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging (MSI) with 100 µm resolution. Infrared laser desorption of hair strands was shown to penetrate into the strand cortex, allowing direct measurement by MSI without analyte extraction. Using optimized desorption conditions, a linear correlation between IR-MALDESI ion abundance and LC-MS/MS response was observed for six common ARVs with estimated limits of detection less than or equal to 1.6 ng/mg hair. The distribution of efavirenz (EFV) was then monitored in a series of hair strands collected from HIV infected, virologically suppressed patients. Because of the role hair melanin plays in accumulation of basic drugs (like most ARVs), an MSI method to quantify the melanin biomarker pyrrole-2,3,5-tricarboxylic acid (PTCA) was evaluated as a means of normalizing drug response between patients to develop broadly applicable adherence criteria.
Assuntos
Antirretrovirais/análise , Cabelo/química , Raios Infravermelhos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Estrutura Molecular , Imagem ÓpticaRESUMO
BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide, but prevalence estimates in former professional athletes are limited. OBJECTIVES: HUDDLE (Heart Health: Understanding and Diagnosing Disease by Leveraging Echocardiograms) aimed to raise awareness and estimate the prevalence of CVD and associated risk factors among members of the National Football League (NFL) Alumni Association and their families through education and screening events. METHODS: HUDDLE was a multicity, cross-sectional study of NFL alumni and family members aged 50 years and older. Subjects reported their health history and participated in CVD education and screening (blood pressure, electrocardiogram, and transthoracic echocardiogram [TTE] assessments). Phone follow-up by investigators occurred 30 days postscreening to review results and recommendations. This analysis focuses on former NFL athletes. RESULTS: Of 498 participants screened, 57.2% (N = 285) were former NFL players, the majority of whom were African American (67.6%). The prevalence of hypertension among NFL alumni was estimated to be 89.8%, though only 37.5% reported a history of hypertension. Of 285 evaluable participants, 61.8% had structural cardiac abnormalities by TTE. Multivariable analysis showed that hypertension was a significant predictor of clinically relevant structural abnormalities on TTE. CONCLUSIONS: HUDDLE identified a large discrepancy between participant self-awareness and actual prevalence of CVD and risk factors, highlighting a significant opportunity for population health interventions. Structural cardiac abnormalities were observed in most participants and were independently predicted by hypertension, affirming the role of TTE for CVD screening in this population aged older than 50 years. (Heart Health: Understanding and Diagnosing Disease by Leveraging Echocardiograms [HUDDLE]; NCT05009589).
Assuntos
Doenças Cardiovasculares , Futebol Americano , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Fatores de Risco , Estados Unidos/epidemiologia , Idoso , Feminino , Atletas/estatística & dados numéricos , EcocardiografiaRESUMO
BACKGROUND: The extent of extravalvular cardiac damage is associated with increased risk of adverse events among patients with severe aortic stenosis undergoing aortic valve replacement (AVR). OBJECTIVES: The goal was to describe the association of cardiac damage on health status before and after AVR. METHODS: Patients from the PARTNER (Placement of Aortic Transcatheter Valves) 2 and 3 trials were pooled and classified by echocardiographic cardiac damage stage at baseline and 1 year as previously described (stage 0-4). We examined the association between baseline cardiac damage and 1-year health status (assessed by the Kansas City Cardiomyopathy Questionnaire Overall Score [KCCQ-OS]). RESULTS: Among 1,974 patients (794 surgical AVR, 1,180 transcatheter AVR), the extent of cardiac damage at baseline was associated with lower KCCQ scores both at baseline and at 1 year after AVR (P < 0.0001) and with increased rates of a poor outcome (death, KCCQ-OS <60, or a decrease in KCCQ-OS of ≥10 points) at 1 year (stages 0-4: 10.6% vs 19.6% vs 29.0% vs 44.7% vs 39.8%; P < 0.0001). In a multivariable model, each 1-stage increase in baseline cardiac damage was associated with a 24% increase in the odds of a poor outcome (95% CI: 9%-41%; P = 0.001). Change in stage of cardiac damage at 1 year after AVR was associated with the extent of improvement in KCCQ-OS over the same period (mean change in 1-year KCCQ-OS: improvement of ≥1 stage +26.8 [95% CI: 24.2-29.4] vs no change +21.4 [95% CI: 20.0-22.7] vs deterioration of ≥1 stage +17.5 [95% CI: 15.4-19.5]; P < 0.0001). CONCLUSIONS: The extent of cardiac damage before AVR has an important impact on health status outcomes, both cross-sectionally and after AVR. (PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - XT Intermediate and High Risk (PII A), NCT01314313; The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves - PII B [PARTNERII B], NCT02184442; PARTNER 3 Trial: Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis [P3], NCT02675114).
Assuntos
Estenose da Valva Aórtica , Implante de Prótese de Valva Cardíaca , Substituição da Valva Aórtica Transcateter , Humanos , Valva Aórtica/cirurgia , Qualidade de Vida , Resultado do Tratamento , Nível de Saúde , Estenose da Valva Aórtica/cirurgia , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Antiretroviral pharmacology in seminal plasma (SP) and rectal tissue (RT) may provide insight into antiretroviral resistance and the prevention of sexual transmission of human immunodeficiency virus (HIV). Saliva may be of utility for noninvasively measuring adherence. METHODS: A pharmacokinetic study was performed in 12 HIV-negative men receiving maraviroc 300 mg twice daily for 8 days. Seven time-matched pairs of blood plasma (BP) and saliva samples were collected over 12 h on day 1 (PK1) and days 7 and 8 (PK2). One RT sample from each subject was collected during PK1 and PK2. Two SP samples were collected from each subject during PK1, and 6 SP samples were collected from each subject during PK2. RESULTS: SP AUCs were â¼50% lower than BP. However, protein binding in SP ranged from 4% to 25%, resulting in protein-free concentrations >2-fold higher than BP. RT AUCs were 7.5- to 26-fold higher than BP. Maraviroc saliva AUCs were â¼70% lower than BP, but saliva concentrations correlated with BP (r(2) = 0.58). CONCLUSIONS: More pharmacologically available maraviroc was found in SP than BP. High RT concentrations are promising for preventing rectal HIV acquisition. Saliva correlation with BP suggests that this may be useful for monitoring adherence. CLINICAL TRIALS REGISTRATION: NCT00775294.
Assuntos
Fármacos Anti-HIV/farmacocinética , Cicloexanos/farmacocinética , Reto/metabolismo , Saliva/química , Sêmen/química , Triazóis/farmacocinética , Adulto , Fármacos Anti-HIV/análise , Fármacos Anti-HIV/sangue , Área Sob a Curva , Cicloexanos/análise , Cicloexanos/sangue , Esquema de Medicação , Humanos , Masculino , Maraviroc , Triazóis/análise , Triazóis/sangue , Adulto JovemRESUMO
New technologies for real-time adherence monitoring hold the potential to enhance antiretroviral therapy adherence interventions by providing objective information about daily medication-taking behavior. To realize this potential, we need to understand how to integrate real-time adherence feedback into existing best practices to promote antiretroviral therapy adherence at the point of care. Using in-depth interviews with 30 HIV-infected patients and 29 HIV care clinicians, our primary aims were to understand patients' and clinicians' perceptions of anticipated benefits and preferred uses of objective feedback to enhance conversations about adherence and to identify concerns about the impact of objective monitoring on patient-clinician relationships and communication. Both patients and clinicians suggested that identifying patterns of nonadherence with real-time feedback could (a) facilitate collaborative adherence problem-solving, (b) motivate patient adherence, and (c) reinforce the importance of optimal adherence. Some clinicians worried that delivery of real-time feedback could imply mistrust of patient-reported adherence and suggested careful framing of monitoring results. A few patients and clinicians were concerned that negative reactions to monitoring could discourage retention in care and reduce adherence motivation. These results indicate the potential of real-time feedback to enhance existing evidence-based adherence interventions targeting the key adherence precursors of adherence information, motivation, and behavioral skills. Guidance for the delivery of real-time adherence feedback should focus on both optimizing adherence and mitigating negative perceptions of adherence monitoring.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Comunicação , Infecções por HIV/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Relações Médico-Paciente , Terapia Antirretroviral de Alta Atividade/psicologia , Aconselhamento , Retroalimentação , Infecções por HIV/psicologia , Humanos , Entrevistas como Assunto , Adesão à Medicação/psicologia , Motivação , Pesquisa QualitativaRESUMO
Understanding antiretroviral disposition in the male genital tract, a distinct viral compartment, can provide insight for the eradication of HIV. Population pharmacokinetic modeling was conducted to investigate the disposition of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine and their metabolites in blood and semen. Blood plasma and seminal plasma (SP) concentrations of tenofovir and emtricitabine were measured, as were tenofovir-diphosphate and emtricitabine-triphosphate concentrations in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells. Sequential compartmental modeling described drug disposition in blood and semen. Our modeling suggests slower elimination of apparent tenofovir-diphosphate PBMC and faster elimination of tenofovir SP after administration of TAF compared with TDF, likely reflecting flip-flop kinetics. Additionally, TAF metabolism to tenofovir appeared slower in semen compared with blood; however, SP elimination of TAF-derived tenofovir appeared faster than its blood plasma elimination. These findings provide valuable insight for further mechanistic study of cellular entry and drug metabolism in the male genital tract.
Assuntos
Adenina/análogos & derivados , Emtricitabina/farmacocinética , Infecções por HIV , HIV-1/efeitos dos fármacos , Plasma/química , Sêmen/química , Tenofovir/farmacocinética , Adenina/farmacocinética , Adulto , Alanina , Antirretrovirais/farmacocinética , Contagem de Células/métodos , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Leucócitos Mononucleares/patologia , Masculino , Taxa de Depuração Metabólica , Distribuição TecidualRESUMO
BACKGROUND: The male genital tract (MGT) is a viral sanctuary and likely HIV reservoir; understanding MGT pharmacokinetics (PK) of antiretrovirals (ARVs) used for curative strategies is critical to eradication and cure. Tenofovir alafenamide (TAF) is a tenofovir (TFV) formulation designed to maximize efficacy/minimize toxicity with unknown MGT PK. METHODS: HIV-positive and HIV-negative men receiving TFV-based regimens provided six paired blood plasma (BP) and semen samples. Extracellular (TFV, TAF, emtricitabine [FTC]) drug concentrations in BP and seminal plasma (SP), and intracellular metabolite (IM) and endogenous nucleotide (EN) concentrations were measured in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells (SMCs). Exposure ratios for SP:BP, SMC:PBMC and IM:EN were calculated from PK parameters generated by noncompartmental analysis. HIV viral load was measured in BP and SP. RESULTS: Sixteen HIV-positive (n=8, TDF/FTC; n=8, TAF/FTC) and eight HIV-negative (TDF/FTC) men provided samples. Median TFV SP:BP ratios differed between TDF and TAF (1.5 versus 7.4), due to lower TFV BP concentrations with TAF coupled with TFV SP concentrations similar to TDF. FTC SP: BP ratios were approximately 3. SMC concentrations of IMs and ENs were a fraction of PBMC concentrations (1-22%), though IM:EN ratios exceed a suggested protective threshold. CONCLUSIONS: TAF SP PK was unexpected. IM SMC concentrations were low relative to PBMC, as were EN concentrations, suggesting differences in cell phenotype and lineage in the MGT; these differences in phenotype and pharmacology may have an impact on selecting and dosing ARVs used in cure strategies.
Assuntos
Adenina/análogos & derivados , Antirretrovirais/farmacocinética , Emtricitabina/farmacocinética , Infecções por HIV/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Tenofovir/farmacocinética , Adenina/administração & dosagem , Adenina/farmacocinética , Antirretrovirais/administração & dosagem , Células Sanguíneas/citologia , Células Sanguíneas/efeitos dos fármacos , Emtricitabina/administração & dosagem , Genitália Masculina/virologia , Humanos , Masculino , Infecções do Sistema Genital/virologia , Sêmen/citologia , Sêmen/efeitos dos fármacos , Tenofovir/administração & dosagemRESUMO
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.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Recursos Audiovisuais , Apresentação de Dados , Infecções por HIV/tratamento farmacológico , Cabelo/química , Adesão à Medicação/estatística & dados numéricos , Educação de Pacientes como Assunto , Adulto , Fármacos Anti-HIV/farmacocinética , Estudos Transversais , Tomada de Decisões , Feminino , Letramento em Saúde , Humanos , MasculinoRESUMO
HIV replication within tissues may increase in response to a reduced exposure to antiretroviral drugs. Traditional approaches to measuring drug concentrations in tissues are unable to characterize a heterogeneous drug distribution. Here, we used mass spectrometry imaging (MSI) to visualize the distribution of six HIV antiretroviral drugs in gut tissue sections from three species (two strains of humanized mice, macaques, and humans). We measured drug concentrations in proximity to CD3+ T cells that are targeted by HIV, as well as expression of HIV or SHIV RNA and expression of the MDR1 drug efflux transporter in gut tissue from HIV-infected humanized mice, SHIV-infected macaques, and HIV-infected humans treated with combination antiretroviral drug therapy. Serial 10-µm sections of snap-frozen ileal and rectal tissue were analyzed by MSI for CD3+ T cells and MDR1 efflux transporter expression by immunofluorescence and immunohistochemistry, respectively. The tissue slices were analyzed for HIV/SHIV RNA expression by in situ hybridization and for antiretroviral drug concentrations by liquid chromatography-mass spectrometry. The gastrointestinal tissue distribution of the six drugs was heterogeneous. Fifty percent to 60% of CD3+ T cells did not colocalize with detectable drug concentrations in the gut tissue. In all three species, up to 90% of HIV/SHIV RNA was found to be expressed in gut tissue with no exposure to drug. These data suggest that there may be gut regions with little to no exposure to antiretroviral drugs, which may result in low-level HIV replication contributing to HIV persistence.
Assuntos
Antirretrovirais/farmacologia , Trato Gastrointestinal/virologia , HIV/efeitos dos fármacos , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Idoso , Animais , Complexo CD3/metabolismo , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Regulação Viral da Expressão Gênica/efeitos dos fármacos , HIV/genética , Humanos , Macaca mulatta , Masculino , Camundongos , Pessoa de Meia-Idade , RNA Viral/genética , RNA Viral/metabolismo , Vírus da Imunodeficiência Símia/genética , Especificidade da Espécie , Linfócitos T/efeitos dos fármacos , Adulto JovemRESUMO
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 5µm 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 8min. 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 3days, and at -80°C for up to 63days. 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.
Assuntos
Fármacos Anti-HIV/sangue , Cromatografia Líquida de Alta Pressão/métodos , Infecções por HIV/tratamento farmacológico , Adesão à Medicação , Espectrometria de Massas em Tandem/métodos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Cromatografia Líquida de Alta Pressão/instrumentação , Teste em Amostras de Sangue Seco/métodos , Quimioterapia Combinada/métodos , Emtricitabina/sangue , Emtricitabina/farmacocinética , Humanos , Lamivudina/sangue , Lamivudina/farmacocinética , Lamivudina/uso terapêutico , Leucócitos Mononucleares/metabolismo , Extração Líquido-Líquido/métodos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/instrumentação , Tenofovir/sangue , Tenofovir/farmacocinética , Tenofovir/uso terapêuticoRESUMO
BACKGROUND: Raltegravir (RTG) and dolutegravir (DTG) have different pharmacokinetic patterns in the gastrointestinal tract. To determine if this results in pharmacodynamic differences, we compared HIV RNA, HIV DNA and immunological markers in gut-associated lymphoid tissue (GALT) of HIV-infected participants receiving RTG or DTG with tenofovir+emtricitabine (TDF/FTC). METHODS: GALT specimens from the terminal ileum, splenic flexure and rectum were obtained by colonoscopy at a single time point in 20 adults treated with RTG (n=10) or DTG (n=10) with HIV RNA <50 copies/ml. Flow cytometry, drug concentrations, and HIV RNA and DNA were analysed in tissue. CD4/8+ T-cells were tested for γδ TCR, and markers of T-cell activation and exhaustion. Data are reported as median (Q1-Q3). RESULTS: A total of 15 men and 5 women were enrolled. There was no difference in time since HIV diagnosis for those on RTG (9.5 [4-22] years) and DTG (17 [1-24] years; P=0.6), although time on RTG (5.4 [2.3-6.7] years) was greater than DTG (1.0 [0.1-1.5] years; P<0.001). Concentrations of RTG and DTG in rectal tissue were similar to previous reports: median tissue:plasma ratio was 11.25 for RTG and 0.44 for DTG. RNA:DNA ratios were 1.14 (0.18-5.10) for the RTG group and 0.90 (0.30-18.87) for the DTG group (P=0.95). No differences (P≥0.1) between CD4+ and CD8+ T-cell markers were found. CONCLUSIONS: RTG produced higher tissue exposures than DTG, but no significant differences in GALT HIV RNA, DNA or most immunological markers were observed. ClinicalTrials.gov NCT02218320.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Tecido Linfoide/efeitos dos fármacos , Raltegravir Potássico/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , Colo Transverso/efeitos dos fármacos , Colo Transverso/patologia , Colo Transverso/virologia , DNA Viral/antagonistas & inibidores , DNA Viral/genética , DNA Viral/metabolismo , Emtricitabina/uso terapêutico , Feminino , Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , Humanos , Íleo/efeitos dos fármacos , Íleo/patologia , Íleo/virologia , Imunidade Inata/efeitos dos fármacos , Tecido Linfoide/patologia , Tecido Linfoide/virologia , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Piridonas , RNA Viral/antagonistas & inibidores , RNA Viral/genética , RNA Viral/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Reto/efeitos dos fármacos , Reto/patologia , Reto/virologia , Tenofovir/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVES: As the HIV-infected population ages, the role of cellular senescence and inflammation on co-morbid conditions and pharmacotherapy is increasingly of interest. p16INK4a expression, a marker for aging and senescence in T-cells, is associated with lower intracellular concentrations of endogenous nucleotides (EN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs). This study expands on these findings by determining whether inflammation is contributing to the association of p16INK4a expression with intracellular metabolite (IM) exposure and endogenous nucleotide concentrations. METHODS: Samples from 73 HIV-infected adults receiving daily tenofovir/emtricitabine (TFV/FTC) with either efavirenz (EFV) or atazanavir/ritonavir (ATV/r) were tested for p16INK4a expression, and plasma cytokine and intracellular drug concentrations. Associations between p16INK4a expression and cytokine concentrations were assessed using maximum likelihood methods, and elastic net regression was applied to assess whether cytokines were predictive of intracellular metabolite/endogenous nucleotide exposures. RESULTS: Enrolled participants had a median age of 48 years (range 23-73). There were no significant associations between p16INK4a expression and cytokines. Results of the elastic net regression showed weak relationships between IL-1Ra and FTC-triphosphate and deoxyadenosine triphosphate exposures, and MIP-1ß, age and TFV-diphosphate exposures. CONCLUSIONS: In this clinical evaluation, we found no relationships between p16INK4a expression and cytokines, or cytokines and intracellular nucleotide concentrations. While inflammation is known to play a role in this population, it is not a major contributor to the p16INK4a association with decreased IM/EN exposures in these HIV-infected participants.