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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.
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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.
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Fármacos Anti-VIH , Infecciones por VIH , Animales , Fármacos Anti-VIH/uso terapéutico , Cromatografía Liquida/métodos , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Ratones , Oxazinas , Piperazinas , Piridonas , Espectrometría de Masas en Tándem/métodos , Tenofovir/uso terapéutico , Distribución TisularRESUMEN
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.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adenina/uso terapéutico , Anciano , Alanina/uso terapéutico , Amidas , Fármacos Anti-VIH/uso terapéutico , Cromatografía Liquida , Emtricitabina/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Humanos , Persona de Mediana Edad , Oxazinas/uso terapéutico , Piperazinas , Piridonas/uso terapéutico , Espectrometría de Masas en Tándem , Tenofovir/uso terapéuticoRESUMEN
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.
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Infecciones por VIH , VIH-1 , Amidas , Sitios de Unión , Compuestos Heterocíclicos con 3 Anillos , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Oxazinas , Piperazinas , Unión Proteica , PiridonasRESUMEN
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.
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Infecciones por VIH , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Humanos , Masculino , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Linfocitos T CD8-positivos , Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Carga ViralRESUMEN
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.
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A sensitive and rapid ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated for 14 antiretroviral drugs and 2 boosters in human plasma. Plasma (100⯵L) was precipitated with a solution of acetonitrile containing labelled internal standards. The compounds were separated with a total chromatic run time of 6â¯min using an Acclaim TM RSLC 120 C18 column (2.1â¯×â¯100â¯mm, 2.2⯵m). The method was fully validated according to the European Medecines Agency guidelines. Linearity of all analytes concentrations was validated up to 5000â¯ng/mL. Lower limits of quantification were ranged from 2.5â¯ng/mL to 10â¯ng/mL according to compounds. Intra-day and inter-day precision ranged from 0.2% to 8.9% and accuracies were below 13%. This UPLC-MS/MS method can be applied to clinical pharmacology research and therapeutic drug monitoring in patients living with HIV.