RESUMO
BACKGROUND: One major barrier to HIV cure is the persistence of virus, possibly linked to an insufficient antiretroviral drug (ARV) distribution into tissues. OBJECTIVES: To draw the whole-body distribution of three antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine and dolutegravir-in non-human primates (NHPs). METHODS: Eight uninfected NHPs received a single injection of a solution containing the three ARVs. Forty-five different tissues were sampled 24 h after injection. RESULTS: Median tissue penetration factors (TPFs) were 45.4, 5.8 and 0.5 for tenofovir, emtricitabine and dolutegravir, respectively, and were statistically different between the three ARVs. Tissues were grouped by system, because TPFs were consistent according to these groups, and ranked in order of decreasing TPFs. The digestive system was the system with the highest tissue concentrations. Next came the two main sites of elimination, the liver and the kidney, as well as the tissues of the cardiopulmonary and urinary systems. Then, it was the whole lymphatic system. The next group included the reproductive system, the adipose tissue and the skin. The last two systems were the muscle and the CNS. The intra-tissue variability was rather low with a median coefficient of variation of the concentrations around 15% and no value greater than 80%. CONCLUSIONS: Overall, this study determines the first whole-body distribution in a validated NHP model. These data have important implications for future preclinical and clinical studies for the development of novel HIV therapies towards an HIV cure.
RESUMO
Tenofovir (TFV) and emtricitabine (FTC) are part of the recommended highly active antiretroviral therapy (ART). Both molecules show a large interindividual pharmacokinetic (PK) variability. Here, we modeled the concentrations of plasma TFV and FTC and their intracellular metabolites (TFV diphosphate [TFV-DP] and FTC triphosphate [FTC-TP]) collected after 4 and 24 weeks of treatment in 34 patients from the ANRS 134-COPHAR 3 trial. These patients received daily (QD) atazanavir (300 mg), ritonavir (100 mg), and a fixed-dose combination of coformulated TFV disoproxil fumarate (300 mg) and FTC (200 mg). Dosing history was collected using a medication event monitoring system. A three-compartment model with absorption delay (Tlag) was selected to describe the PK of, respectively, TFV/TFV-DP and FTC/FTC-TP. TFV and FTC apparent clearances, 114 L/h (relative standard error [RSE] = 8%) and 18.1 L/h (RSE = 5%), respectively, were found to decrease with age. However, no significant association was found with the polymorphisms ABCC2 rs717620, ABCC4 rs1751034, and ABCB1 rs1045642. The model allows prediction of TFV-DP and FTC-TP concentrations at steady state with alternative regimens.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Humanos , Tenofovir , Emtricitabina , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacocinéticaRESUMO
BACKGROUND: Studies of antiretroviral drug (ARV) tissue distribution in preclinical models, such as mice, are key to understanding viral persistence. OBJECTIVES: To determine the plasma and tissue pharmacokinetics and tissue distributions of tenofovir, emtricitabine and dolutegravir in mice. METHODS: ARVs were simultaneously administered to two different strains, and their levels in plasma and tissue samples were determined by a validated LC-MS/MS method. A non-compartmental analysis was performed to estimate the main pharmacokinetic parameters. A tissue penetration factor (TPF) was calculated as the ratio of the concentration in the tissue concerned to that in plasma. RESULTS: ARV plasma pharmacokinetic parameters in both strains were similar to those estimated in the clinical context. Tissue concentrations were highest in the digestive tract, followed by the liver and kidneys, lymphatic system, pancreas, adipose tissue and lungs. Tissue concentrations were lowest in the brain. Triple therapy could not be considered effective in any of the tissues considered. The TPF values obtained showed that tenofovir diffused widely, especially in the digestive tract, liver and kidneys. Emtricitabine had a TPF above 100% in two-thirds of the tissues. Dolutegravir was poorly distributed to all tissues. CONCLUSIONS: Drug specificity was observed, with higher levels of exposure to tenofovir than to emtricitabine or dolutegravir. Tissue specificity was also observed, with strong penetration of the digestive tract and weak penetration of the brain. These data have important implications for future preclinical and clinical studies for developing new HIV therapies with the goal of an HIV cure.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Animais , Fármacos Anti-HIV/uso terapêutico , Cromatografia Líquida/métodos , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis , Camundongos , Oxazinas , Piperazinas , Piridonas , Espectrometria de Massas em Tandem/métodos , Tenofovir/uso terapêutico , Distribuição TecidualRESUMO
OBJECTIVES: The penetration of antiretroviral drugs into deep compartments, such as the CNS, is a crucial component of strategies towards an HIV cure. This study aimed to determine CSF concentrations of bictegravir, emtricitabine and tenofovir in patients with HIV-related CNS impairment (HCI) enrolled in a real-life observational study. METHODS: Patients with HCI treated by optimized ART, including bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) for at least 1 month were enrolled. Plasma and CSF concentrations were measured by quality control-validated assays (LC-MS/MS). The inhibitory quotient (IQARV) was calculated as the ratio of unbound (bictegravir) or total (emtricitabine and tenofovir) concentration to half (or 90%) maximal inhibitory concentration for bictegravir (or emtricitabine and tenofovir). All numerical variables are expressed as median (range). RESULTS: Twenty-four patients (nine women) were enrolled. The age was 45 (26-68) years. Unbound bictegravir and total emtricitabine and tenofovir CSF concentrations were 4.4 (1.6-9.6), 84.4 (28.6-337.4) and 1.6 (0.7-4.3) ng/mL, respectively. The unbound bictegravir CSF fraction was 34% (15%-82%) versus 0.33% (0.11%-0.92%) in plasma. Three patients had an IQARV above unity for the three antiretrovirals. Factors positively associated with the CSF concentration (unbound for bictegravir) were age and total plasma concentration for the three antiretrovirals. Patients aged over 51 years had higher CSF concentrations (unbound for bictegravir). CONCLUSIONS: We observed low CSF exposure to bictegravir, emtricitabine and tenofovir. These results suggest that BIC/FTC/TAF should be used with caution as first-line treatment for people living with HIV with HCI under 51 years of age.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Adenina/uso terapêutico , Idoso , Alanina/uso terapêutico , Amidas , Fármacos Anti-HIV/uso terapêutico , Cromatografia Líquida , Emtricitabina/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis , Humanos , Pessoa de Meia-Idade , Oxazinas/uso terapêutico , Piperazinas , Piridonas/uso terapêutico , Espectrometria de Massas em Tandem , Tenofovir/uso terapêuticoRESUMO
This study aimed to characterize in vitro dolutegravir (DTG) and bictegravir (BIC) binding. They had a preferential binding to human serum albumin (HSA) with two classes of albumin sites. Human alpha-1-acid glycoprotein (HAAG) binding of DTG and BIC showed an atypical nonlinear binding. The low-affinity site on HSA, the main plasma binding protein, suggests that the high protein binding rate should not impair passive diffusion.
Assuntos
Infecções por HIV , HIV-1 , Amidas , Sítios de Ligação , Compostos Heterocíclicos com 3 Anéis , Compostos Heterocíclicos de 4 ou mais Anéis , Humanos , Oxazinas , Piperazinas , Ligação Proteica , PiridonasRESUMO
BACKGROUND: High-dose rifampicin is considered to shorten anti-TB treatment duration but its effect on antiretroviral metabolism is unknown. OBJECTIVES: To assess the effect of doubling the rifampicin dose (to 20 mg/kg/day, R20) on efavirenz pharmacokinetics (PK) in HIV/TB coinfected patients. METHODS: Open-label Phase 2 drug-drug interaction randomized trial. Pulmonary TB, ART-naive adults were randomized to R20 and either efavirenz 600 mg (EFV600) or 800 mg (EFV800), or rifampicin 10 mg/kg/day (R10) and EFV600 with a 1:1:1 ratio. Patients were first started on TB treatment and 2-4 weeks later started on ART. They were switched to R10 and EFV600 after 8 weeks. Full PK sampling was done 4 weeks (on rifampicin) and 24 weeks (off rifampicin) after ART initiation. Transaminases, plasma HIV-1 RNA and sputum cultures were monitored. The efavirenz geometric mean ratio (GMR) of AUC at 4 and 24 weeks after ART initiation within the same patient was calculated in each arm and its 90% CI was compared with a preset range (0.70-1.43). RESULTS: Of 98 enrolled patients (32 in the R20EFV600 arm, 33 in the R20EFV800 arm and 33 in the R10EFV600 arm), 87 had full PK sampling. For the R20EFV600, R20EFV800 and R10EFV600 arms, GMRs of efavirenz AUC were 0.87 (90% CI: 0.75-1.00), 1.12 (90% CI: 0.96-1.30) and 0.96 (90% CI: 0.84-1.10). Twelve weeks after ART initiation, 78.6%, 77.4% and 72.4% of patients had HIV-1 RNA below 100 copies/mL and 85.7%, 86.7% and 80.0% had Week 8 culture conversion, respectively. Two patients per arm experienced a severe increase in transaminases. CONCLUSIONS: Doubling the rifampicin dose had a small effect on efavirenz concentrations and was well tolerated.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Preparações Farmacêuticas , Adulto , Alcinos , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , Ciclopropanos , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Humanos , Rifampina/uso terapêuticoRESUMO
Ceftolozane-tazobactam is considered to be a last resort treatment for infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa Although, resistance to this antimicrobial have been described in vitro, development of resistance in vivo was rarely reported. Here, we described the evolution of resistance to ceftolozane-tazobactam of P. aeruginosa isolates recovered from the same patient during recurrent infections over 2.5 years.Antimicrobial susceptibility testing results showed that 24 of the 27 P. aeruginosa isolates recovered from blood (n=18), wound (n=2), pulmonary sample (n=1), bile (n=2) and stools (n=4) of the same patient were susceptible to ceftolozane-tazobactam and ceftazidime-avibactam but resistant to ceftazidime, piperacillin-tazobactam, imipenem and meropenem. Three clinical isolates acquired resistance to ceftolozane-tazobactam and ceftazidime-avibactam along with a partial restoration of piperacillin-tazobactam and carbapenems susceptibilities. Whole genome sequencing analysis reveals that all isolates were clonally related (ST-111) with a median of 24.9 single nucleotide polymorphisms (SNPs) (range 8-48). The ceftolozane-tazobactam and ceftazidime-avibactam resistance was likely linked to the same G183D substitution in the chromosome-encoded cephalosporinase.Our results suggest resistance to ceftolozane-tazobactam in P. aeruginosa might occur in vivo upon treatment through amino-acid substitution in the intrinsic AmpC leading to ceftolozane-tazobactam and ceftazidime-avibactam resistance accompanied by re-sensitization to piperacillin-tazobactam and carbapenems.
RESUMO
PURPOSE: Direct-acting antiviral agents have demonstrated their efficacy in treating HCV recurrence after liver transplantation and particularly the sofosbuvir/daclatasvir combination. Pharmacokinetic data on both calcineurin inhibitors and direct-acting antiviral exposure in liver transplant recipients remain sparse. METHODS: Patients were enrolled from the ANRS CO23 CUPILT cohort. All patients treated with sofosbuvir/daclatasvir with or without ribavirin were included in this study when blood samples were available to estimate the clearance of immunosuppressive therapy before direct-acting antiviral initiation and during follow-up. Apparent tacrolimus and cyclosporine clearances were estimated from trough concentrations measured using validated quality control assays. RESULTS: Sixty-seven mainly male patients (79%) were included, with a mean age of 57 years and mean MELD score of 8.2; 50 were on tacrolimus, 17 on cyclosporine. Ribavirin was combined with sofosbuvir/daclatasvir in 52% of patients. Cyclosporine clearance remained unchanged as well as tacrolimus clearance under the ribavirin-free regimen. Tacrolimus clearance increased 4 weeks after direct-acting antivirals and ribavirin initiation versus baseline (geometric mean ratio 1.81; 90% CI 1.30-2.52). Patients under ribavirin had a significantly higher fibrosis stage (> 2) (p = 0.02) and lower haemoglobin during direct-acting antiviral treatment (p = 0.02) which impacted tacrolimus measurements. Direct-acting antiviral exposure was within the expected range. CONCLUSION: Our study demonstrated that liver transplant patients with a recurrence of hepatitis C who are initiating ribavirin combined with a sofosbuvir-daclatasvir direct-acting antiviral regimen may be at risk of lower tacrolimus concentrations because of probable ribavirin-induced anaemia and higher fibrosis score, although there are no effects on cyclosporine levels. TRIAL REGISTRATION: NCT01944527.
Assuntos
Antivirais/administração & dosagem , Ciclosporina/farmacocinética , Imidazóis/administração & dosagem , Imunossupressores/farmacocinética , Ribavirina/administração & dosagem , Sofosbuvir/administração & dosagem , Tacrolimo/farmacocinética , Idoso , Anemia/induzido quimicamente , Antivirais/efeitos adversos , Antivirais/sangue , Antivirais/farmacocinética , Carbamatos , Ciclosporina/administração & dosagem , Ciclosporina/sangue , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Hepatite C/tratamento farmacológico , Hepatite C/metabolismo , Humanos , Imidazóis/sangue , Imidazóis/farmacocinética , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Pirrolidinas , Ribavirina/efeitos adversos , Sofosbuvir/sangue , Sofosbuvir/farmacocinética , Tacrolimo/administração & dosagem , Tacrolimo/sangue , Valina/análogos & derivadosRESUMO
Raltegravir pharmacokinetics was studied in 20 patients included in the ANRS HC30 QUADRIH Study before and after addition of anti-hepatitis C virus (anti-HCV) quadritherapy, including pegylated-interferon-ribavirin and asunaprevir plus daclatasvir. Raltegravir pharmacokinetic parameters remained unchanged whether administered on or off anti-HCV therapy. In addition, concentrations of raltegravir, asunaprevir, and daclatasvir were not affected by liver cirrhosis. These data suggest that in human immunodeficiency virus (HIV)-HCV-coinfected patients, whether cirrhotic or not, asunaprevir and daclatasvir could be administered safely with raltegravir.
Assuntos
Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Isoquinolinas/uso terapêutico , Raltegravir Potássico/farmacocinética , Sulfonamidas/uso terapêutico , Adulto , Carbamatos , Coinfecção , Quimioterapia Combinada , Feminino , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Pirrolidinas , Raltegravir Potássico/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Valina/análogos & derivadosRESUMO
OBJECTIVES: We describe nevirapine and efavirenz exposure on and off tuberculosis treatment and consequences for virological efficacy and tolerance in patients included in the ANRS 12146/12214-CARINEMO trial. METHODS: Participants were randomly selected to receive either nevirapine at 200 mg twice daily (n = 256) or efavirenz at 600 mg daily (n = 270), both combined with two nucleoside analogues. Blood samples were drawn 12 h after nevirapine or efavirenz administration, while on tuberculosis treatment and after tuberculosis treatment discontinuation. In 62 participants, samples taken 12 h after drug administration were drawn weekly for the first month of ART. Sixteen participants participated in an extensive pharmacokinetic study of nevirapine. Concentrations were compared with the therapeutic ranges of 3000-8000 ng/mL for nevirapine and 1000-4000 ng/mL for efavirenz. RESULTS: Nevirapine concentrations at the end of the first week of treatment (on antituberculosis drugs) did not differ from concentrations off tuberculosis treatment, but declined thereafter. Concentrations at steady-state were 4111 ng/mL at week 12 versus 6095 ng/mL at week 48 (P < 0.0001). Nevirapine concentrations <3000 ng/mL were found to be a risk factor for virological failure. Efavirenz concentrations were higher on than off tuberculosis treatment (2700 versus 2450 ng/mL, P < 0.0001). CONCLUSIONS: The omission of the 2 week lead-in dose of nevirapine prevented low concentrations at treatment initiation but did not prevent the risk of virological failure. Results support the WHO recommendation to use efavirenz at 600 mg daily in patients on rifampicin-based antituberculosis therapy.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Benzoxazinas/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Nevirapina/uso terapêutico , Tuberculose/complicações , Adulto , Alcinos , Antituberculosos/uso terapêutico , Ciclopropanos , Tolerância a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Tuberculose/tratamento farmacológicoRESUMO
HIV remission can be achieved in some people, called post-treatment HIV controllers, after antiretroviral treatment discontinuation. Treatment initiation close to the time of infection was suggested to favor post-treatment control, but the circumstances and mechanisms leading to this outcome remain unclear. Here we evaluate the impact of early (week 4) vs. late (week 24 post-infection) treatment initiation in SIVmac251-infected male cynomolgus macaques receiving 2 years of therapy before analytical treatment interruption. We show that early treatment strongly promotes post-treatment control, which is not related to a lower frequency of infected cells at treatment interruption. Rather, early treatment favors the development of long-term memory CD8+ T cells with enhanced proliferative and SIV suppressive capacity that are able to mediate a robust secondary-like response upon viral rebound. Our model allows us to formally demonstrate a link between treatment initiation during primary infection and the promotion of post-treatment control and provides results that may guide the development of new immunotherapies for HIV remission.
Assuntos
Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Humanos , Masculino , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Linfócitos T CD8-Positivos , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Carga ViralRESUMO
The objective of this study was to characterize raltegravir (RAL) binding to albumin and alpha-1-acid glycoprotein (AAG). Unbound and bound RAL were separated by ultrafiltration. The association constant (Ka) was estimated by a graphical method. In HIV-infected patients, the average plasma protein binding is 76%. RAL did not bind to AAG but bound to nonsaturable, low-affinity albumin sites with an n (number of sites) · Ka product of 9.8 × 10(2) liters/mol. A pH increase of 0.2 U led to a 2% increase in the bound fraction.
Assuntos
Proteínas Sanguíneas/química , Pirrolidinonas/química , Humanos , Orosomucoide/química , Ligação Proteica , Raltegravir PotássicoRESUMO
Nevirapine is one of the most extensively prescribed antiretrovirals worldwide. The present analyses used data and specimens from two prior studies to characterize and compare plasma nevirapine phase I metabolite profiles following a single 200-mg oral dose of nevirapine in 10 HIV-negative African Americans and a steady-state 200-mg twice-daily dose in 10 HIV-infected Cambodians. Nevirapine was assayed by high-performance liquid chromatography (HPLC). The 2-, 3-, 8- and 12-hydroxy and 4-carboxy metabolites of nevirapine were assayed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Pharmacokinetic parameters were calculated by noncompartmental analysis. The metabolic index for each metabolite was defined as the ratio of the metabolite area under the concentration-time curve (AUC) to the nevirapine AUC. Every metabolite concentration was much less than the corresponding nevirapine concentration. The predominant metabolite after single dose and at steady state was 12-hydroxynevirapine. From single dose to steady state, the metabolic index increased for 3-hydroxynevirapine (P < 0.01) but decreased for 2-hydroxynevirapine (P < 0.001). The 3-hydroxynevirapine metabolic index was correlated with nevirapine apparent clearance (P < 0.001). These findings are consistent with induction of CYP2B6 (3-hydroxy metabolite) and a possible inhibition of CYP3A (2-hydroxy metabolite), although these are preliminary data. There were no such changes in metabolic indexes for 12-hydroxynevirapine or 4-carboxynevirapine. Two subjects with the CYP2B6 *6*6 genetic polymorphism had metabolic indexes in the same range as other subjects. These results suggest that nevirapine metabolite profiles change over time under the influence of enzyme induction, enzyme inhibition, and host genetics. Further work is warranted to elucidate nevirapine biotransformation pathways and implications for drug efficacy and toxicity.
Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , Nevirapina/farmacocinética , Adulto , Negro ou Afro-Americano , Fármacos Anti-HIV/sangue , Área Sob a Curva , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Povo Asiático , Biotransformação , Estudos de Casos e Controles , Cromatografia Líquida , Citocromo P-450 CYP2B6 , Esquema de Medicação , Feminino , Infecções por HIV/etnologia , Infecções por HIV/microbiologia , HIV-1/efeitos dos fármacos , Humanos , Masculino , Nevirapina/sangue , Oxirredutases N-Desmetilantes/genética , Oxirredutases N-Desmetilantes/metabolismo , Polimorfismo Genético , Espectrometria de Massas em TandemRESUMO
The adherence profile of HIV-infected patients predicts the therapeutic outcome, in particular during the early phase of antiretroviral therapy (ART). We conducted a prospective observational multicenter trial monitoring adherence and virological and immunological parameters over the initial 6 months of treatment. Thirty-five subjects were starting a treatment regimen including atazanavir, ritonavir, and emtricitabine-tenofovir. Adherence was assessed using self-completed questionnaires, announced pill counts, and the medication event monitoring system (MEMS) for each drug. Three MEMS measures were defined: the percentages of doses taken, days with the correct dosing, and doses taken on time (± 3 h). Dynamic virological suppression (DVS) was defined as a reduction in the plasma HIV-RNA level of >1 log10 per month or <40 copies/ml. The cumulative treatment time was 5,526 days. A high level of adherence was observed. The MEMS-defined adherence for correct dosing (-0.68% per 4-week period, P < 0.03) and timing compliance (-1.60% per 4-week period, P < 0.003) decreased significantly over time. The MEMS-defined adherence data were concordant with the pill counts during the trial but not with the data from the questionnaires. The median [range] percentages of doses taken (100% [50 to 102]), days with the correct dosing (95% [41 to 100]), and doses taken on time (86% [32 to 100]) were significantly associated with DVS in separate models. Among these three measures, the percentage of doses taken on time had the greatest ability to predict DVS. Timing compliance should be supported to optimize DVS during the early phase of treatment by once-daily boosted protease inhibitor-based ART. (This study has been registered at ClinicalTrials.gov under registration no. NCT00528060.).
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Oligopeptídeos/uso terapêutico , Organofosfonatos/uso terapêutico , Piridinas/uso terapêutico , Ritonavir/uso terapêutico , Adenina/uso terapêutico , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade , Sulfato de Atazanavir , Contagem de Linfócito CD4 , Desoxicitidina/uso terapêutico , Esquema de Medicação , Emtricitabina , Feminino , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Tenofovir , Carga Viral/efeitos dos fármacosAssuntos
Colchicina/uso terapêutico , Ciclosporina/uso terapêutico , Interações Medicamentosas , Rejeição de Enxerto/prevenção & controle , Transplante de Rim/métodos , Complicações Pós-Operatórias/prevenção & controle , Tacrolimo/uso terapêutico , Quimioterapia Combinada , Rejeição de Enxerto/diagnóstico , Humanos , Imunossupressores/uso terapêutico , Falência Renal Crônica/cirurgia , Complicações Pós-Operatórias/diagnóstico , Prognóstico , Transplante HomólogoRESUMO
AIMS: The aims were to estimate the mycophenolic acid (MPA) population pharmacokinetic parameters in paediatric liver transplant recipients, to identify the factors affecting MPA pharmacokinetics and to develop a limited sampling strategy to estimate individual MPA AUC(0,12 h). METHODS: Twenty-eight children, 1.1 to 18.0 years old, received oral mycophenolate mofetil (MMF) therapy combined with either tacrolimus (n= 23) or ciclosporin (n= 5). The population parameters were estimated from a model-building set of 16 intensive pharmacokinetic datasets obtained from 16 children. The data were analyzed by nonlinear mixed effect modelling, using a one compartment model with first order absorption and first order elimination and random effects on the absorption rate (k(a)), the apparent volume of distribution (V/F) and apparent clearance (CL/F). RESULTS: Two covariates, time since transplantation (≤ and >6 months) and age affected MPA pharmacokinetics. k(a), estimated at 1.7 h(-1) at age 8.7 years, exhibited large interindividual variability (308%). V/F, estimated at 64.7 l, increased about 2.3 times in children during the immediate post transplantation period. This increase was due to the increase in the unbound MPA fraction caused by the low albumin concentration. CL/F was estimated at 12.7 l h(-1). To estimate individual AUC(0,12 h), the pharmacokinetic parameters obtained with the final model, including covariates, were coded in Adapt II(®) software, using the Bayesian approach. The AUC(0,12 h) estimated from concentrations measured 0, 1 and 4 h after administration of MMF did not differ from reference values. CONCLUSIONS: This study allowed the estimation of the population pharmacokinetic MPA parameters. A simple sampling procedure is suggested to help to optimize pediatric patient care.
Assuntos
Imunossupressores/farmacocinética , Transplante de Fígado , Modelos Biológicos , Ácido Micofenólico/análogos & derivados , Administração Oral , Adolescente , Fatores Etários , Área Sob a Curva , Teorema de Bayes , Criança , Pré-Escolar , Ciclosporina/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/administração & dosagem , Lactente , Masculino , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/farmacocinética , Dinâmica não Linear , Tacrolimo/administração & dosagem , Distribuição TecidualRESUMO
The development of animal models undergoing long-term antiretroviral treatment (ART) makes it possible to understand a number of immunological, virological, and pharmacological issues, key factors in the management of HIV infection. We aimed to pharmacologically validate a non-human primate (NHP) model treated in the long term with antiretroviral drugs after infection with the pathogenic SIVmac251 strain. A single-dose pharmacokinetic study of tenofovir disoproxil fumarate, emtricitabine, and dolutegravir was first conducted on 13 non-infected macaques to compare three different routes of administration. Then, 12 simian immunodeficiency virus (SIV)-infected (SIV+) macaques were treated with the same regimen for two years. Drug monitoring, virological efficacy, and safety were evaluated throughout the study. For the single-dose pharmacokinetic study, 24-h post-dose plasma concentrations for all macaques were above or close to 90% inhibitory concentrations and consistent with human data. During the two-year follow-up, the pharmacological data were consistent with those observed in humans, with low inter- and intra-individual variability. Rapid and sustained virological efficacy was observed for all macaques, with a good safety profile. Overall, our SIV+ NHP model treated with the ART combination over a two-year period is suitable for investigating the question of pharmacological sanctuaries in HIV infection and exploring strategies for an HIV cure.
RESUMO
During chronic SIV/HIV infection, adipose tissue (AT) is the target of both antiretroviral treatment (ART) and the virus. AT might subsequently contribute to the low-grade systemic inflammation observed in patients on ART. To evaluate the inflammatory profile of AT during chronic SIV/HIV infection, we assayed subcutaneous and visceral abdominal AT from non-infected (SIV-, control), ART-naïve SIV-infected (SIV+) and ART-controlled SIV-infected (SIV+ART+) cynomolgus macaques for the mRNA expression of genes coding for factors related to inflammation. Significant differences were observed only when comparing the SIV+ART+ group with the SIV+ and/or SIV- groups. ART-treated infection impacted the metabolic fraction (with elevated expression of PPARγ and CEBPα), the extracellular matrix (with elevated expression of COL1A2 and HIF-1α), and the inflammatory profile. Both pro- and anti-inflammatory signatures were detected in AT, with greater mRNA expression of anti-inflammatory markers (adiponectin and CD163) and markers associated with inflammation (TNF-α, Mx1, CCL5 and CX3CL1). There were no intergroup differences in other markers (IL-6 and MCP-1). In conclusion, we observed marked differences in the immune and metabolic profiles of AT in the context of an ART-treated, chronic SIV infection; these differences were related more to ART than to SIV infection per se.
Assuntos
Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Adiponectina , Tecido Adiposo/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , HIV , Inflamação/complicações , Interleucina-6 , Macaca fascicularis , Macaca mulatta , PPAR gama , RNA Mensageiro/uso terapêutico , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Fator de Necrose Tumoral alfaRESUMO
For people living with HIV, treatment with integrase-strand-transfer-inhibitors (INSTIs) can promote adipose tissue (AT) gain. We previously demonstrated that INSTIs can induce hypertrophy and fibrosis in AT of macaques and humans. By promoting energy expenditure, the emergence of beige adipocytes in white AT (beiging) could play an important role by limiting excess lipid storage and associated adipocyte dysfunction. We hypothesized that INSTIs could alter AT via beiging inhibition. Fibrosis and gene expression were measured in subcutaneous (SCAT) and visceral AT (VAT) from SIV-infected, dolutegravir-treated (SIVART) macaques. Beiging capacity was assessed in human adipose stromal cells (ASCs) undergoing differentiation and being exposed to dolutegravir, bictegravir, or raltegravir. Expression of beige markers, such as positive-regulatory-domain-containing-16 (PRDM16), were lower in AT of SIVART as compared to control macaques, whereas fibrosis-related genes were higher. Dolutegravir and bictegravir inhibited beige differentiation in ASCs, as shown by lower expression of beige markers and lower cell respiration. INSTIs also induced a hypertrophic insulin-resistant state associated with a pro-fibrotic phenotype. Our results indicate that adipocyte hypertrophy induced by INSTIs is involved via hypoxia (revealed by a greater hypoxia-inducible-factor-1-alpha gene expression) in fat fibrosis, beiging inhibition, and thus (via positive feedback), probably, further hypertrophy and associated insulin resistance.
Assuntos
Inibidores de Integrase de HIV , Resistência à Insulina , Adipócitos/metabolismo , Tecido Adiposo , Amidas , Fibrose , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Hipertrofia/metabolismo , Hipóxia/metabolismo , Oxazinas , Piperazinas , PiridonasRESUMO
We compared tipranavir and darunavir concentrations measured at steady state in 20 human immunodeficiency virus (HIV)-infected patients enrolled in the EASIER-ANRS 138 clinical trial who switched from enfuvirtide to raltegravir while maintaining the same background regimen. The geometric mean ratios of the observed predose concentration (C(trough)), maximum concentration of drug observed in plasma (C(max)), and area under the plasma concentration-time curve (AUC) before (day 0) and after (week 24) the switch were 0.49, 0.76, and 0.67 and 0.82, 0.68, and 0.64 for tipranavir and darunavir, respectively. The virologic consequences of these drug interactions have yet to be determined.