Randomised pharmacokinetic trial of rifabutin with lopinavir/ritonavir-antiretroviral therapy in patients with HIV-associated tuberculosis in Vietnam.

BACKGROUND: Rifampicin and protease inhibitors are difficult to use concomitantly in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there is concern that the current recommended dose is suboptimal. The principal aim of this study was to compare bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in patients with HIV-associated tuberculosis who initiated lopinavir/ritonavir-based antiretroviral therapy in Vietnam. Concentrations of lopinavir/ritonavir were also measured. METHODS: This was a randomized, open-label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis in Ho Chi Minh City (Clinical trial registry number NCT00651066). Rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir -based antiretroviral therapy using patient randomization lists. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after 2 weeks of rifabutin 300 mg daily, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir. RESULTS: Sixteen and seventeen patients were respectively randomized to the two arms, and pharmacokinetic analysis carried out in 12 and 13 respectively. Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2 - 5 fold increases of the 25-O-desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations. CONCLUSIONS: Based on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00651066

Niveau de preuve du suivi thérapeutique pharmacologique du lopinavir

Le lopinavir, inhibiteur de la protéase du virus de l’immunodéficience humaine (VIH), présente une variabilité pharmacocinétique importante, du fait d’un métabolisme hépatique et intestinal par le CYP3A. Les données de la littérature ont été analysées pour évaluer le niveau de preuve du suivi thérapeutique du lopinavir. Chez les patients naïfs ou prétraités, la relation entre concentrations et efficacité virologique n’a pas été mise en évidence, les concentrations obtenues chez un patient adhérent sont probablement supérieures aux concentrations virales inhibitrices. La survenue d’hyperlipidémie semble associée à des concentrations résiduelles de lopinavir > 8 000 ng/mL. Ces données permettent de proposer un niveau de preuve pour le suivi thérapeutique du lopinavir, recommandé chez les enfants, la femme enceinte, les patients en échec virologique, sous réserve que le nombre de mutations sur la protéase du virus soit < 5, en cas d’association avec des inducteurs enzymatiques, et en cas de toxicité

Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study

International audienceBackground and Objective Mycophenolate mofetil is widely used in kidney transplant recipients. Mycophenolate mofetil is hydrolysed by blood esterases to mycophenolic acid (MPA), the active drug. Although MPA therapeutic drug monitoring has been recommended to optimise the treatment efficacy by the area under the plasma concentration vs time curve, little is known regarding MPA concentrations in peripheral blood mononuclear cells, where MPA inhibits inosine monophosphate dehydrogenase. This study aimed to build a pharmacokinetic model using a population approach to describe MPA total and unbound concentrations in plasma and into peripheral blood mononuclear cells in 78 adult kidney transplant recipients receiving mycophenolate mofetil therapy combined with tacrolimus and prednisone. Methods Total and unbound plasma concentrations and peripheral blood mononuclear cell concentrations were assayed. A three-compartment model, two for plasma MPA and one for peripheral blood mononuclear cell MPA, with a zero-order absorption and a first-order elimination was used to describe the data. Results Mycophenolic acid average concentrations in peripheral blood mononuclear cells were well above half-maximal effective concentration for inosine monophosphate dehydrogenase and no relationship was found with the occurrence of graft rejection. Three covariates affected unbound and intracellular MPA pharmacokinetics: creatinine clearance, which has an effect on unbound MPA clearance, human serum albumin, which influences fraction unbound MPA and theABCB1 3435 C>T(rs1045642) genetic polymorphism, which has an effect on MPA efflux transport from peripheral blood mononuclear cells. Conclusion This population pharmacokinetic model demonstrated the intracellular accumulation of MPA, the efflux of MPA out of the cells being dependent on P-glycoprotein transporters. Nevertheless, further studies are warranted to investigate the relevance of MPA concentrations in peripheral blood mononuclear cells to dosing regimen optimisation

Pharmacological Validation of Long-Term Treatment with Antiretroviral Drugs in a Model of SIV-Infected Non-Human Primates

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

Specific Biological Features of Adipose Tissue, and Their Impact on HIV Persistence

International audienceAlthough white AT can contribute to anti-infectious immune responses, it can alsobe targeted and perturbed by pathogens. The AT’s immune involvement is primarilydue to strong pro-inflammatory responses (with both local and paracrine effects),and the large number of fat-resident macrophages. Adipocytes also exert directantimicrobial responses. In recent years, it has been found that memory T cellsaccumulate in AT, where they provide efficient secondary responses against viralpathogens. These observations have prompted researchers to re-evaluate the linksbetween obesity and susceptibility to infections. In contrast, AT serves as a reservoirfor several persistence pathogens, such as human adenovirus Ad-36,Trypanosomagondii,Mycobacterium tuberculosis, influenza A virus, and cytomegalovirus (CMV). Thepresence and persistence of bacterial DNA in AT has led to the concept of a tissue-specific microbiota. The unexpected coexistence of immune cells and pathogens withinthe specific AT environment is intriguing, and its impact on anti-infectious immuneresponses requires further evaluation. AT has been recently identified as a site ofHIV persistence. In the context of HIV infection, AT is targeted by both the virusand the antiretroviral drugs. AT’s intrinsic metabolic features, large overall mass, andwide distribution make it a major tissue reservoir, and one that may contribute to thepathophysiology of chronic HIV infections. Here, we review the immune, metabolic, viral,and pharmacological aspects that contribute to HIV persistence in AT. We also evaluatethe respective impacts of both intrinsic and HIV-induced factors on AT’s involvement asa viral reservoir. Lastly, we examine the potential consequences of HIV persistence onthe metabolic and immune activities of AT

Effect of adherence as measured by MEMS, ritonavir boosting, and CYP3A5 genotype on atazanavir pharmacokinetics in treatment-naive HIV-infected patients.

International audienceWe investigated population pharmacokinetics and pharmacogenetics of ritonavir-boosted atazanavir (ATV), using drug intake times exactly recorded by the Medication Event Monitoring System. The ANRS 134-COPHAR 3 trial was conducted in 35 HIV-infected treatment-naive patients. ATV (300 mg), ritonavir (100 mg), and tenofovir (300 mg) + emtricitabine (200 mg), in bottles with MEMS caps, were taken once daily for 6 months. Six blood samples were collected at week 4 to measure drug concentrations, and trough levels were measured bimonthly. A model integrating ATV and ritonavir pharmacokinetics and pharmacogenetics used nonlinear mixed effects. Use of exact dosing data halved unexplained variability in ATV clearance. The ritonavir-ATV interaction model suggested that optimal boosting effect is achievable at lower ritonavir exposures. Patients with at least one copy of the CYP3A5*1 allele exhibited 28% higher oral clearance. We provide evidence that variability in ATV pharmacokinetics is defined by adherence, CYP3A5 genotype, and ritonavir exposure