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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.

We regret that this article is behind a paywall., 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.

Background 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 the ABCB1 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. Electronic supplementary material The online version of this article (10.1007/s40268-020-00319-y) contains supplementary material, which is available to authorized users.

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.

Background Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (MPS) is now commonly used in pediatric intestinal transplantation (Tx), but to date, no clear recommendations regarding the dosing regimen have been made in this population. The aim of this study was to determine the MMF/MPS dosage required to achieve an area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12) for mycophenolic acid (MPA) greater than 30 mg·h·L in children after intestinal transplantation. Methods A pharmacokinetic study was conducted in 8 children (median, 9.4 years; range, 0.75-15.8 years) at a median time of 113 months (range, 1.5-160 months) after intestinal transplantation. Results MMF was initially introduced at a low median starting dose of 687 mg·m·d (range, 310-1414 mg·m·d). One of the 3 patients who received MPS and 2 of the 6 patients who received MMF had an MPA AUC0-12 value below 30 mg.h.L. The median MMF dosage had to be increased by 91% (1319 mg·m·d versus 687 mg·m·d) to reach AUC0-12 values above the defined target level of 30 mg·h·L. Conclusions When used in combination with tacrolimus and steroids, an initial MMF dose of 600 mg/m twice a day would be recommended to children after intestinal transplantation to achieve MPA exposure similar to those observed in adults and children after the transplantation of other organs. Further studies are required to recommend a suitable dosage for pediatric intestinal transplant recipients who receive MPA.

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 μL) was precipitated with a solution of acetonitrile containing labelled internal standards. The compounds were separated with a total chromatic run time of 6 min using an Acclaim TM RSLC 120 C18 column (2.1 × 100 mm, 2.2 μm). The method was fully validated according to the European Medecines Agency guidelines. Linearity of all analytes concentrations was validated up to 5000 ng/mL. Lower limits of quantification were ranged from 2.5 ng/mL to 10 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.

Summary Background Mucopolysaccharidosis type IIIB syndrome (also known as Sanfilippo type B syndrome) is a lysosomal storage disease resulting in progressive deterioration of cognitive acquisition after age 2–4 years. No treatment is available for the neurological manifestations of the disease. We sought to assess the safety and efficacy of a novel intracerebral gene therapy. Methods Local regulatory authorities in France allowed inclusion of up to four children in this phase 1/2 study. Treatment was 16 intraparenchymal deposits (four in the cerebellum) of a recombinant adenoassociated viral vector serotype 2/5 (rAAV2/5) encoding human α-N-acetylglucosaminidase (NAGLU) plus immunosuppressive therapy. We assessed tolerance, neurocognitive progression, brain growth, NAGLU enzymatic activity in CSF, and specific anti-NAGLU immune response for 30 months after surgery. This trial is registered with EudraCT, number 2012-000856-33, and the International Standard Clinical Trial Registry, number ISRCTN19853672. Findings Of seven eligible children, the four youngest, from France (n=2), Italy (n=1), and Greece (n=1), aged 20, 26, 30, and 53 months, were included between February, 2012, and February, 2014. 125 adverse events were recorded, of which 117 were treatment emergent and included six classified as severe, but no suspected unexpected serious adverse drug reactions were seen. Vector genomes were detected in blood for 2 days after surgery. Compared with the natural history of mucopolysaccharidosis type III syndromes, neurocognitive progression was improved in all patients, with the youngest patient having function close to that in healthy children. Decrease in developmental quotient was −11·0 points in patient one, −23·0 in patient two, −29·0 in patient three, and −17·0 in patient four, compared with −37·7 in the natural history of the disease. NAGLU activity was detected in lumbar CSF and was 15–20% of that in unaffected children. Circulating T lymphocytes that proliferated and produced tumour necrosis factor α upon ex-vivo exposure to NAGLU antigens were detectable at 1–12 months and 3–12 months, respectively, but not at 30 months in three of four patients. Interpretation Intracerebral rAVV2/5 was well tolerated and induced sustained enzyme production in the brain. The initial specific anti-NAGLU immune response that later subsided suggested acquired immunological tolerance. The best results being obtained in the youngest patient implies a potential window of opportunity. Longer follow-up is needed to further assess safety outcomes and persistence of improved cognitive development. Funding Association Francaise Contre les Myopathies, Vaincre les Maladies Lysosomales, Institut Pasteur, and UniQure.

BACKGROUND Few direct anti-hepatitis C virus (HCV) agents have been studied in difficult-to-treat null responder and cirrhotic human immunodeficiency virus (HIV)-coinfected patients. Daclatasvir and asunaprevir combined with pegylated interferon/ribavirin (peg-IFN/RBV) have shown promising results in HCV-monoinfected patients. METHODS An open-label, single-arm, phase 2 study was conducted in HIV/HCV genotype 1/4-coinfected patients who were null responders to prior peg-IFN/RBV standard therapy and on a raltegravir-based regimen with HIV RNA

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.

Introduction Le syndrome nephrotique idiopathique (SNi) constitue la glomerulopathie acquise la plus frequente responsable de plus 90 % des SN chez l’adulte. Son traitement repose en premiere intention sur la corticotherapie prolongee a fortes doses. En cas d’echec, l’ajout d’immunosuppresseurs (IS) plus specifiquement la ciclosporine represente une alternative. Le tacrolimus a montre, dans un nombre limite d’etudes et en association aux corticoides, son interet dans le SNi. Nous rapportons le cas d’un patient atteint d’un SNi traite par le tacrolimus en monotherapie. Materiels et methode M. X. (42 ans) a developpe un SNi impur confirme cliniquement par un syndrome œdemateux, une hypertension arterielle et biologiquement par une proteinurie a 8,4 g/24 h, une hypoalbuminemie a 20 g/L, une hypoprotidemie a 41 g/L et une hematurie. Il presente une complication, une dyslipidemie. Apres un traitement symptomatique par le furosemide, le ramipril et l’atorvastatine, le patient a recu dans un premier temps du rituximab (8 doses a 375 mg/m2), puis du tacrolimus a la dose initiale de 0,10 mg/kg/j. La dose de tacrolimus a ete adaptee en fonction des concentrations residuelles sanguines (cibles 8 a 10 ng/mL) mesurees par electrochimiluminescence. Les parametres biologiques ont ete etudies pendant toute la periode de suivi du patient (8 mois). Resultats et discussion Le traitement par rituximab a conduit a une remission partielle de la proteinurie (diminution de 21 %). Un mois apres l’initiation de la monotherapie par tacrolimus, la proteinurie a diminue de 83 % et est passee a 1,4 g/24 h. La concentration residuelle du tacrolimus etait alors a 7,2 ng/mL. Apres une remontee de la proteinurie a 2,94 g/24 h suite a un probleme d’adhesion au traitement (tacrolimus sanguin indetectable), la posologie du tacrolimus a ete augmentee a 0,18 mg/kg/j et la concentration a atteint une valeur superieure a la cible (12 ng/mL). La proteinurie a ensuite rediminue et s’est stabilisee a 1,3 g/24 h. La concentration elevee du tacrolimus a conduit a une hyperkaliemie, effet indesirable concentration-dependant de cet IS, traitee par kayexalate. Devant une reponse clinique tres favorable, apres evaluation du rapport benefice/risque, il a ete decide de poursuivre le tacrolimus a cette concentration cible de 12 ng/mL. La decision d’utiliser le tacrolimus sans corticotherapie plutot que la ciclosporine etait de limiter les effets indesirables de la corticotherapie et l’hypertrophie gingivale et l’hirsutisme specifiques de la ciclosporine. Conclusion L’interet du cas clinique presente ici, est le traitement inhabituel du SNi par tacrolimus sans association aux corticoides. Apres induction par le rituximab, le tacrolimus a montre son efficacite prouvee par une diminution de 85 % de la proteinurie et la disparition des signes cliniques. Cependant, des etudes complementaires restent necessaires pour evaluer l’efficacite et la tolerance du tacrolimus a long terme et de determiner une cible therapeutique.