RESUMO
OBJECTIVES: Charaterization of the plasma concentrations of antiretrovirals in a 4-days-a-week maintenance treatment strategy in the ANRS-170-QUATUOR study. METHODS: Patients were randomized in two groups receiving triple therapy taken 4-days-ON and 3-days-OFF (4/7) or continuous therapy (7/7). Plasma antiretroviral concentrations were monitored during the 'ON-treatment period' (Day 3 or 4 of the 4-day treatment block) and the 'OFF-treatment period' (Day 3 of the 3-day drug cessation) for the 4/7 group, or before the daily drug intake for the 7/7 group, until week-48 (W48). After W48, all patients switched to the 4/7 strategy and were followed until W96. RESULTS: W0 measured concentrations were comparable in both groups, except for raltegravir, concentrations of which were higher in the 4/7 group, and were all above the values usually recommended to be effective in therapeutic drug monitoring. Comparison of ON-period median concentrations between the two groups showed a statistical difference for rilpivirine [88 ng/mL (interquartile range (IQR)â=â64-112) for 4/7 arm versus 130 ng/mL (82-160) for 7/7 arm, Pâ<â0.001] and tenofovir [tenofovir disoproxil fumarate: 93 ng/mL (73-135) for 4/7 arm versus 117 ng/mL (83-160) for 7/7 arm, Pâ<â0.001; tenofovir alafenamide: 11 ng/mL (7-15) for 4/7 arm versus 14 ng/mL (11-18) for 7/7 arm, Pâ=â0.001]. Median OFF concentrations were significantly lower (Pâ<â0.001) at the 48 week analysis for all medications except for raltegravir (Pâ=â0.493) and atazanavir (Pâ=â0.105), for which the numbers of patients were very small. CONCLUSIONS: The 4/7-day treatment option led to antiretroviral blood levels close to continuous treatment after the four consecutive days of medication, and to low levels at the end of the non-treatment period.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/sangue , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Monitoramento de Medicamentos/métodos , Terapia Antirretroviral de Alta Atividade , Quimioterapia de Manutenção/métodos , Resultado do Tratamento , Carga Viral , Tenofovir/sangue , Tenofovir/uso terapêutico , Tenofovir/farmacocinética , Tenofovir/administração & dosagemRESUMO
BACKGROUND: Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence interventions. OBJECTIVES: We report the pharmacokinetics of tenofovir [dosed as tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF)], emtricitabine (FTC), lamivudine (3TC) and dolutegravir (DTG) in plasma and urine following drug cessation to evaluate adherence targets in urine for POCT. METHODS: Subjects were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15â days. Plasma and spot urine were collected on Day 15 (0-336â h post final dose). Drug concentrations were quantified using LC-MS, and non-linear mixed-effects models applied to determine drug disposition between matrices and relationship with relevant plasma [dolutegravir protein-adjusted 90% inhibitory concentration (PA-IC90â=â64â ng/mL) and minimum effective concentration (MECâ=â324â ng/mL)] and urinary thresholds [tenofovir disoproxil fumarate 1500â ng/mL]. RESULTS: Of 30 individuals enrolled, 29 were included (72% female at birth, 90% Caucasian). Median (range) predicted time to plasma dolutegravir PA-IC90 and MEC were 83.5 (41.0-152) and 49.0â h (23.7-78.9), corresponding to geometric mean (90%) urine concentrations of 5.42 (4.37-6.46) and 27.4â ng/mL (22.1-32.7). Tenofovir in urine reached 1500â ng/mL by 101â h (58.6-205) with an equivalent plasma concentration of 6.20â ng/mL (4.21-8.18). CONCLUSIONS: These data support use of a urinary tenofovir threshold of <1500â ng/mL (tenofovir disoproxil fumarate-based regimens) as a marker of three or more missed doses for a POCT platform. However, due to low dolutegravir concentrations in urine, POCT would be limited to a readout of recent dolutegravir intake (one missed dose).
Assuntos
Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Lamivudina , Oxazinas , Piperazinas , Testes Imediatos , Piridonas , Tenofovir , Humanos , Piridonas/urina , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/urina , Compostos Heterocíclicos com 3 Anéis/sangue , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Masculino , Emtricitabina/urina , Emtricitabina/farmacocinética , Emtricitabina/uso terapêutico , Emtricitabina/sangue , Adulto , Piperazinas/urina , Piperazinas/sangue , Lamivudina/urina , Lamivudina/farmacocinética , Lamivudina/sangue , Feminino , Infecções por HIV/tratamento farmacológico , Tenofovir/urina , Tenofovir/farmacocinética , Tenofovir/uso terapêutico , Tenofovir/sangue , Fármacos Anti-HIV/urina , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Pessoa de Meia-Idade , Profilaxia Pré-Exposição/métodos , Adulto Jovem , Plasma/química , Adesão à MedicaçãoRESUMO
OBJECTIVES: We measured the intracellular concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) for pre-exposure prophylaxis (PrEP) adherence using sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: A total of 191 DBS were obtained from 85 participants who were receiving tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) as PrEP at the Sexual Health Clinic, National Center for Global Health and Medicine, Tokyo, Japan. DBS punch (3 mm) added to 25 µL of 50% methanol and 400 µL of internal standard solution was used for solid phase extraction. Chromatographic separation was achieved on an Atlantis Premier BEH C18 AX Column (50 mm × 2.1 mm i.d.; particle size 1.7 µm) using gradient elution (flow rate: 0.6 mL/min); injection volume: 7 µL and run time: 5.5 min. Calibration curves for the two drugs were linear in the range 0.05-12.5 ng/punch. RESULTS: We determined the intracellular TFV-DP and FTC-TP concentrations in 191 DBS obtained from 85 patients administered with TDF and FTC as PrEP. The analytical performance data (calibration curve and QC samples) for all the analytical runs met the acceptance criteria. Intracellular concentrations of TFV-DP and FTC-TP in the DBS remained stable for at least 24 h after oral administration. CONCLUSIONS: A multiplex LC-MS/MS method was successfully developed for DBS, which can be useful for monitoring the levels of TFV-DP and FTC-TP in individuals receiving PrEP.
Assuntos
Fármacos Anti-HIV , Teste em Amostras de Sangue Seco , Emtricitabina , Infecções por HIV , Profilaxia Pré-Exposição , Espectrometria de Massas em Tandem , Tenofovir , Humanos , Emtricitabina/farmacocinética , Emtricitabina/administração & dosagem , Emtricitabina/sangue , Profilaxia Pré-Exposição/métodos , Infecções por HIV/prevenção & controle , Teste em Amostras de Sangue Seco/métodos , Espectrometria de Massas em Tandem/métodos , Masculino , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Feminino , Adulto , Cromatografia Líquida/métodos , Pessoa de Meia-Idade , Tenofovir/sangue , Tenofovir/farmacocinética , Tenofovir/administração & dosagem , Adenina/análogos & derivados , Adenina/administração & dosagem , Adenina/farmacocinética , Adenina/sangue , Adenina/uso terapêutico , Adesão à Medicação , Organofosfatos/sangue , Organofosfatos/farmacocinética , Organofosfatos/administração & dosagem , Organofosfatos/análise , Polifosfatos/análise , Polifosfatos/sangueRESUMO
Antiretroviral therapy (ART) to treat and pre-exposure prophylaxis (PrEP) to prevent HIV infection are effective tools to help end the HIV epidemic. However, their use could affect HIV transfusion-transmission risk. Three different ART/PrEP prevalence analyses in blood donors were conducted. First, blood samples from HIV-positive and a comparison group of infection-nonreactive donors were tested under blind using liquid chromatography-tandem mass spectrometry for ART. Second, blood donor samples from infection-nonreactive, 18- to 45-year-old, male, first-time blood donors in 6 US locations were tested for emtricitabine and tenofovir. Third, in men who have sex with men (MSM) participating in the 2017 Centers for Disease Control and Prevention National HIV Behavioral Surveillance (NHBS) from 5 US cities, self-reported PrEP use proximate to donation was assessed. In blind testing, no ART was detected in 300 infection-nonreactive donor samples, but in 299 HIV confirmed-infected donor samples, 46 (15.4%; 95% confidence interval [CI], 11.5% to 20.0%) had evidence of ART. Of the 1494 samples tested from first-time male donors, 9 (0.6%; 95% CI, 0.03% to 1.1%) had tenofovir and emtricitabine. In the NHBS MSM survey, 27 of 591 respondents (4.8%; 95% CI, 3.2% to 6.9%) reported donating blood in 2016 or 2017 and PrEP use within the same time frame as blood donation. Persons who are HIV positive and taking ART and persons taking PrEP to prevent HIV infection are donating blood. Both situations could lead to increased risk of HIV transfusion transmission if blood screening assays are unable to detect HIV in donations from infected donors.
Assuntos
Fármacos Anti-HIV/sangue , Doadores de Sangue , Segurança do Sangue , Infecções por HIV/prevenção & controle , Profilaxia Pós-Exposição , Profilaxia Pré-Exposição , Adolescente , Adulto , Fármacos Anti-HIV/uso terapêutico , Cromatografia Líquida , Emtricitabina/sangue , Feminino , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Método Simples-Cego , Espectrometria de Massas em Tandem , Tenofovir/sangue , Revelação da Verdade , Estados Unidos , Viremia/sangue , Viremia/transmissão , Adulto JovemRESUMO
Tenofovir disoproxyl fumarate (TDF) has been associated with renal tubular abnormalities, phosphaturia and proteinuria (retinol binding protein, RBP, loss): vitamin D (VD) and PTH affect these markers. Aim was to understand if some single nucleotide polymorphisms (SNPs) were predictors of renal abnormalities in an Italian cohort of HIV-affected patients. DNA was analyzed through real-time PCR, urinary RBP corrected by creatinine (uRBP/Cr). The majority of patients received TDF. Abnormal uRBP/Cr was more frequent in TDF recipients: eGFR <90 mL/min and TDF were predictors in the whole cohort, whereas eGFR <90 mL/min, TDF concentrations and CYP24A1-3999TT in TDF-treated patients. Phosphate levels were higher low VD level patients: age <50 years, CYP27B1 + 2838CC genotype and non-European ancestry were predictors. PTH levels were border-line higher in TDF patients: non-European ancestry, females, TDF, VD levels < 30 ng/mL and SLC28A2-124CT/TT and ABCC2-24CC were predictors. For the first time, SNPs were associated with PTH, phosphate, calcium and tubular dysfunction in HIV-infected patients.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Nefropatias/genética , Polimorfismo de Nucleotídeo Único , Tenofovir/efeitos adversos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Creatinina/urina , Feminino , Taxa de Filtração Glomerular , Infecções por HIV/genética , Humanos , Nefropatias/induzido quimicamente , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Fosfatos/sangue , Receptores de Calcitriol/genética , Proteínas de Ligação ao Retinol/urina , Tenofovir/sangue , Tenofovir/uso terapêutico , Vitamina D3 24-Hidroxilase/genéticaRESUMO
Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are both tenofovir (TFV) prodrugs, with the same active intracellular metabolite, TFV-diphosphate (TFV-DP). TAF delivers TFV-DP to target cells more efficiently and at lower doses than TDF, thereby substantially reducing systemic exposure to TFV, which results in improved bone and renal safety relative to TDF. As such, the method developed for the determination of TFV following TAF administration involved two key differences from determination of TFV following TDF administration. First, human plasma samples (500 µL) immediately upon collection were treated with 20% formic acid (40 µL) (plasma: formic acid ratio of 100:8) to minimize hydrolysis of TAF to TFV, and thereby avoided overestimation of TFV concentrations. Second, various TFV validation tests were conducted in the presence of TAF to mimic the high TAF:TFV ratios in clinical samples collected within ~2 h after dosing. The method for determination of TFV was developed and validated at a US lab and followed FDA and EMA guidelines. To support global clinical studies of TAF, the method was cross-validated (one-way) between the US lab and a China lab and was successfully used for TFV determination in plasma samples from a clinical study that involved healthy Chinese subjects.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/farmacocinética , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Tenofovir/sangue , Adenina/farmacocinética , Alanina , Formiatos/química , Humanos , Pró-Fármacos/farmacocinéticaRESUMO
PURPOSE OF REVIEW: In this report, we review the need for point-of-care (POC) or near real-time testing for antiretrovirals, progress in the field, evidence for guiding implementation of these tests globally, and future directions in objective antiretroviral therapy (ART) or pre-exposure prophylaxis (PrEP) adherence monitoring. RECENT FINDINGS: Two cornerstones to end the HIV/AIDS pandemic are ART, which provides individual clinical benefits and eliminates forward transmission, and PrEP, which prevents HIV acquisition with high effectiveness. Maximizing the individual and public health benefits of these powerful biomedical tools requires high and sustained antiretroviral adherence. Routine monitoring of medication adherence in individuals receiving ART and PrEP may be an important component in interpreting outcomes and supporting optimal adherence. Existing practices and subjective metrics for adherence monitoring are often inaccurate or unreliable and, therefore, are generally ineffective for improving adherence. Laboratory measures of antiretroviral concentrations using liquid chromatography tandem mass spectrometry have been utilized in research settings to assess medication adherence, although these are too costly and resource-intensive for routine use. Newer, less costly technologies such as antibody-based methods can provide objective drug-level measurement and may allow for POC or near-patient adherence monitoring in clinical settings. When coupled with timely and targeted counseling, POC drug-level measures can support adherence clinic-based interventions to ART or PrEP in near real time.
Assuntos
Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Adesão à Medicação , Sistemas Automatizados de Assistência Junto ao Leito , Profilaxia Pré-Exposição/métodos , Aconselhamento , Feminino , Humanos , Saúde Pública , Tenofovir/sangue , Tenofovir/uso terapêuticoRESUMO
RATIONALE: Tenofovir (TFV) is a first-line antiviral agent against hepatitis B virus (HBV) and is recommended for the prevention of mother-to-infant transmission of HBV. To study the distribution of TFV in umbilical cord plasma and amniotic fluid of HBV-infected pregnant women, a rapid and sensitive method for TFV determination was developed and validated. METHODS: The quantification method was developed using liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). The analytes were separated on an Acquity UPLC HSS T3 column under gradient elution with methanol and 0.01% ammonia solution in 10 mM ammonium acetate/water. This is the first reported method for the determination of TFV using alkaline rather than acidic mobile phases. Linearity, accuracy, precision, limit of quantification, specificity and stability were assessed. RESULTS: Detection of TFV was achieved within 4 min. The calibration curves for TFV quantification showed excellent linearity in the range of 1-500 ng/mL. The intra- and interbatch precision and accuracy ranged from -4.35% to 6.92%. This method was successfully applied to determination of samples from 50 HBV mono-infected women undergoing tenofovir disoproxil fumarate therapy. The mean concentrations of TFV in the umbilical cord and amniotic fluid samples were 29.2 (4.6-86) and 470.9 (156-902) ng/mL, respectively, which showed a moderate positive correlation (r = 0.5299, P<0.001). CONCLUSIONS: A simple, rapid but sensitive bioanalytical method to determine TFV concentration in both umbilical cord plasma and amniotic fluid using LC/MS/MS was developed and applied to HBV-infected women during labor who were undergoing TDF therapy, which will help us understand the efficacy and safety of tenofovir during pregnancy.
Assuntos
Líquido Amniótico/química , Antivirais/análise , Sangue Fetal/química , Espectrometria de Massas em Tandem/métodos , Tenofovir/análise , Animais , Antivirais/sangue , Cromatografia Líquida de Alta Pressão/economia , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/economia , Monitoramento de Medicamentos/métodos , Feminino , Hepatite B/sangue , Hepatite B/tratamento farmacológico , Humanos , Limite de Detecção , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/tratamento farmacológico , Espectrometria de Massas em Tandem/economia , Tenofovir/sangue , Cordão Umbilical/irrigação sanguíneaRESUMO
BACKGROUND: There is extensive evidence to show that pre-exposure prophylaxis (PrEP) using tenofovir disoproxil fumarate (TDF)-based formulations dramatically reduces the risk of HIV acquisition among individuals without HIV infection. Here, the authors aim to compare tenofovir plasma predose concentrations in subjects taking PrEP daily versus on demand and using different TDF-based generic formulations. METHODS: Subjects providing informed signed consent for the measurement of tenofovir plasma levels were included in the study. Predose drug concentrations were stratified according to PrEP administration and the type of TDF-based formulation. The control group consisted of patients with HIV infection who were matched for renal function and were administered branded TDF that was not combined with boosted-antiretroviral drugs. RESULTS: The study consisted of 100 subjects (mean age, 39 ± 10 years; body weight, 77 ± 11 kg). A wide distribution in tenofovir predose concentrations was observed, with values ranging from 17 to 297 ng/mL (coefficient of variation 77%). No significant differences were noted in tenofovir predose concentrations between subjects who were administered PrEP daily (n = 75) or on demand (n = 25) [94 (35-255) versus 104 (37-287) ng/mL; P = 0.476]. Comparable tenofovir predose concentrations were found between patients with HIV infection (n = 220) who were administered branded TDF and those without HIV infection who were treated with 5 different generic TDF-based formulations with generics-to-branded ratios. These were always within the range of 80%-125% and were used to define bioequivalence. CONCLUSIONS: The marketed generic formulations of TDF delivered tenofovir plasma predose concentrations comparable with those delivered by branded formulations.
Assuntos
Fármacos Anti-HIV/sangue , Medicamentos Genéricos/metabolismo , Tenofovir/sangue , Adulto , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Profilaxia Pré-Exposição/métodos , Estudos Retrospectivos , Tenofovir/uso terapêuticoRESUMO
AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (ka ), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: ka = 2.87 h-1, CL/F = 37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ritonavir or efavirenz were significantly associated with CL/F (P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.
Assuntos
Fármacos Anti-HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/etnologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Tenofovir/sangue , Adulto , Alcinos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/sangue , Benzoxazinas/uso terapêutico , Ciclopropanos , Didesoxinucleosídeos/sangue , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Emtricitabina/sangue , Emtricitabina/uso terapêutico , Feminino , Inibidores da Protease de HIV/farmacocinética , Humanos , Lamivudina/sangue , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Tenofovir/farmacocinética , Tenofovir/uso terapêuticoRESUMO
The Partners Demonstration Project was a prospective, open-label, implementation science-driven study of preexposure prophylaxis (PrEP) among heterosexual HIV serodiscordant couples in Kenya and Uganda. Adherence data were collected using the Medication Event Monitoring System (MEMS), and time of sexual activity was collected using the mobile phone short message service (SMS). Two plasma samples were collected at a single study visit. We integrated adherence, pharmacokinetics, and SMS data using a population pharmacokinetic (PopPK) model to simulate tenofovir plasma concentrations from PrEP at the time of sexual activity. In the first stage of this analysis, we used data from the current study to update a prior PopPK model of tenofovir (TFV) developed with data from the Partners PrEP Study (a phase III clinical trial). The second stage involved simulating plasma concentrations at the time of sexual activity using empirical Bayes estimates (EBEs) derived from the final model. In addition, EBEs from a previously published parent metabolite model of TFV (MTN-001, an open-label 3-way crossover study in healthy women) was used to simulate tenofovir diphosphate (TFV-DP) concentrations. We estimated percent PrEP "coverage" as the number of reported sexual events during which simulated concentrations were above an a priori threshold concentrations associated with a high degree of protection from HIV infection: plasma TFV of >40 ng/ml and peripheral blood mononuclear cell (PBMC) TFV-DP concentration of >36 fmol/million cells. The levels of coverage were 72% for TFV and 81% for TFV-DP. These levels are consistent with a high degree of protection against HIV acquisition in this study of a pragmatic delivery model for antiretroviral-based HIV prevention.
Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Tenofovir/farmacocinética , Tenofovir/uso terapêutico , Adenina/análogos & derivados , Adenina/sangue , Adenina/farmacocinética , Adenina/uso terapêutico , Fármacos Anti-HIV/sangue , Teorema de Bayes , Estudos Cross-Over , Feminino , Humanos , Quênia , Leucócitos Mononucleares/virologia , Masculino , Organofosfatos/sangue , Organofosfatos/farmacocinética , Organofosfatos/uso terapêutico , Profilaxia Pré-Exposição/métodos , Estudos Prospectivos , Parceiros Sexuais , Tenofovir/sangue , UgandaRESUMO
We assessed tenofovir exposure during pregnancy and postpartum in hepatitis B virus (HBV)-infected HIV-uninfected women receiving tenofovir disoproxil fumarate (TDF) to prevent mother-to-child transmission of HBV. Data from 154 women who received TDF within a randomized controlled trial were included. Individual plasma tenofovir exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were estimated using a population pharmacokinetic approach. The estimated geometric mean tenofovir AUC0-24 was 20% (95% confidence interval [95% CI], 19 to 21%) lower during pregnancy than during postpartum; this modest reduction in the absence of HBV transmission suggests that no dose adjustment is needed.
Assuntos
Antivirais/farmacocinética , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/transmissão , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Tenofovir/farmacocinética , Administração Oral , Adulto , Antivirais/sangue , Antivirais/farmacologia , Área Sob a Curva , Feminino , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/crescimento & desenvolvimento , Hepatite B Crônica/virologia , Humanos , Período Pós-Parto , Gravidez , Tenofovir/sangue , Tenofovir/farmacologia , Carga Viral/efeitos dos fármacosRESUMO
We evaluate the impact of ledipasvir on both tenofovir plasma trough concentration and estimated glomerular renal function in human immunodeficiency virus-hepatitis C virus coinfected patients receiving a tenofovir-based antiretroviral regimen and treated with ledipasvir/sofosbuvir. Twenty-six patients [81% male, median age: 51 years; hepatitis C virus genotype 1(75%)/4(15%)] were included. Tenofovir trough concentration (interquartile range) increased from 78 ng ml-1 (53-110) at baseline to 141 ng ml-1 (72-176) at 1 month (P = 0.003). No significant difference on estimated glomerular renal function using both Cockroft-Gault and Modification of Diet in Renal Disease formulae, respectively, [median (interquartile range)] was observed between baseline [101.3 ml min-1 (91.1-114.1); 95.6 ml min-1 (86.5-111.2)], 1 month [102.4 ml min-1 (89.8-112.9), P = 0.26; 92.5 ml min-1 (88.1-114.3), P = 0.27], end-of-treatment [96.5 ml min-1 (82.4-115.4), P = 0.39; 95.4 ml min-1 (84.2-105.4), P = 0.16] and 12 weeks after the end of treatment [100.5 ml min-1 (83.3-111.9), P = 0.24; 93.4 ml min-1 (82.2-103.5), P = 0.16]. Three patients progressed from chronic kidney disease stage 1 to stage 2 at 12 weeks post-treatment. A significant increase in tenofovir exposure through P-glycoprotein inhibition by ledipasvir was confirmed without significant impact on glomerular renal function in our population with normal renal function or mild renal impairment.
Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Hepatite C/tratamento farmacológico , Tenofovir/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antivirais/efeitos adversos , Antivirais/sangue , Benzimidazóis/efeitos adversos , Benzimidazóis/sangue , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Fluorenos/efeitos adversos , Fluorenos/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Infecções por HIV/complicações , Hepatite C/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tenofovir/efeitos adversos , Tenofovir/sangueRESUMO
Measuring PrEP adherence remains challenging. In 2009-2010, the International AIDS Vaccine Initiative randomized phase II trial participants to daily tenofovir disoproxil fumarate/emtricitabine or placebo in Uganda and Kenya. Adherence was measured by electronic monitoring (EM), self-report (SR), and drug concentrations in plasma and hair. Each adherence measure was categorised as low, moderate, or high and also considered continuously; the incremental value of combining measures was determined. Forty-five participants were followed over 4 months. Discrimination for EM adherence by area under receiver operating curves (AROC) was poor for SR (0.53) and best for hair (AROC 0.85). When combining hair with plasma or hair with self-report, discrimination was improved (AROC > 0.9). Self-reported adherence was of low utility by itself. Hair level was the single best PK measure to predict EM-assessed adherence; the other measurements had lower discrimination values. Combining short-term (plasma) and long-term (hair) metrics could be useful to assess patterns of drug-taking in the context of PrEP.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Emtricitabina/administração & dosagem , Infecções por HIV/prevenção & controle , Cabelo/metabolismo , Adesão à Medicação , Profilaxia Pré-Exposição/métodos , Autorrelato , Tenofovir/administração & dosagem , Administração Oral , Adulto , Fármacos Anti-HIV/sangue , Emtricitabina/sangue , Feminino , Infecções por HIV/psicologia , Cabelo/química , Humanos , Quênia , Masculino , Tenofovir/sangue , UgandaRESUMO
OBJECTIVE: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detecting tenofovir in human plasma. METHODS: Twenty four healthy male volunteers received a single oral dose of 300 mg tenofovir disoproxil fumarate tablets under fasting and high-fat diet conditions in a randomized four-way crossover bioequivalence study with two preparations of tablets. Plasma samples were taken and analyzed using the LC-MS/MS method. The pharmacokinetic parameters of the two preparations were calculated and compared statistically to evaluate their bioequivalence using Phoenix Winnonlin6.3. RESULTS: Linear detection responses were obtained for tenofovir at the range from 3.13 to 500 ng/mL. The intra- and inter-day precisions were high,with lower than 5.43% [relative standard deviation (RSD)%],high recovery and good stability. The 90% confidence intervals of peak concentration (Cmax) of tenofovir and its area under the curve (AUC0-t and AUC0-∞ ) all fell within the bioequivalence limit 80.00%-125.00% under both fasting and high-fat diet conditions. No significant difference in peak time (Tmax) was demonstrated between the two preparations (P>0.05) . CONCLUSION: The LC-MS/MS method can be used for simultaneous determination of tenofovir in human plasma. The two preparations of tablets are bioequivalent.
Assuntos
Tenofovir/sangue , Equivalência Terapêutica , Área Sob a Curva , Cromatografia Líquida , Estudos Cross-Over , Humanos , Masculino , Comprimidos , Espectrometria de Massas em Tandem , Tenofovir/farmacocinéticaRESUMO
Black women bear the highest burden of human immunodeficiency virus (HIV) infection among US women. Tenofovir/emtricitabine HIV prevention trials among women in Africa have yielded varying results. Ideally, a randomized controlled trial (RCT) among US women would provide data for guidelines for US women's HIV preexposure prophylaxis use. However, even among US black women at high risk for HIV infection, sample size requirements for an RCT with HIV incidence as its outcome are prohibitively high. We propose to circumvent this large sample size requirement by evaluating relationships between HIV incidence and drug concentrations measured among participants in traditional phase 3 trials in high-incidence settings and then applying these observations to drug concentrations measured among at-risk individuals in lower-incidence settings, such as US black women. This strategy could strengthen the evidence base to enable black women to fully benefit from prevention research advances and decrease racial disparities in HIV rates.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Negro ou Afro-Americano , Infecções por HIV/etnologia , Infecções por HIV/prevenção & controle , Projetos de Pesquisa , Adulto , Fármacos Anti-HIV/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Emtricitabina/sangue , Emtricitabina/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Incidência , Adesão à Medicação , Profilaxia Pré-Exposição , Racismo , Tamanho da Amostra , Tenofovir/sangue , Tenofovir/uso terapêutico , Estados Unidos/epidemiologiaRESUMO
The aims of this study were to describe the blood plasma (BP) and seminal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1-infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract, and to evaluate the impact of TFV SP exposure on seminal plasma HIV load (spVL). Men from the Evarist-ANRS EP 49 study treated with TFV as part of their antiretroviral therapy were included in the study. A total of 248 and 217 TFV BP and SP concentrations from 129 men were available for the analysis. For pharmacogenetic assessment, a total of 121 single nucleotide polymorphisms (SNP) were genotyped. Data were analyzed using a nonlinear mixed-effects modeling approach. TFV pharmacokinetics were best described by a two-compartment model for BP and by an effect compartment with different input and output constants for SP. TFV exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were higher in SP than in BP (median AUC0-24, 7.01 versus 2.97 mg · liter-1 · h, respectively). The median (range) SP-to-BP AUC0-24 ratio was 2.24 (0.53 to 34.13). After correction for multiple testing, none of the SNPs were significantly associated with the TFV transfer rate constant. The impact of the TFV SP AUC0-24 or TFV SP-to-BP AUC0-24 ratio on spVL was not significant (P = 0.808 and 0.768, respectively). This is the first population model describing TFV pharmacokinetics in the male genital tract. TFV SP concentrations were higher than BP concentrations. Despite TFV SP exposures being higher than BP exposures, an spVL was detectable for 12.2% of the men.
Assuntos
Fármacos Anti-HIV/farmacocinética , Genitália Masculina/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Modelos Estatísticos , Tenofovir/farmacocinética , Adulto , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacologia , Área Sob a Curva , Teorema de Bayes , Disponibilidade Biológica , Peso Corporal , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Expressão Gênica , Genitália Masculina/química , Genitália Masculina/virologia , Infecções por HIV/sangue , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/genética , HIV-1/crescimento & desenvolvimento , Humanos , Masculino , Cadeias de Markov , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Método de Monte Carlo , Polimorfismo de Nucleotídeo Único , Sêmen/química , Sêmen/efeitos dos fármacos , Sêmen/virologia , Tenofovir/sangue , Tenofovir/farmacologiaRESUMO
OBJECTIVES: In the ANRS IPERGAY pre-exposure prophylaxis (PrEP) trial, a single dose of tenofovir disoproxil fumarate and emtricitabine was taken orally 2-24 h before sexual intercourse. A sub-study was conducted to assess the pharmacokinetics of tenofovir and emtricitabine in blood, saliva and rectal tissue following this initial oral intake. METHODS: Plasma, PBMC, saliva and rectal tissue sampling was performed over 24 h in 12 seronegative men before enrolment in the ANRS IPERGAY trial, following a single dose of 600 mg tenofovir disoproxil fumarate/400 mg emtricitabine. Ex vivo HIV infectibility of rectal biopsies was also assessed. RESULTS: The median plasma Tmax of tenofovir (median Cmax: 401 µg/L) and emtricitabine (median Cmax: 2868 µg/L) was obtained 1 h (range: 0.5-4) and 2 h (range: 1-4) after dosing, respectively. The median C24 of tenofovir and emtricitabine was 40 and 63 µg/L, respectively. The median PBMC tenofovir diphosphate and emtricitabine triphosphate levels were 12.2 and 16.7 fmol/106 cells and 2800 and 2000 fmol/106 cells at 2 and 24 h after dosing, respectively. Saliva/plasma AUC0-24 ratios were 2% and 17% for tenofovir and emtricitabine, respectively. Emtricitabine was detected in rectal tissue 30 min after dosing, whereas tenofovir was only detectable at 24 h. Ex vivo HIV infectibility assays of rectal biopsies showed partial protection after dosing (Pâ<â0.07). DISCUSSION: A single high dose of oral tenofovir disoproxil fumarate/emtricitabine provides rapid and high blood levels of tenofovir and emtricitabine, with rapid diffusion of emtricitabine in saliva and rectal tissue.
Assuntos
Fármacos Anti-HIV/farmacocinética , Antibioticoprofilaxia/métodos , Emtricitabina/farmacocinética , Infecções por HIV/prevenção & controle , Profilaxia Pré-Exposição/métodos , Saliva/química , Tenofovir/farmacocinética , Adulto , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/sangue , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Placebos/farmacologia , Tenofovir/sangue , Tenofovir/uso terapêutico , Sexo sem ProteçãoRESUMO
Objectives: To assess, in a clinical cohort, the efficacy of switching current ART in virologically suppressed patients to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate as a single-tablet regimen (STR) using the PCR signal of the plasma viral load (pVL) assay and determination of plasma drug concentration ( C 24 ). Patients and methods: This was an observational single-centre study enrolling antiretroviral-treated patients with pVL <50â copies/mL initiating elvitegravir-based STR. PCRneg was defined as an undetected PCR signal. Results: One hundred and fifty-one patients were enrolled. At STR baseline, the median time since first ART and time of virological suppression were 5â years (IQR 3-9) and 24â months (IQR 9-44), respectively. By week (W) 48, 26 (17%) of the patients had discontinued STR due to adverse events. The proportion of patients maintaining pVL <50â copies/mL on treatment was 98%, 96%, 93% and 97% at W12, W24, W36 and W48, respectively. Five patients (3.3%) experienced a virological failure and emergence of resistance was observed in two of them with the selection of M184V and N155H mutations. At baseline, W12, W24, W36 and W48, 70%, 57%, 72%, 61% and 74% of the patients with pVL <20â copies/mL had a PCRneg, respectively. The median elvitegravir plasma C 24 value was 648â ng/mL (IQR 348-989; n = 237), with 84% of elvitegravir C 24 values >45â ng/mL, the protein-adjusted IC 95 . Conclusions: In this clinical cohort of virologically suppressed patients switching to STR, most subjects had adequate elvitegravir C 24 values with a high proportion maintaining virological suppression with no residual viraemia until W48.
Assuntos
Cobicistat/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Quinolonas/uso terapêutico , Tenofovir/uso terapêutico , Carga Viral , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Cobicistat/administração & dosagem , Cobicistat/sangue , Estudos de Coortes , Emtricitabina/administração & dosagem , Emtricitabina/sangue , Feminino , Infecções por HIV/sangue , HIV-1/efeitos dos fármacos , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Quinolonas/administração & dosagem , Quinolonas/sangue , RNA Viral/sangue , Comprimidos , Tenofovir/administração & dosagem , Tenofovir/sangue , Viremia/tratamento farmacológicoRESUMO
PURPOSE: Non-adherence to the antiretroviral (ARV) regimen is a critical factor in determining efficacy of ARV drugs for pre-exposure prophylaxis (PrEP). A long-acting parenteral formulation may be an effective alternative to daily oral dosing. A pharmacokinetic and tissue distribution study of drug-loaded nanoparticle (NP) was performed in female humanized CD34+-NSG mice. METHODS: Mice received 200 mg/kg each of tenofovir alafenamide (TAF) and elvitegravir (EVG) as free drugs (TAF + EVG solution) or as drug loaded NP (TAF + EVG NP) formulation by subcutaneous (SubQ) administration. Plasma and tissue were collected to determine tenofovir (TFV) and EVG concentrations using LC-MS/MS. Non-compartmental analysis was performed using WinNonlin. RESULTS: SubQ administration of TAF + EVG NP formulation resulted in long residence time and exposure for both drugs. The AUC(0-72h) of TFV and EVG was 14.1 ± 2.0, 7.2 ± 1.8 µg × hr./mL from drugs in solution (free) and the AUC(0-14day) for the same drugs was 23.1 ± 4.4, 39.7 ± 6.7 µg × hr./mL from NPs. The observed elimination half-life (t1/2) for TFV of free and NPs were 14.2 h, 5.1 days and for EVG 10.8 h, 3.3 days, respectively. CONCLUSION: This study documents that a TAF + EVG NP provides sustained release, which can overcome patient non-adherence to dosing and may facilitate prediction of appropriate protective drug concentration for HIV prophylaxis.