Author: "Minh Patrick Lê" - Searchworks@Jio Institute Digital Library Search Results

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1. A case of tuberculosis and black-grain eumycetoma co-infection in a non-endemic country: clinical presentation and therapeutic management

Author: Sonia Vu, Nicolas Belaube, Ana Canestri, Michel Develoux, Alicia Moreno, Eric Fourniols, Minh Patrick Lê, Ludovic Lassel, Gilles Pialoux, and Ruxandra Calin
Subjects: Mycetoma, Black-grain eumycetoma, Tuberculosis, Therapeutic drug monitoring, Infectious and parasitic diseases, RC109-216
Abstract: We report a case of black-grain eumycetoma co-localized with Mycobacterium tuberculosis infection, presenting as a painless leg abscess and associated with vertebral tuberculosis. The rare association of these two pathogens raises several challenges regarding foreseeable drug interactions, side effects, the most appropriate management, and the potential link between these two diseases.
Published: 2021
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2. Placental transfer of Letermovir & Maribavir in the ex vivo human cotyledon perfusion model. New perspectives for in utero treatment of congenital cytomegalovirus infection.

Author: Valentine Faure Bardon, Gilles Peytavin, Minh Patrick Lê, Tiffany Guilleminot, Elisabeth Elefant, Julien Stirnemann, Marianne Leruez-Ville, and Yves Ville
Subjects: Medicine, Science
Abstract: BACKGROUND:Congenital cytomegalovirus infection can lead to severe sequelae. When fetal infection is confirmed, we hypothesize that fetal treatment could improve the outcome. Maternal oral administration of an effective drug crossing the placenta could allow fetal treatment. Letermovir (LMV) and Maribavir (MBV) are new CMV antivirals, and potential candidates for fetal treatment. METHODS:The objective was to investigate the placental transfer of LMV and MBV in the ex vivo method of the human perfused cotyledon. Term placentas were perfused, in an open-circuit model, with LMV or MBV at concentrations in the range of clinical peak plasma concentrations. Concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. Mean fetal transfer rate (FTR) (fetal (FC) /maternal concentration), clearance index (CLI), accumulation index (AI) (retention of each drug in the cotyledon tissue) were measured. Mean FC were compared with half maximal effective concentrations of the drugs (EC50(LMV) and EC50(MBV)). RESULTS:For LMV, the mean FC was (± standard deviation) 1.1 ± 0.2 mg/L, 1,000-fold above the EC50(LMV). Mean FTR, CLI and AI were 9 ± 1%, 35 ± 6% and 4 ± 2% respectively. For MBV, the mean FC was 1.4 ± 0.2 mg/L, 28-fold above the EC50(MBV). Mean FTR, CLI and AI were 10 ± 1%, 50 ± 7% and 2 ± 1% respectively. CONCLUSIONS:Drugs' concentrations in the fetal side should be in the range for in utero treatment of fetuses infected with CMV as the mean FC was superior to the EC50 for both molecules.
Published: 2020
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3. Use of PCR Signal and Therapeutic Drug Monitoring in a Switch Cohort Study to Tenofovir/Emtricitabine/Rilpivirine: A W96 Follow-Up.

Author: Charlotte Charpentier, Minh Patrick Lê, Véronique Joly, Benoit Visseaux, Sylvie Lariven, Bao Phung, Patrick Yéni, Yazdan Yazdanpanah, Diane Descamps, Gilles Peytavin, and Roland Landman
Subjects: Medicine, Science
Abstract: To assess, in a clinical cohort, the efficacy of switching treatment in virologically-suppressed patients to tenofovir/emtricitabine/rilpivirine as a single-tablet regimen (STR) using the PCR signal of the viral load (VL) assay and plasma drug determination (C24h).An observational single-centre study enrolling patients with VL50 ng/mL, the target effective concentration.In this clinical cohort of virologically-suppressed patients switching to a new STR, most subjects had adequate rilpivirine C24h and displayed a high level of virological suppression with no residual viremia until W96.
Published: 2015
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4. Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial

Author: Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, Julien Poissy, Drifa Belhadi, Alpha Diallo, Christelle Delmas, Juliette Saillard, Aline Dechanet, Claire Fougerou, Minh-Patrick Lê, Gilles Peytavin, Noémie Mercier, Priyanka Velou, Sarah Tubiana, Xavier Lescure, Emmanuel Faure, Saad Nseir, Jean-Christophe Richard, Florent Wallet, François Goehringer, Benjamin Lefèvre, Antoine Kimmoun, François Raffi, Benjamin Gaborit, Jean Reignier, Jean-Philippe Lanoix, Claire Andrejak, Yoann Zerbib, Firouzé Bani-Sadr, Bruno Mourvilliers, François Danion, Yvon Ruch, Raphaël Clere-Jehl, Vincent Le Moing, Kada Klouche, Karine Lacombe, Guillaume Martin-Blondel, Fanny Vardon-Bounes, André Cabié, Jean-Marie Turmel, Lionel Piroth, Mathieu Blot, Élisabeth Botelho-Nevers, Amandine Gagneux-Brunon, Guillaume Thiery, François Bénézit, Rostane Gaci, Joy Mootien, Sébastien Gallien, Denis Garot, Kevin Bouiller, Loïc Epelboin, Stéphane Jauréguiberry, Alexandre Gaymard, Gil Verschelden, Sandra Braz, Joao Miguel Ferreira Ribeiro, Michael Joannidis, Thérèse Staub, Antoine Altdorfer, Richard Greil, Alexander Egle, Jérémie Guedj, Marion Noret, Roberto Roncon-Albuquerque, Jose-Artur Paiva, Bruno Lina, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, France Mentré, Hospices Civils de Lyon (HCL), Université libre de Bruxelles (ULB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle de Recherche Clinique [Paris] (PRC), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), and Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie
Subjects: [SDV]Life Sciences [q-bio]
Abstract: BackgroundThe antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring.MethodsIn this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-β-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.FindingsBetween March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420).At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29).InterpretationRemdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15.FundingEuropean Union Commission, French Ministry of Health, DIM One Health Île-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER “European Regional Development Fund”, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead.
Published: 2023

5. Comment on: Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV

Author: Sihem Benaboud, Caroline Solas, Stephane Bouchet, Matthieu Gregoire, Florian Lemaitre, Nicolas Venisse, Minh Patrick Lê, Patrice Muret, Francois Parant, Nadege Neant, Sana Boujafaar, Jennifer Lagoutte-Renosi, Rodolphe Garraffo, Gilles Peytavin, Pharmacologie et évaluations thérapeutiques chez l'enfant et la femme enceinte (URP_7323), Université Paris Cité (UPCité), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cibles et Médicaments des Infections et de l'Immunité (IICiMed), Nantes Université - UFR des Sciences Pharmaceutiques et Biologiques (Nantes Univ - UFR Pharmacie), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Nice (CHU Nice), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord
Subjects: Pharmacology, Microbiology (medical), Infectious Diseases, [SDV]Life Sciences [q-bio], Pharmacology (medical)
Abstract: International audience
Published: 2023
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6. HIV-1 RNA Kinetics in Blood Plasma and in Seminal Plasma of Men Starting a Dolutegravir-Based Triple-Combination Regimen at the Time of Primary HIV-1 Infection

Author: Jade Ghosn, Robert Nzalakanda, Marie-Laure Chaix, Karine Amat, Roland Landman, Constance Delaugerre, Caroline Lascoux-Combe, Minh Patrick Lê, Lambert Assoumou, Gilles Peytavin, Audrey Gabassi, and Nadia Valin
Subjects: Adult, Male, medicine.medical_specialty, Anti-HIV Agents, Pyridones, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, Primary HIV infection, Gastroenterology, Piperazines, Hiv 1 rna, chemistry.chemical_compound, Semen, Internal medicine, Oxazines, Blood plasma, Triple combination, Humans, Immunology and Allergy, Medicine, business.industry, Middle Aged, Viral Load, Kinetics, Regimen, Infectious Diseases, Drug concentration, chemistry, Dolutegravir, HIV-1, RNA, Viral, business, Heterocyclic Compounds, 3-Ring
Abstract: We compared the proportion of participants achieving first undetectable HIV-1 RNA (VL) in seminal plasma (SP) and blood plasma (BP) in 19 men starting dolutegravir-based regimen at primary HIV infection. At baseline, median VL was 6.5 (interquartile range [IQR], 5.6–7.9) and 4.5 (IQR, 3.5–5.0) log10 copies/mL in BP and SP, respectively. Between baseline and week 48, significantly higher proportion of participants achieved first VL below limit of quantification in SP (93.0%) than in BP (84.2%; P = .008). Time to first undetectable VL was 8 weeks in SP (95% confidence interval [CI], 5.6–10.4) and 24 weeks in BP (95% CI, 14.1–33.9).
Published: 2021
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7. Placental transfer of doravirine, a recent HIV-1 NNRTI in the ex vivo human cotyledon perfusion model

Author: Laurent Mandelbrot, Florian Bouchet-Crivat, Lucile Pencolé, Gilles Peytavin, and Minh Patrick Lê
Subjects: 0301 basic medicine, Microbiology (medical), food.ingredient, Pyridones, Placenta, 030106 microbiology, Andrology, 03 medical and health sciences, chemistry.chemical_compound, food, Pregnancy, Doravirine, Humans, Medicine, Pharmacology (medical), Transfer technique, Maternal-Fetal Exchange, Pharmacology, Fetus, business.industry, Triazoles, medicine.disease, 030112 virology, Perfusion, Infectious Diseases, medicine.anatomical_structure, chemistry, HIV-1, business, Cotyledon, Ex vivo
Abstract: Background The recent HIV-1 NNRTI doravirine is likely to be used in pregnant women despite the complete lack of data on safety and exposure in the fetus. The objective of this study was to determine its placental transfer. Methods Maternal-to-fetal transfer was investigated using the open-circuit ex vivo dually perfused human cotyledon model. Doravirine was added to a maternal perfusate (theoretical doravirine concentration of 250 ng/mL) containing 2 g/L human albumin and 20 g/L antipyrine, a marker to validate the cotyledon’s viability, and cotyledons were dually perfused for up to 90 min. Results In five experiments, the median (IQR) doravirine concentrations in the maternal and fetal compartments were, respectively, 303 (178–420) and 40 (30–54) ng/mL, the fetal-to-maternal ratio was 16% (12%–18%) and the clearance index (in comparison with antipyrine transfer) was 48% (35%–64%). The median accumulation index in cotyledon tissue was 39% (range 10%–66%). Conclusions Doravirine both crosses and accumulates in the placenta. This may be useful as pre/post-exposure prophylaxis to reduce the risk of vertical HIV transmission but carries the potential for fetal toxicities. Further investigation is required to determine the safety and efficacy of this new antiretroviral agent in pregnancy.
Published: 2021
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8. Bictegravir pharmacokinetics in a late-presenting HIV-1-infected pregnant woman: a case report

Author: Minh Patrick Lê, Agnès Bourgeois-Moine, Jade Ghosn, Diane Descamps, Florence Damond, Fabienne Mazy, Sophie Matheron, Gilles Peytavin, and Valentine Marie Ferré
Subjects: Pharmacology, Microbiology (medical), Pediatrics, medicine.medical_specialty, Bictegravir, business.industry, Human immunodeficiency virus (HIV), MEDLINE, medicine.disease_cause, Infectious Diseases, Pharmacokinetics, medicine, Pharmacology (medical), business
Published: 2021
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9. Risk of HIV transmission during combined ART initiation for HIV-infected persons with severe immunosuppression

Author: Supervie, V, Assoumou, L, Breban, R, Lert, F, Costagliola, D, Pialoux, G, Landman, R, Girard, P. M, Slama, L, Cabié, André, Abel, Sylvie, Hochedez, Patrick, Pierre-François, Sandrine, Rozé, Benoît, Simon, Anne, Lupin, Catherine, Katlama, Christine, Valentin, Marc Antoine, Autran, Brigitte, Samri, Assia, Lambert, Sidonie, Marcelin, Anne Geneviève, Landman, Roland, Joly, Véronique, Julia, Zélie, Harent, Stanislas, Papot, Emmanuelle, Phung, Bao-Chau, Peytavin, Gilles, Minh, Patrick Lê, Rami, Agathe, Diemer, Myriam, Parrinello, Maguy, Cahitte, Isabelle, Zeng, Feng, Mortier, Emmanuel, Pialoux, Gilles, L’Yavanc, Thomas, Le Loup, Guillaume, Bonnard, Philippe, Lebrette, Marie Gisèle, Chas, Julie, Berrebi, Valérie, Velazquez, Nadège, Adda, Anne, Duvivier, Claudine, Touam, Fatima, Lortholary, Olivier, Shoai-Tehrani, Michka, Rouzaud, Claire, Denes, Eric, Ducroux-Roubertou, Sophie, Durox, Hélène, Genet, Claire, Rogez, Jean-Philippe, Rogez, Sylvie, Pascual, Jose, Weiss, Laurence, Pavie, Juliette, Bourzam, Erila, Aumaître, Hugues, Ferreyra, Milagros, Saada, Matthieu, Malet, Martine, Palacios, Christia, Honore, Patricia, Zamord, Irene, Berthe, Huguette, Landowski, Stéphanie, de Truchis, Pierre, Perre, Philippe, Girard, Pierre-Marie, Valin, Nadia, Campa, Pauline, Lefebvre, Bénédicte, Meynard, Jean-Luc, Pauchard, Michèle, and Surgers, Laure
Published: 2017
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10. Persistent low-level viraemia in antiretroviral treatment-experienced patients is not linked to viral resistance or inadequate drug concentrations

Author: B. Abdi, Marc-Antoine Valantin, Sophie Seang, Romain Palich, Gilles Peytavin, Vincent Calvez, Marc Wirden, Cathia Soulié, A G Marcelin, Olivier Paccoud, Minh Patrick Lê, Roland Tubiana, Christine Katlama, and Luminita Schneider
Subjects: Microbiology (medical), Drug, medicine.medical_specialty, Anti-HIV Agents, media_common.quotation_subject, Patient characteristics, HIV Infections, Viremia, Drug resistance, Viral resistance, Antiretroviral Therapy, Highly Active, Internal medicine, Drug Resistance, Viral, Antiretroviral treatment, Humans, Medicine, Pharmacology (medical), In patient, media_common, Pharmacology, business.industry, Middle Aged, Viral Load, medicine.disease, CD4 Lymphocyte Count, Infectious Diseases, Anti-Retroviral Agents, Pharmaceutical Preparations, HIV-1, business, Viral load
Abstract: Objectives To assess genotypic sensitivity scores (GSSs), plasma antiretroviral concentrations (PACs) and immunovirological outcomes at Week 96 (W96) in patients with persistent low-level viraemia (LLV). Methods On 1 January 2017, we analysed data from patients on three-drug regimens with persistent LLV defined as at least two consecutive plasma viral loads (pVLs) between 21 and 200 copies/mL (including one pVL of ≥50 copies/mL), at the Pitié-Salpêtrière Hospital. Outcomes were: GSS, PACs and HIV-DNA load at study entry; and virological status and proportion of patients with resistance-associated mutations (RAMs) at W96. Results Fifty-seven patients were included, with median age of 52.6 years (IQR 45.2–57.9), last CD4 count of 658 cells/mm3 (IQR 462–909) and total ART duration of 10.2 years (IQR 5.7–15.2). LLV duration was 14.0 months (IQR 5.5–22.3). GSS was 3 in 46/57 (81%) patients and PACs were adequate in 53/57 (93%) patients. Median total HIV-DNA was 2.65 log10 copies/106 cells (IQR 2.44–2.86). During follow-up, 26/57 (46%) had experienced ART modifications. At W96, 38/57 (67%) patients remained with LLV, 15/60 (26%) had achieved confirmed pVL of Conclusions A substantial number of patients harbouring LLV had no resistance to ART and adequate PACs. Two-thirds of these patients remained with this LLV status.
Published: 2020
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11. Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial

Author: Minh Patrick Lê, Nathan Peiffer-Smadja, Jeremie Guedj, Nadège Néant, France Mentré, Florence Ader, Yazdan Yazdanpanah, and Gilles Peytavin
Subjects: Pharmacology, Microbiology (medical), Coronavirus disease 2019 (COVID-19), business.industry, Hydroxychloroquine sulphate, Maintenance dose, Hydroxychloroquine, Leading Article, Loading dose, Regimen, Infectious Diseases, Target drug, Medicine, Pharmacology (medical), Once daily, business, medicine.drug
Abstract: Around the world, several dose regimens of hydroxychloroquine have been used for COVID-19 infection treatment, with the objective of identifying a short-term course. Hydroxychloroquine was found to decrease the viral replication in a concentration-dependent manner in vitro and to be more active when added prior to the viral challenge. A loading dose is used to rapidly attain a target drug concentration, which is usually considered as approximately the steady-state concentration. With a loading dose, the minimum effective concentration is reached much more rapidly than when using only the maintenance dose from the start. Thus, we propose a hydroxychloroquine sulphate dose regimen of 400 mg twice daily at Day 1 then 400 mg once daily from Day 2 to Day 10. We aim to evaluate this in the C-20-15 DisCoVeRy trial.
Published: 2020
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12. M184V/I does not impact the efficacy of abacavir/lamivudine/dolutegravir use as switch therapy in virologically suppressed patients

Author: Anne-Geneviève Marcelin, Diane Descamps, Minh Patrick Lê, Gilles Peytavin, Aude Jary, Charlotte Charpentier, Marc Wirden, Vincent Calvez, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de virologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Service de Virologie [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gestionnaire, Hal Sorbonne Université, Service de Virologie [CHU Pitié-Salpêtrière], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord
Subjects: 0301 basic medicine, Microbiology (medical), Anti-HIV Agents, Pyridones, 030106 microbiology, Integrase inhibitor, HIV Infections, Emtricitabine, Piperazines, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, immune system diseases, Abacavir, Oxazines, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Retrospective Studies, Pharmacology, business.industry, virus diseases, Lamivudine, Abacavir/Lamivudine, Viral Load, Resistance mutation, Virology, Dideoxynucleosides, 3. Good health, Infectious Diseases, chemistry, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Dolutegravir, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, Heterocyclic Compounds, 3-Ring, Viral load, medicine.drug
Abstract: Background M184V/I NRTI resistance mutations can be selected by either lamivudine/emtricitabine or abacavir. There are controversies about the use of abacavir/lamivudine/dolutegravir combinations in HIV-1-infected treatment-experienced patients with a fully suppressed HIV viral load (VL) and harbouring M184V/I. Objectives We assessed the efficacy of abacavir/lamivudine/dolutegravir when used in HIV-infected pretreated patients with an undetectable VL who previously harboured M184V/I as a unique NRTI resistance mutation in a genotypic resistance test and had no resistance to integrase inhibitors. Patients and methods A total of 154 patients with a fully suppressed HIV-1 plasma VL ( Results During the 12 months of follow-up, three patients had a blip of VL (53, 62 and 106 copies/mL) at Month 3 followed by a subsequent VL Conclusions M184V/I as a unique NRTI resistance mutation, regardless of possible selection by regimens containing lamivudine/emtricitabine or abacavir, does not affect the virological response of well-controlled patients who switched to abacavir/lamivudine/dolutegravir for at least 12 months.
Published: 2020
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13. An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19 – Final results from the DisCoVeRy trial

Author: Florence Ader, Nathan Peiffer-Smadja, Julien Poissy, Maude Bouscambert-Duchamp, Drifa Belhadi, Alpha Diallo, Christelle Delmas, Juliette Saillard, Aline Dechanet, Noémie Mercier, Axelle Dupont, Toni Alfaiate, François-Xavier Lescure, François Raffi, François Goehringer, Antoine Kimmoun, Stéphane Jaureguiberry, Jean Reignier, Saad Nseir, François Danion, Raphael Clere-Jehl, Kévin Bouiller, Jean-Christophe Navellou, Violaine Tolsma, André Cabie, Clément Dubost, Johan Courjon, Sylvie Leroy, Joy Mootien, Rostane Gaci, Bruno Mourvillier, Emmanuel Faure, Valérie Pourcher, Sébastien Gallien, Odile Launay, Karine Lacombe, Jean-Philippe Lanoix, Alain Makinson, Guillaume Martin-Blondel, Lila Bouadma, Elisabeth Botelho-Nevers, Amandine Gagneux-Brunon, Olivier Epaulard, Lionel Piroth, Florent Wallet, Jean-Christophe Richard, Jean Reuter, Thérèse Staub, Bruno Lina, Marion Noret, Claire Andrejak, Minh Patrick Lê, Gilles Peytavin, Maya Hites, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, and France Mentre
Subjects: immune system diseases, virus diseases
Abstract: ObjectivesWe evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring.MethodsWe conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely.ResultsThe intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-β-1a, n=147; hydroxychloroquine, n=150; control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36); lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08); hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.ConclusionIn adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.
Published: 2022
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14. Final results of the DisCoVeRy trial of remdesivir for patients admitted to hospital with COVID-19

Author: Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, France Mentré, Charles Burdet, Jérôme Aboab, Hafid Ait-Oufella, Antoine Altdorfer, Claire Andrejak, Pascal Andreu, Laurent Argaud, Firouzé Bani-Sadr, Drifa Belhadi, Leila Belkhir, François Benezit, Marc Berna, Mathieu Blot, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, David Bougon, Kevin Bouiller, Fanny Bounes-Vardon, David Boutoille, Alexandre Boyer, Sandra Braz, Cédric Bruel, André Cabié, Emmanuel Canet, Charles Cazanave, Cyrille Chabartier, Catherine Chirouze, Raphaël Clere-Jehl, Dominique Costagliola, Sandrine Couffin-Cadièrgues, Johan Courjon, Flora Crockett, François Danion, Aline Dechanet, Agathe Delbove, Jean Dellamonica, Christelle Delmas, Alpha Diallo, Félix Djossou, Clément Dubost, Alexandre Duvignaud, Alexander Egle, Olivier Epaulard, Loïc Epelboin, Hélène Esperou, Murielle Fartoukh, Karine Faure, Emmanuel Faure, Joao-Miguel Ferreira Ribeiro, Tristan Ferry, Cécile Ficko, Samy Figueiredo, Claire Fougerou, Vincent Fraipont, Benjamin Gaborit, Rostane Gaci, Amandine Gagneux-Brunon, Sébastien Gallien, Denis Garot, Alexandre Gaymard, Guillaume Geri, Sébastien Gibot, François Goehringer, Marie Gousseff, Richard Greil, Didier Gruson, Jérémie Guedj, Yves Hansmann, Olivier Hinschberger, Stéphane Jaureguiberry, Vanessa Jeanmichel, Michael Joannidis, Solen Kerneis, Antoine Kimmoun, Kada Klouche, Marie Lachâtre, Karine Lacombe, Fabrice Laine, Bernd Lamprecht, Jean-Philippe Lanoix, Odile Launay, Bruno Laviolle, Minh-Patrick Lê, Vincent Le Moing, Jérôme Le Pavec, Yves Le Tulzo, Paul Le Turnier, David Lebeaux, Benjamin Lefevre, Sylvie Leroy, François-Xavier Lescure, Henry Lessire, Benjamin Leveau, Bruno Lina, Paul Loubet, Alain Makinson, Denis Malvy, Charles-Hugo Marquette, Guillaume Martin-Blondel, Martin Martinot, Julien Mayaux, Armand Mekontso-Dessap, Noémie Mercier, Ferhat Meziani, Jean-Paul Mira, Jean-Michel Molina, Xavier Monnet, Joy Mootien, Bruno Mourvillier, Bruno Mourvilliers, Marlène Murris-Espin, Jean-Christophe Navellou, Marion Noret, Saad Nseir, Walid Oulehri, José-Artur Paiva, Thomas Perpoint, Gilles Peytavin, Gilles Pialoux, Benoît Pilmis, Vincent Piriou, Lionel Piroth, Julien Poissy, Valérie Pourcher, Jean-Pierre Quenot, François Raffi, Jean Reignier, Jean Reuter, Matthieu Revest, Jean-Christophe Richard, Béatrice Riu-Poulenc, Céline Robert, Pierre-Alexandre Roger, Claire Roger, Roberto Roncon-Albuquerque, Elisabeth Rouveix-Nordon, Yvon Ruch, Nadia Saidani, Juliette Saillard, Naomi Sayre, Eric Senneville, Albert Sotto, Thérèse Staub, Francois Stefan, Charles Tacquard, Nicolas Terzi, Julien Textoris, Guillaume Thiery, Jean-François Timsit, Violaine Tolsma, Sarah Tubiana, Jean-Marie Turmel, Florent Valour, Fanny Vardon-Bounes, Priyanka Velou, Gil Verschelden, Florent Wallet, Guilhem Wattecamps, Yazdan Yazdanpanah, Yoann Zerbib, UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, and UCL - (SLuc) Service de médecine interne générale
Subjects: Hospitalization, Clinical Trials as Topic, Alanine, Infectious Diseases, COVID-19, Humans, Adenosine Monophosphate, COVID-19 Drug Treatment
Published: 2022
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15. A case of tuberculosis and black-grain eumycetoma co-infection in a non-endemic country: clinical presentation and therapeutic management

Author: Michel Develoux, E. Fourniols, Minh Patrick Lê, Alicia Moreno, Ruxandra Calin, Gilles Pialoux, Sonia Vu, Nicolas Belaube, Ana Canestri, Ludovic Lassel, Service de Maladies infectieuses et tropicales [CHU Tenon], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Parasitologie - Mycologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Service de Chirurgie Orthopédique et Traumatologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), HAL-SU, Gestionnaire, Service des maladies infectieuses et tropicales [CHU Tenon], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d’orthopédie et de traumatologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: Microbiology (medical), medicine.medical_specialty, Tuberculosis, 030231 tropical medicine, Infectious and parasitic diseases, RC109-216, Eumycetoma, Therapeutic drug monitoring, Mycobacterium tuberculosis, 03 medical and health sciences, 0302 clinical medicine, Medicine, Non endemic, Mycetoma, 030304 developmental biology, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, business.industry, Leg abscess, General Medicine, Black-grain eumycetoma, medicine.disease, biology.organism_classification, Dermatology, 3. Good health, Black grain, Infectious Diseases, Presentation (obstetrics), business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Co infection
Abstract: International audience; We report a case of black-grain eumycetoma co-localized with Mycobacterium tuberculosis infection, presenting as a painless leg abscess and associated with vertebral tuberculosis. The rare association of these two pathogens raises several challenges regarding foreseeable drug interactions, side effects, the most appropriate management and the potential link between these two diseases.
Published: 2021
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16. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial

Author: Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, Julien Poissy, Drifa Belhadi, Alpha Diallo, Minh-Patrick Lê, Gilles Peytavin, Thérèse Staub, Richard Greil, Jérémie Guedj, Jose-Artur Paiva, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, France Mentré, Alexander Egle, Michael Joannidis, Bernd Lamprecht, Antoine Altdorfer, Leila Belkhir, Vincent Fraipont, Gil Verschelden, Jérôme Aboab, Hafid Ait-Oufella, Claire Andrejak, Pascal Andreu, Laurent Argaud, Firouzé Bani-Sadr, François Benezit, Mathieu Blot, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, David Bougon, Kevin Bouiller, Fanny Bounes-Vardon, David Boutoille, Alexandre Boyer, Cédric Bruel, André Cabié, Emmanuel Canet, Charles Cazanave, Cyrille Chabartier, Catherine Chirouze, Raphaël Clere-Jehl, Johan Courjon, Flora Crockett, François Danion, Agathe Delbove, Jean Dellamonica, Félix Djossou, Clément Dubost, Alexandre Duvignaud, Olivier Epaulard, Loïc Epelboin, Murielle Fartoukh, Karine Faure, Emmanuel Faure, Tristan Ferry, Cécile Ficko, Samy Figueiredo, Benjamin Gaborit, Rostane Gaci, Amandine Gagneux-Brunon, Sébastien Gallien, Denis Garot, Guillaume Geri, Sébastien Gibot, François Goehringer, Marie Gousseff, Didier Gruson, Yves Hansmann, Olivier Hinschberger, Stéphane Jaureguiberry, Vanessa Jeanmichel, Solen Kerneis, Antoine Kimmoun, Kada Klouche, Marie Lachâtre, Karine Lacombe, Fabrice Laine, Jean-Philippe Lanoix, Odile Launay, Bruno Laviolle, Vincent Le Moing, Jérôme Le Pavec, Yves Le Tulzo, Paul Le Turnier, David Lebeaux, Benjamin Lefevre, Sylvie Leroy, François-Xavier Lescure, Henry Lessire, Benjamin Leveau, Paul Loubet, Alain Makinson, Denis Malvy, Charles-Hugo Marquette, Guillaume Martin-Blondel, Martin Martinot, Julien Mayaux, Armand Mekontso-Dessap, Ferhat Meziani, Jean-Paul Mira, Jean-Michel Molina, Xavier Monnet, Joy Mootien, Bruno Mourvillier, Marlène Murris-Espin, Jean-Christophe Navellou, Saad Nseir, Walid Oulehri, Thomas Perpoint, Gilles Pialoux, Benoît Pilmis, Vincent Piriou, Lionel Piroth, Valérie Pourcher, Jean-Pierre Quenot, François Raffi, Jean Reignier, Matthieu Revest, Jean-Christophe Richard, Béatrice Riu-Poulenc, Céline Robert, Pierre-Alexandre Roger, Claire Roger, Elisabeth Rouveix-Nordon, Yvon Ruch, Nadia Saidani, Naomi Sayre, Eric Senneville, Albert Sotto, Francois Stefan, Charles Tacquard, Nicolas Terzi, Julien Textoris, Guillaume Thiery, Jean-François Timsit, Violaine Tolsma, Jean-Marie Turmel, Florent Valour, Florent Wallet, Guilhem Wattecamps, Yoann Zerbib, Marc Berna, Jean Reuter, Sandra Braz, Joao-Miguel Ferreira Ribeiro, José-Artur Paiva, Roberto Roncon-Albuquerque, Alexandre Gaymard, Bruno Lina, Sarah Tubiana, Sandrine Couffin-Cadièrgues, Hélène Esperou, Aline Dechanet, Christelle Delmas, Claire Fougerou, Noémie Mercier, Marion Noret, Juliette Saillard, Priyanka Velou, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Internal Medicine, Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Imperial College London, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Universidade do Porto = University of Porto, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, and UCL - (SLuc) Service de médecine interne générale
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, 030204 cardiovascular system & hematology, Antiviral Agents, law.invention, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, 0302 clinical medicine, Randomized controlled trial, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, law, Internal medicine, Humans, Medicine, media_common.cataloged_instance, 030212 general & internal medicine, European union, education, Contraindication, ComputingMilieux_MISCELLANEOUS, Aged, media_common, Mechanical ventilation, education.field_of_study, Alanine, business.industry, COVID-19, Standard of Care, Odds ratio, Articles, Middle Aged, Respiration, Artificial, Adenosine Monophosphate, COVID-19 Drug Treatment, 3. Good health, Europe, Hospitalization, Oxygen, Clinical trial, Infectious Diseases, Clinical research, Female, business
Abstract: Summary Background The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. Methods DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. Findings Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77–1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). Interpretation No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. Funding European Union Commission, French Ministry of Health, Domaine d'interet majeur One Health Ile-de-France, REACTing, Fonds Erasme-COVID-Universite Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Translation For the French translation of the abstract see Supplementary Materials section.
Published: 2021
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17. Plasma pharmacokinetics of bedaquiline administered by nasogastric tube in an intensive care unit

Author: Sayagh F, Timsit Jf, Neuville M, Minh Patrick Lê, Sinnah F, Dang E, and Gilles Peytavin
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, Antitubercular Agents, law.invention, Plasma, Young Adult, chemistry.chemical_compound, Pharmacokinetics, Oral administration, law, Moxifloxacin, Tuberculosis, Multidrug-Resistant, Humans, Medicine, Diarylquinolines, Ethambutol, medicine.diagnostic_test, business.industry, Intensive care unit, Intensive Care Units, Infectious Diseases, Pharmaceutical Preparations, chemistry, Therapeutic drug monitoring, Anesthesia, Bedaquiline, business, medicine.drug, Blood sampling
Abstract: We present the case of a 21-year-old man admitted to the intensive care unit with multi-organ failure due to multidrug-resistant tuberculosis (TB). TB treatment initially comprised moxifloxacin, ethambutol, linezolid and amikacin administered intravenously. Due to suspected moxifloxacin-induced liver injury, we stopped all fluoroquinolones and switched to bedaquiline (BDQ), which is only available in tablets for oral administration. Since our patient had to be fed through a nasogastric tube (NGT), BDQ was administered after being crushed and dissolved in water; drug pharmacokinetics were studied using repeated blood sampling. Therapeutic drug monitoring showed that BDQ was detectable in blood plasma with a trough concentration above the supposed efficacy threshold, suggesting that this molecule could be administered through NGT.
Published: 2020
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18. Lack of a Clinically Significant Pharmacokinetic Interaction between Etravirine and Raltegravir Using an Original Approach Based on Drug Metabolism, Protein Binding, and Penetration in Seminal Fluid: A Pharmacokinetic Substudy of the <scp>ANRS</scp> ‐163 <scp>ETRAL</scp> Study

Author: Christine Katlama, Jacques Reynes, Soizic Le Mestre, Marc Antoine Valantin, Olivier Bouchaud, Laurence Weiss, Vincent Calvez, Gilles Peytavin, Anne-Geneviève Marcelin, Minh Patrick Lê, Cathia Soulié, Lambert Assoumou, Yazdan Yazdanpanah, Jean-Michel Molina, François Raffi, and Dominique Costagliola
Subjects: 0301 basic medicine, business.industry, 030106 microbiology, Glucuronidation, Etravirine, 030204 cardiovascular system & hematology, Pharmacology, Raltegravir, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Interquartile range, Blood plasma, medicine, Pharmacology (medical), business, Pharmacokinetic interaction, Drug metabolism, medicine.drug
Abstract: Study objective: The ANRS163-ETRAL study showed that etravirine 200 mg/raltegravir 400 mg twice-daily dual therapy was highly effective in the treatment of human immunodeficiency virus (HIV)-infected patients older than 45 years, with virologic and therapeutic success rates at week 48 of 99.4% and 94.5%, respectively. The objective of this study was to determine whether a clinically significant pharmacokinetic interaction between etravirine and raltegravir exists by assessing steady-state total and unbound etravirine, raltegravir, and inactive raltegravir-glucuronide concentrations 12 hours after last intake (C12h ) in blood plasma (BP) and seminal plasma (SP). Design: Pharmacokinetic analysis of data from the ANRS163-ETRAL study. Patients: One hundred forty-six HIV-1-infected patients (of the 165 patients included in the ANRS-163 ETRAL study) who were receiving etravirine 200 mg and raltegravir 400 mg twice daily. Measurements and main results: Blood was collected from all 146 patients at weeks 2-4, 12, 24, and 48, and semen was collected from 21 patients at week 48. The extent of BP and SP protein binding was determined by using ultrafiltration assay. Total and unbound etravirine, raltegravir, and raltegravir-glucuronide C12h were determined by ultra high performance liquid chromatography coupled with tandem mass spectrometry and interpreted by using the in vitro calculated protein-bound 95% inhibitory concentration (PBIC95 ) for wild-type (WT) HIV: etravirine (116 ng/ml) and raltegravir (15 ng/ml). Median (interquartile range [IQR]) total BP etravirine C12h (536 ng/ml [376-719]) and raltegravir (278 ng/ml [97-690]) were adequate in 99% and 96% of patients, respectively. Median (IQR) SP:BP C12h ratio and BP unbound fraction were etravirine 0.3 (0.2-0.5) and 99%, respectively. The BP raltegravir metabolic ratio (raltegravir glucuronide:raltegravir ratio) was 1.7, suggesting only weak induction of raltegravir glucuronidation by etravirine. Only three patients had etravirine and raltegravir C12h < PBIC95 simultaneously. Conclusion: No clinically significant pharmacokinetic interaction between etravirine and raltegravir was detected. Total etravirine and raltegravir BP concentrations were adequate in most patients, favoring virologic efficacy and confirming good treatment adherence (> 95%), despite twice-daily administration. The long half-life of etravirine and higher unbound fraction SP of raltegravir (57%) ensured adequate concentrations of dual therapy in genital compartments. Our results indicate that etravirine and raltegravir have good, complementary pharmacokinetic profiles, suggesting that they could be used in a dual-treatment strategy.
Published: 2019
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19. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19

Author: Lionel Piroth, Bruno Mourvillier, Joy Mootien, François-Xavier Lescure, Emmanuel Faure, S. Gallien, Dominique Costagliola, Jean-Christophe Richard, Noemie Mercier, Florent Wallet, Yazdan Yazdanpanah, Marion Noret, Claire Andrejak, Jean-Philippe Lanoix, Julien Poissy, Johan Courjon, Saad Nseir, François Danion, Violaine Tolsma, Alain Makinson, Odile Launay, Raphaël Clere-Jehl, Bruno Lina, Drifa Belhadi, Valérie Pourcher, Antoine Kimmoun, Karine Lacombe, Juliette Saillard, Maude Bouscambert-Duchamp, Stéphane Jauréguiberry, Charles Burdet, Toni Alfaiate, Olivier Epaulard, Minh Patrick Lê, Gilles Peytavin, Elisabeth Botelho-Nevers, Thérèse Staub, Guillaume Martin-Blondel, Alpha Diallo, Lila Bouadma, Aline Dechanet, François Goehringer, Florence Ader, Nathan Peiffer-Smadja, Jean-Christophe Navellou, Christelle Delmas, Rostane Gaci, Kevin Bouiller, Maya Hites, André Cabié, Jean Reuter, Sylvie Leroy, Axelle Dupont, François Raffi, Amandine Gagneux-Brunon, Jean Reignier, Clément Dubost, Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Services de Maladies Infectieuses et Tropicales [CHU Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, National Institute for Health Research [Cambridge, UK], Imperial College London, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Lille, Centre National de Reference des virus des Infections Respiratoires France Sud [HCL, Lyon], Virology and human respiratory Pathologies - Virology and human respiratory Pathologies (VirPath), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANRS France Recherche Nord & sud Sida-hiv hépatites, Institut de Santé Publique, Université de Médecine Carol Davila, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Service de Réanimation Médicale [CHRU Nancy], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre National de Référence du Paludisme [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN), Les Hôpitaux Universitaires de Strasbourg (HUS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), Nouvel Hôpital Civil de Strasbourg, Fédération Hospitalo-Universitaire (OMICARE), Centre de Recherche d’Immunologie et d’Hématologie [Strasbourg], Fédération de Médecine Translationnelle de Strasbourg (FMTS), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], Etablissement français du don du sang [Montpellier], CHU de la Martinique [Fort de France], Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, Université Paris-Saclay, Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), CB - Centre Borelli - UMR 9010 (CB), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université de Paris (UP), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Centre Hospitalier Universitaire de Reims (CHU Reims), Université de Reims Champagne-Ardenne (URCA), Université Lille Nord de France (COMUE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP)-Groupe hospitalier Broca-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Infectious and Tropical Diseases Department [Montpellier], Institut de Recherche pour le Développement (IRD)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Physiopathologie et biothérapies des infections muqueuses (GIMAP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Fédération d’Infectiologie Multidisciplinaire de l’Arc Alpin [CHU Grenoble-Alpes], Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Institut des Agents Infectieux [Lyon] (IAI), Réseau national de recherche clinique en infectiologie (RENARCI), CHU Amiens-Picardie, Université libre de Bruxelles (ULB), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Université de Lorraine (UL), Hôpital Bicêtre, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Université des Antilles (UA)-Etablissement français du don du sang [Montpellier]-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles et de la Guyane (UAG), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université de Lille, Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CIC Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Département d'Epidemiologie, Biostatistique et Recherche Clinique (DEBRC), Centre National de Référence du Paludisme [CHU Pitié-Salpétrière] (CNRpalu), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPCité), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Maladies Infectieuses et Tropicales [CHU Pitié-Salpêtrière], AP-HP, Hôpital Henri-Mondor Albert-Chenevier, Service d'Immunologie Clinique et Maladies Infectieuses 94000 Créteil, France, Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Services des Maladies Infectieuses et Tropicales [CHU Saint-Antoine], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service des maladies infectieuses et tropicales [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM), CHU Grenoble, Université Grenoble Alpes (UGA), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Laboratoire Chrono-environnement (UMR 6249) (LCE), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Université Sorbonne Paris Nord, Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Lopinavir/ritonavir, law.invention, 0302 clinical medicine, Randomized controlled trial, law, immune system diseases, MESH: Antiviral Agents* / therapeutic use, 030212 general & internal medicine, MESH: Treatment Outcome, education.field_of_study, MESH: Middle Aged, virus diseases, Lopinavir, General Medicine, MESH: Lopinavir / therapeutic use, 3. Good health, Infectious Diseases, MESH: Interferon beta-1a / therapeutic use, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Pharmaceutical Preparations, MESH: Hydroxychloroquine / therapeutic use, [SDV.IMM]Life Sciences [q-bio]/Immunology, Original Article, medicine.drug, Hydroxychloroquine, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Population, Antiviral Agents, 03 medical and health sciences, Interferon β-1a, Internal medicine, medicine, Humans, education, Adverse effect, MESH: COVID-19* / drug therapy, MESH: Drug Combinations, MESH: Humans, business.industry, SARS-CoV-2, Drug Repositioning, Interferon beta-1a, COVID-19, MESH: Adult, MESH: Male, MESH: Ritonavir / therapeutic use, Ritonavir, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Objectives: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support.Methods: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely.Results: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-β-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.Conclusion: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.
Published: 2021
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20. Remdesivir for the Treatment of Hospitalised Patients with COVID-19 (DisCoVeRy): A Randomised, Controlled, Open-Label Trial

Author: Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, Julien Poissy, Drifa Belhadi, Alpha Diallo, Christelle Delmas, Juliette Saillard, Aline Dechanet, Claire Fougerou, Minh-Patrick Lê, Gilles Peytavin, Noémie Mercier, Priyanka Velou, Sarah Tubiana, Xavier Lescure, Emmanuel Faure, Saad Nseir, Jean-Christophe Richard, Florent Wallet, François Goehringer, Benjamin Lefèvre, Antoine Kimmoun, François Raffi, Bejamin Gaborit, Jean Reignier, Jean-Philippe Lanoix, Claire Andrejak, Yoann Zerbib, Firouzé Bani-Sadr, Bruno Mourvilliers, François Danion, Yvon Ruch, Raphaël Clere-Jehl, Vincent Le Moing, Kada Klouche, Karine Lacombe, Guillaume Martin-Blondel, Fanny Vardon-Bounes, André Cabié, Jean-Marie Turmel, Lionel Piroth, Mathieu Blot, Elisabeth Botelho-Nevers, Amandine Gagneux-Brunon, Guillaume Thiery, François Bénézit, Rostane Gaci, Joy Mootien, Sébastien Gallien, Denis Garot, Kevin Bouiller, Loïc Epelboin, Stéphane Jauréguiberry, Alexandre Gaymard, Gil Verschelden, Sandra Braz, Joao-Miguel Ferreira Ribeiro, Michael Joannidis, Thérèse Staub, Antoine Altdorfer, Richard Greil, Alexander Egle, Jérémie Guedj, Marion Noret, Roberto Roncon-Albuquerque Jr, Jose-Artur Paiva, Bruno Lina, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, France Mentré, Hospices Civils de Lyon (HCL), Laboratoire de Virologie [Lyon], Institut des Agents Infectieux [Lyon] (IAI), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control (Virpath), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Imperial College London, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Département d'épidémiologie, biostatistique et recherche clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], ANRS France Recherche Nord & sud Sida-hiv hépatites, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Veille Sanitaire (INVS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Faculté de Médecine Henri Warembourg - Université de Lille, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), and Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie
Subjects: education.field_of_study, medicine.medical_specialty, business.industry, Population, Declaration, Commission, Treatment and control groups, Informed consent, Family medicine, Health care, medicine, media_common.cataloged_instance, European union, education, business, Psychology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Declaration of Helsinki, media_common
Abstract: Background: The antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in patients with COVID-19 requiring oxygen and/or ventilator support. Methods: In this European multicentre, open-label, parallel-group, randomised, controlled trial in adults hospitalised with COVID-19 (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care alone or in combination with intravenous remdesivir (200 mg on day 1, then 100 mg once-daily for 9 days or until discharge). Treatment assignation was performed via web-based randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population. Findings: Between March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 832 participants were included for the evaluation of remdesivir (control, n=418; remdesivir, n=414). There was no difference in the clinical status neither at day 15 between treatment groups (OR for remdesivir, 0.98, 95% CI, 0.77 to 1.25, P=0.85) nor at day 29. The proportion of deaths at day 28 was not significantly different between control (8.9%) and remdesivir (8.2%) treatment groups (OR for remdesivir, 0.93 95%CI 0.57 to 1.52, P=0.77). There was also no difference on SARS-CoV-2 viral kinetics (effect of remdesivir on viral load slope, -0.004 log10 cp/10,000 cells/day, 95% CI, -0.03 to 0.02, P=0.75). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups. Interpretation: The use of remdesivir for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15 or day 29, nor with a reduction in mortality, nor with a reduction in SARS-CoV-2 RNA. Trial Registration: DisCoVeRy, NCT04315948; EudraCT2020-000936-23 Funding: European Union Commission, French Ministry of Health, DIM One Health Ile-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE) Declaration of Interests: Dr. Costagliola reports grants and personal fees from Janssen, personal fees from Gilead, outside the submitted work. Dr. Mentre reports grants from INSERM Reacting (French Government), grants from Ministry of Health (French Government), grants from European Commission, during the conduct of the study; grants from Sanofi, grants from Roche, outside the submitted work. Dr. Hites reports grants from The Belgian Center for Knowledge (KCE), grants from Fonds Erasme-COVID-ULB, during the conduct of the study; personal fees from Gilead, outside the submitted work. Dr. Mootien reports non-financial support from GILEAD, outside the submitted work. Dr. Gaborit reports non-financial support from Gilead, non- financial support from MSD, outside the submitted work. Dr. Botelho-Nevers reports other from Pfizer, other from Janssen, outside the submitted work. Dr. Lacombe reports personal fees and non-financial support from Gilead, personal fees and non-financial support from Janssen, personal fees and non-financial support from MSD, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Abbvie, during the conduct of the study. Dr. Wallet reports personal fees and non-financial support from Jazz pharmaceuticals, personal fees and non-financial support from Novartis, personal fees and nonPage financial support from Kite-Gilead, outside the submitted work. Dr. Kimmoun reports personal fees from Aguettan, personal fees from Aspen, outside the submitted work. Dr. Thiery reports personal fees from AMGEN, outside the submitted work. Dr. Burdet reports personal fees from Da Volterra, personal fees from Mylan Pharmaceuticals, outside the submitted work. Dr. Poissy reports personal fees from Gilead for lectures, outside the submitted work. Dr. Goehringer reports personal fees from Gilead Sciences, non-financial support from Gilead Sciences, grants from Biomerieux, non-financial support from Pfizer, outside the submitted work. Dr. Peytavin reports personal fees from Gilead Sciences, personal fees from Merck France, personal fees from ViiV Healthcare, personal fees from TheraTechnologies, outside the submitted work. Dr. Danion reports personal fees from Gilead, outside the submitted work. Dr. Raffi reports personal fees from Gilead, personal fees from Janssen, personal fees from MSD, personal fees from Abbvie, personal fees from ViiV Healthcare, personal fees from Theratechnologies, personal fees from Pfizer, outside the submitted work. Dr. Gallien reports personal fees from Gilead, personal fees from Pfizer, personal fees from ViiV, personal fees from MSD, outside the submitted work; and has received consulting fee from Gilead in August 2020 to check the registration file of remdesivir for the French administration. Dr. Nseir reports personal fees from MSD, personal fees from Pfizer, personal fees from Gilead, personal fees from Biomerieux, personal fees from BioRad, outside the submitted work. Dr. Lefevre reports personal fees from Mylan, personal fees from Gilead, outside the submitted work. Dr. Guedj reports personal fees from Roche, outside the submitted work. Other authors have nothing to disclose. Ethics Approval Statement: The trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744), and is sponsored by the Institut national de la sante et de la recherche medicale (Inserm, France); it was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all included participants (or their legal representatives if unable to consent). The present analysis is based on the protocol v11.0 of December 12th, 2020.
Published: 2021
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21. Identifying lithium‐poisoned patients who may benefit from haemodialysis remains highly challenging

Author: Laurence Labat, Bruno Mégarbane, Minh Patrick Lê, Dominique Vodovar, Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], VODOVAR, Dominique, Centre antipoison et de toxicovigilance (Paris) (CAPTV Paris), Université Paris Diderot - Paris 7 (UPD7)-Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand-Widal, Université Paris Cité (UPCité), Service de Réanimation Médicale et Toxicologique [Hôpital Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], and Mégarbane, Bruno
Subjects: medicine.medical_specialty, Lithium (medication), [SDV]Life Sciences [q-bio], MEDLINE, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, nomogram, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Pharmacology (medical), MESH: Renal Dialysis, Intensive care medicine, Pharmacology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Humans, MESH: Lithium, business.industry, renal clearance, Nomogram, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, haemodialysis, poisoning, [SDV] Life Sciences [q-bio], [SDV.TOX] Life Sciences [q-bio]/Toxicology, lithium, [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Poisons, MESH: Antidepressive Agents, business, Clearance, medicine.drug
Abstract: International audience; No abstract available
Published: 2020
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22. Reply to Yan and Muller, 'Captisol and GS-704277, but Not GS-441524, Are Credible Mediators of Remdesivir’s Nephrotoxicity'

Author: Quentin Le Hingrat, Jean-François Timsit, Pierre Jaquet, Christine Le Beller, Laurent Massias, Hervé Mal, Gilles Peytavin, Diane Descamps, Benoit Visseaux, Minh Patrick Lê, Vincent Bunel, Paul-Henri Wicky, and Jonathan Messika
Subjects: 2019-20 coronavirus outbreak, Adenosine, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Nephrotoxicity, 03 medical and health sciences, Renal Dialysis, Medicine, Humans, Pharmacology (medical), Pyrroles, Furans, Letter to the Editor, Lung, Pandemics, Pharmacology, 0303 health sciences, Alanine, 030306 microbiology, business.industry, SARS-CoV-2, Triazines, beta-Cyclodextrins, COVID-19, Virology, Adenosine Monophosphate, Transplant Recipients, Infectious Diseases, business, Neuroglia, Lung Transplantation
Abstract: We thank Yan VC and Muller FL (1) for taking their valuable time to comment on our article.….
Published: 2020

23. Impact of Loading Dose of Caspofungin in Pharmacokinetic-Pharmacodynamic Target Attainment for Severe Candidiasis Infections in Patients in Intensive Care Units: the CASPOLOAD Study

Author: Jordane Lebut, Claire Dupuis, Elodie Gautier-Veyret, Minh Patrick Lê, Sébastien Bailly, Laurent Massias, Michel Wolff, Romain Sonneville, Lila Bouadma, Bruno Mourvillier, Aguila Radjou, Olivier Andremont, Roland Smonig, Mathilde Neuville, Jean-François Timsit, and Eric Magalhaes
Subjects: Antifungal Agents, Population, Cmax, Microbial Sensitivity Tests, Loading dose, Echinocandins, Lipopeptides, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, Caspofungin, Intensive care, Humans, Medicine, Pharmacology (medical), 030212 general & internal medicine, education, PK/PD models, Pharmacology, 0303 health sciences, education.field_of_study, 030306 microbiology, business.industry, Candidiasis, Liter, Intensive Care Units, Infectious Diseases, chemistry, Anesthesia, business, Monte Carlo Method
Abstract: This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. PK-PD targets were ratios of area under the concentration-time curve from 0 to 24 h (AUC0–24h) divided by the MIC (AUC0–24h/MIC) of 250, 450, and 865 and maximal concentration (Cmax) divided by the MIC (Cmax/MIC) of 5, 10, 15, and 20. Among 13 included patients, CAS clearance was 0.98 ± 0.13 liters/h and distribution volumes were V1 = 9.0 ± 1.2 liters and V2 = 11.9 ± 2.9 liters. Observed and simulated CAS AUC0–24h were 79.1 (IQR 55.2; 108.4) and 81.3 (IQR 63.8; 102.3) mg · h/liter during the first 24 h of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were >90% for MICs of 0.19 and 0.5 mg/liter, considering AUC/MIC = 250 and Cmax/MIC = 10 as PK-PD targets, respectively. Thus, a high loading dose of CAS (140 mg) increased CAS exposure in the first 24 h of therapy, allowing early achievement of PK-PD targets for most Candida strains. Such a strategy seems to improve treatment efficacy, though further studies are needed to assess the impact on clinical outcomes. (This study has been registered at ClinicalTrials.gov under identifier {"type":"clinical-trial","attrs":{"text":"NCT02413892","term_id":"NCT02413892"}}NCT02413892.)
Published: 2020
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24. Management of oral antiretroviral administration in patients with swallowing disorders or with an enteral feeding tube

Author: Gilles Peytavin, Minh Patrick Lê, J. F. Timsit, Sophie Matheron, Michel Wolff, Yazdan Yazdanpanah, Carine San, Marion Caseris, Diane Descamps, Bruno Mourvillier, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpital Robert Debré, CCSD, Accord Elsevier, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord
Subjects: Drug, medicine.medical_specialty, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Administration, Oral, HIV Infections, Enteral administration, law.invention, 03 medical and health sciences, law, Intensive care, Humans, Medicine, Intensive care medicine, Feeding tube, media_common, 0303 health sciences, 030306 microbiology, business.industry, Swallowing Disorders, Intensive care unit, Dysphagia, Antiretroviral agents, Drug monitoring, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Parenteral nutrition, Anti-Retroviral Agents, medicine.symptom, Deglutition Disorders, business, Enteral nutrition, Drug administration routes
Abstract: International audience; HIV infection has evolved into a chronic disease with comorbidities since the combination antiretroviral therapy era. Complications still occur and patients may need to be admitted to an intensive care unit. Acute respiratory failure is the first cause of these admissions, questioning the administration of solid oral dosage formulations. This issue is also observed in geriatric units where the prevalence of dysphagia is high and underestimated. The problem of antiretroviral administration is critical: altered solid oral dosage formulations and/or administration via enteral feeding tubes are sometimes the only option. The aim is to help manage antiretroviral treatment in unconscious or intubated patients and those with swallowing disorders who are hospitalized in intensive care units or geriatric units. This review provides information on the main antiretroviral regimens and on practical and legal aspects of manipulating solid oral dosage formulations and administration via enteral feeding tubes. Alternatives to the solid formulation are available for most of the 27 oral antiretrovirals available, or manufacturers provide recommendations for patients who are unable to swallow. Manipulation of solid oral dosage formulations such as crushing tablets or opening capsules and administration via feeding tubes are frequently reported but should be the last option for safety and liability issues. Before any off-label administration of a drug, physicians should consider alternatives to the solid oral dosage formulation and check whether the drug can be altered. Therapeutic monitoring is important in this particular setting as the pharmacokinetic profile of drugs is difficult to predict.
Published: 2020
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25. Removal of Remdesivir’s Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19

Author: Quentin Le Hingrat, Pierre Jaquet, Paul Henri Wicky, Minh Patrick Lê, Gilles Peytavin, Jean-François Timsit, Hervé Mal, Benoit Visseaux, Vincent Bunel, Jonathan Messika, Diane Descamps, and Laurent Massias
Subjects: medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), medicine.medical_treatment, Metabolite, remdesivir, Urine, Antiviral Agents, Gastroenterology, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, In vivo, law, Internal medicine, medicine, Lung transplantation, Pharmacology (medical), 030212 general & internal medicine, Pharmacology, 0303 health sciences, hemodialysis, 030306 microbiology, business.industry, Intensive care unit, Infectious Diseases, chemistry, Hemodialysis, business, pharmacokinetics
Abstract: Remdesivir has reported efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and in vivo. Drug-drug interactions limit therapeutic options in transplant patients. Remdesivir and its metabolite GS-441524 are excreted principally in urine. In intensive care unit (ICU) settings, in which multiple-organ dysfunctions can occur rapidly, hemodialysis may be a viable option for maintaining remdesivir treatment, while improving tolerance, by removing both remdesivir’s metabolite (GS-441524) and sulfobutylether β-cyclodextrin sodium (SEBCD)., Remdesivir has reported efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and in vivo. Drug-drug interactions limit therapeutic options in transplant patients. Remdesivir and its metabolite GS-441524 are excreted principally in urine. In intensive care unit (ICU) settings, in which multiple-organ dysfunctions can occur rapidly, hemodialysis may be a viable option for maintaining remdesivir treatment, while improving tolerance, by removing both remdesivir’s metabolite (GS-441524) and sulfobutylether β-cyclodextrin sodium (SEBCD). Additional studies may prove informative, particularly in the evaluations of therapeutic options for coronavirus disease 2019 (COVID-19).
Published: 2020
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26. Pharmacokinetics of lopinavir/ritonavir oral solution to treat COVID-19 in mechanically ventilated ICU patients

Author: Benoit Visseaux, Juliette Kauv, Jean-François Timsit, Quentin Le Hingrat, Minh Patrick Lê, Gilles Peytavin, Lila Bouadma, Etienne de Montmollin, Paul-Henri Wicky, Diane Descamps, Juliette Patrier, Cédric Laouénan, Marc Veyrier, Romain Sonneville, and Pierre Jaquet
Subjects: Male, Lopinavir/ritonavir, Administration, Oral, 030226 pharmacology & pharmacy, Gastroenterology, Lopinavir, law.invention, 0302 clinical medicine, Oral administration, law, immune system diseases, Pharmacology (medical), Prospective Studies, Original Research, virus diseases, Middle Aged, Intensive care unit, Intensive Care Units, Pharmaceutical Solutions, AcademicSubjects/MED00290, Infectious Diseases, 030220 oncology & carcinogenesis, Drug Therapy, Combination, Female, Coronavirus Infections, medicine.drug, Microbiology (medical), medicine.medical_specialty, Pneumonia, Viral, Renal function, 03 medical and health sciences, Betacoronavirus, Pharmacokinetics, Internal medicine, medicine, Humans, AcademicSubjects/MED00740, Pandemics, Pharmacology, Ritonavir, business.industry, SARS-CoV-2, COVID-19, Respiration, Artificial, Regimen, Cytochrome P-450 CYP3A Inhibitors, business, AcademicSubjects/MED00230
Abstract: Background The combination lopinavir/ritonavir is recommended to treat HIV-infected patients at the dose regimen of 400/100 mg q12h, oral route. The usual lopinavir trough plasma concentrations are 3000–8000 ng/mL. A trend towards a 28 day mortality reduction was observed in COVID-19-infected patients treated with lopinavir/ritonavir. Objectives To assess the plasma concentrations of lopinavir and ritonavir in patients with severe COVID-19 infection and receiving lopinavir/ritonavir. Patients and methods Mechanically ventilated patients with COVID-19 infection included in the French COVID-19 cohort and treated with lopinavir/ritonavir were included. Lopinavir/ritonavir combination was administered using the usual adult HIV dose regimen (400/100 mg q12h, oral solution through a nasogastric tube). A half-dose reduction to 400/100 mg q24h was proposed if lopinavir Ctrough was >8000 ng/mL, the upper limit considered as toxic and reported in HIV-infected patients. Lopinavir and ritonavir pharmacokinetic parameters were determined after an intensive pharmacokinetic analysis. Biological markers of inflammation and liver/kidney function were monitored. Results Plasma concentrations of lopinavir and ritonavir were first assessed in eight patients treated with lopinavir/ritonavir. Median (IQR) lopinavir Ctrough reached 27 908 ng/mL (15 928–32 627). After the dose reduction to 400/100 mg q24h, lopinavir/ritonavir pharmacokinetic parameters were assessed in nine patients. Lopinavir Ctrough decreased to 22 974 ng/mL (21 394–32 735). Conclusions In mechanically ventilated patients with severe COVID-19 infections, the oral administration of lopinavir/ritonavir elicited plasma exposure of lopinavir more than 6-fold the upper usual expected range. However, it remains difficult to safely recommend its dose reduction without compromising the benefit of the antiviral strategy, and careful pharmacokinetic and toxicity monitoring are needed.
Published: 2020
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27. Once-daily etravirine/raltegravir (400/800 mg q24h) dual therapy maintains viral suppression over 48 weeks in HIV-infected patients switching from a twice-daily etravirine/raltegravir (200/400 mg q12h) regimen

Author: Romain, Palich, Clotilde, Allavena, Gilles, Peytavin, Cathia, Soulie, Roland, Tubiana, Laurence, Weiss, Ana, Montoya Ferrer, Claudine, Duvivier, Olivier, Bouchaud, Julie, Bottero, Aurore, Durand, Minh-Patrick, Lê, Anne-Geneviève, Marcelin, Yasmine, Dudoit, Lambert, Assoumou, Christine, Katlama, L, Lenclume, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de maladies infectieuses et tropicales [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de maladies infectieuses et tropicales [CHU Avicenne], Hôpital Avicenne [AP-HP], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service des maladies infectieuses et tropicales [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Jean Verdier [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], Service de Maladies Infectieuses et Tropicales [CHU Pitié-Salpêtrière], and Gestionnaire, HAL Sorbonne Université 5
Subjects: 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Anti-HIV Agents, 030106 microbiology, Etravirine, HIV Infections, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, Raltegravir Potassium, Nitriles, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Adverse effect, Pharmacology, business.industry, Middle Aged, Viral Load, Raltegravir, 3. Good health, Discontinuation, Regimen, Infectious Diseases, Pyrimidines, Treatment Outcome, Tolerability, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, HIV-1, business, Viral load, medicine.drug
Abstract: Background Etravirine/raltegravir dual therapy has been shown to be highly effective as a twice-daily (q12h) regimen in suppressed HIV-infected patients enrolled in the ANRS-163 study. Objectives As a once-daily (q24h) regimen is easier for daily life, we aimed to evaluate the capacity of etravirine/raltegravir (400/800 mg) q24h to maintain viral suppression in patients on etravirine/raltegravir q12h. Methods Patients on a suppressive etravirine/raltegravir q12h regimen for at least 96 weeks were switched to etravirine/raltegravir q24h in this prospective, multicentre, open-label, single-arm study. Primary outcome was the rate of virological failure (VF: confirmed pVL >50 copies/mL, single pVL >400 copies/mL or single pVL >50 copies/mL with ART change) at Week 48 (W48). Secondary outcomes included treatment strategy success rate (no VF and no treatment discontinuation), regimen tolerability, plasma drug concentrations and resistance profile in the case of VF. Results A total of 111 patients were enrolled, with a median (IQR) age of 57 years (52–62), CD4 count of 710 cells/mm3 (501–919) and viral suppression for 7.9 years (5.9–10.7). Two patients experienced viral rebound at W24 and W48, leading to a VF rate of 2.0% (95% CI 0.5–7.8) at W48, associated with INSTI resistance in one case. Both had past NNRTI mutations. Ten patients discontinued treatment for adverse events (n = 2), investigator or patient decisions (n = 3), lost to follow-up (n = 3), death (n = 1) or pregnancy (n = 1). Overall, the strategy success rate was 89% (95% CI 81.5–93.6) at W48. In a subgroup of 64 patients, median (IQR) plasma C24h concentrations were 401 ng/mL (280–603) for etravirine and 62 ng/mL (31–140) for raltegravir. Conclusions Switching patients virally suppressed on etravirine/raltegravir q12h to the same regimen but given q24h was highly effective in maintaining virological suppression in HIV-infected patients.
Published: 2020
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28. Early administration of ritonavir-boosted lopinavir could prevent severe COVID-19

Author: Anne-Geneviève Marcelin, David Boutolleau, Vincent Calvez, Nagisa Godefroy, Sonia Burrel, Gilles Peytavin, Elise Klement-Frutos, Eric Caumes, Stéphane Marot, Valérie Pourcher, and Minh Patrick Lê
Subjects: 0301 basic medicine, Oncology, Microbiology (medical), 2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), viruses, 030106 microbiology, Severe Acute Respiratory Syndrome, Antiviral Agents, Article, Disease Outbreaks, protease inhibitor, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Internal medicine, medicine, Humans, Protease inhibitor (pharmacology), 030212 general & internal medicine, Prospective Studies, skin and connective tissue diseases, Letter to the Editor, Ritonavir, business.industry, SARS-CoV-2, fungi, virus diseases, COVID-19, Lopinavir, Pneumonia, Viral Load, biochemical phenomena, metabolism, and nutrition, virology, lopinavir, Infectious Diseases, pharmacology, business, Viral load, medicine.drug
Abstract: Highlights No specific treatment against SARS-CoV-2 is available after 6 months of COVID-19 worldwide outbreak Antivirals could decrease the viral load and reduce direct and indirect damages of SARSCoV-2 infection Ritonavir-bosted lopinavir is effective against SARS-CoV-2 in vitro Sequential virological and pharmacological monitoring helped to understand the efficacy of ritonavir-boosted lopinavir in a SARS-CoV-2 infected patient Ritonavir-boosted lopinavir could be proposed as early treatment for SARS-CoV-2 infection
Published: 2020

29. Placental transfer of Letermovir & Maribavir in the ex vivo human cotyledon perfusion model. New perspectives for in utero treatment of congenital cytomegalovirus infection

Author: Julien Stirnemann, Valentine Faure Bardon, Minh Patrick Lê, Gilles Peytavin, Elisabeth Elefant, Yves Ville, Tiffany Guilleminot, Marianne Leruez-Ville, Fetal Medicine and Obstetric Department [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Pharmacology & Toxicology Laboratory [Paris], Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Virology Laboratory [Paris], National Reference Laboratory for congenital CMV [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by the University Paris Descartes., Bodescot, Myriam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord
Subjects: 0301 basic medicine, Cytomegalovirus Infection, Embryology, Viral Diseases, Placenta, Acetates, Toxicology, Pathology and Laboratory Medicine, Biochemistry, Letermovir, 0302 clinical medicine, Pregnancy, Tandem Mass Spectrometry, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine and Health Sciences, Medicine, Maternal-Fetal Exchange, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 030219 obstetrics & reproductive medicine, Multidisciplinary, Antimicrobials, Pharmaceutics, Drugs, Maribavir, Antivirals, 3. Good health, Perfusion, medicine.anatomical_structure, Infectious Diseases, In utero, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cytomegalovirus Infections, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, Anatomy, medicine.drug, Research Article, Adult, Placental cotyledon, Science, 030106 microbiology, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Antiviral Agents, Models, Biological, Microbiology, Andrology, 03 medical and health sciences, Drug Therapy, Albumins, Microbial Control, Virology, Placental Cotyledon, Humans, Serum Albumin, Pharmacology, Fetus, Fetuses, Toxicity, business.industry, Reproductive System, Biology and Life Sciences, Proteins, Kinetics, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Quinazolines, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Benzimidazoles, Ribonucleosides, business, Ex vivo, Chromatography, Liquid, Developmental Biology
Abstract: International audience; Background: Congenital cytomegalovirus infection can lead to severe sequelae. When fetal infection is confirmed, we hypothesize that fetal treatment could improve the outcome. Maternal oral administration of an effective drug crossing the placenta could allow fetal treatment. Letermovir (LMV) and Maribavir (MBV) are new CMV antivirals, and potential candidates for fetal treatment.Methods: The objective was to investigate the placental transfer of LMV and MBV in the ex vivo method of the human perfused cotyledon. Term placentas were perfused, in an open-circuit model, with LMV or MBV at concentrations in the range of clinical peak plasma concentrations. Concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. Mean fetal transfer rate (FTR) (fetal (FC) /maternal concentration), clearance index (CLI), accumulation index (AI) (retention of each drug in the cotyledon tissue) were measured. Mean FC were compared with half maximal effective concentrations of the drugs (EC50(LMV) and EC50(MBV)).Results: For LMV, the mean FC was (± standard deviation) 1.1 ± 0.2 mg/L, 1,000-fold above the EC50(LMV). Mean FTR, CLI and AI were 9 ± 1%, 35 ± 6% and 4 ± 2% respectively. For MBV, the mean FC was 1.4 ± 0.2 mg/L, 28-fold above the EC50(MBV). Mean FTR, CLI and AI were 10 ± 1%, 50 ± 7% and 2 ± 1% respectively.Conclusions: Drugs' concentrations in the fetal side should be in the range for in utero treatment of fetuses infected with CMV as the mean FC was superior to the EC50 for both molecules.
Published: 2020
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30. Placental Transfer of the integrase strand inhibitors cabotegravir and bictegravir in the Ex Vivo Human Cotyledon Perfusion Model

Author: Dominique Duro, Florian Bouchet-Crivat, Laurent Mandelbrot, Gilles Peytavin, Minh Patrick Lê, Lucile Pencolé, Service de Gynécologie-Obstétrique [Hôpital Louis-Mourier - APHP], Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pharmacologie et toxicologie [AP-HP Hôpital Bichat-Claude-Bernard], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Comets, Emmanuelle, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, food.ingredient, Pyridones, Placenta, Immunology, Integrase inhibitor, HIV Infections, In Vitro Techniques, Heterocyclic Compounds, 4 or More Rings, Models, Biological, Piperazines, Andrology, 03 medical and health sciences, chemistry.chemical_compound, Fetus, 0302 clinical medicine, Cabotegravir, food, Pharmacokinetics, Pregnancy, Humans, Immunology and Allergy, HIV Integrase Inhibitors, 030212 general & internal medicine, Maternal-Fetal Exchange, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Bictegravir, Transplacental, Amides, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Perfusion, 030104 developmental biology, Infectious Diseases, chemistry, Female, Cotyledon, Heterocyclic Compounds, 3-Ring, Ex vivo
Abstract: International audience; Data on placental transfer is lacking for the recent HIV integrase inhibitors, bictegravir and cabotegravir, although their future use in pregnancy is to be expected. The objective of this study was to determine their transplacental pharmacokinetics.Maternal-to-fetal transfer was investigated using the open-circuit ex-vivo dually perfused human cotyledon model.Cabotegravir or bictegravir was added to a maternal perfusate containing 2 g/l of human albumin and antipyrine, a marker to validate the cotyledon's viability, and cotyledons were dually perfused for up to 90 min.For cabotegravir, in five experiments, the median (IQR 25-75) cabotegravir concentrations in the maternal and in the fetal compartments were, respectively, 550 ng/ml (344-788) and 48 ng/ml (37-54), with a maternal-to-fetal ratio of 10% (5-16) and a clearance index (in comparison with antipyrine transfer) of 22% (19-28). The median cotyledon accumulation index was 10% (2-21).For bictegravir, in six experiments, the median (IQR 25-75) bictegravir concentrations in the maternal and in the fetal compartments were, respectively, 1650 ng/ml (1455-1960) and 126 ng/ml (112-142), with a maternal-to-fetal ratio of 7% (6-9.5) and a clearance index (in comparison with antipyrine transfer) of 21% (17-29). The median cotyledon accumulation index was 4% (3-5).Placental transfer of cabotegravir and bictegravir were low. This may not only limit the potential for fetal toxicities but also be a limit to their usefulness at the time of labor and delivery to reduce the risk of vertical HIV transmission. The safety and efficacy of these new integrase inhibitors in pregnancy requires more investigation.
Published: 2020
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31. Prevalence and clinical impact of minority resistant variants in patients failing an integrase inhibitor-based regimen by ultra-deep sequencing

Author: Eve Todesco, Maxime Grude, Sidonie Lambert-Niclot, A G Marcelin, Nathalie Désiré, Diane Descamps, Gilles Peytavin, Minh Patrick Lê, Christine Katlama, Philippe Flandre, Charlotte Charpentier, Thuy Van Nguyen, Marc Wirden, D. B. Fofana, Laurence Morand-Joubert, Vincent Calvez, Gestionnaire, Hal Sorbonne Université, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Virologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Virologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Virologie [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Service de Maladies Infectieuses et Tropicales [CHU Pitié-Salpêtrière]
Subjects: Adult, Male, 0301 basic medicine, Microbiology (medical), Paris, medicine.medical_specialty, Genotyping Techniques, [SDV]Life Sciences [q-bio], 030106 microbiology, Integrase inhibitor, HIV Infections, Drug resistance, 03 medical and health sciences, chemistry.chemical_compound, symbols.namesake, Antiretroviral Therapy, Highly Active, Internal medicine, Drug Resistance, Viral, Prevalence, medicine, Humans, Pharmacology (medical), HIV Integrase Inhibitors, Treatment Failure, Pharmacology, Sanger sequencing, Elvitegravir, business.industry, High-Throughput Nucleotide Sequencing, Middle Aged, Raltegravir, Resistance mutation, [SDV] Life Sciences [q-bio], Regimen, Infectious Diseases, chemistry, Dolutegravir, HIV-1, symbols, Female, business, medicine.drug
Abstract: Background Integrase strand transfer inhibitors (INSTIs) are recommended by international guidelines as first-line therapy in antiretroviral-naive and -experienced HIV-1-infected patients. Objectives This study aimed at evaluating the prevalence at failure of INSTI-resistant variants and the impact of baseline minority resistant variants (MiRVs) on the virological response to an INSTI-based regimen. Methods Samples at failure of 134 patients failing a raltegravir-containing (n = 65), an elvitegravir-containing (n = 20) or a dolutegravir-containing (n = 49) regimen were sequenced by Sanger sequencing and ultra-deep sequencing (UDS). Baseline samples of patients with virological failure (VF) (n = 34) and of those with virological success (VS) (n = 31) under INSTI treatment were sequenced by UDS. Data were analysed using the SmartGene platform, and resistance was interpreted according to the ANRS algorithm version 27. Results At failure, the prevalence of at least one INSTI-resistant variant was 39.6% by Sanger sequencing and 57.5% by UDS, changing the interpretation of resistance in 17/134 (13%) patients. Among 53 patients harbouring at least one resistance mutation detected by both techniques, the most dominant INSTI resistance mutations were N155H (45%), Q148H/K/R (23%), T97A (19%) and Y143C (11%). There was no difference in prevalence of baseline MiRVs between patients with VF and those with VS. MiRVs found at baseline in patients with VF were not detected at failure either in majority or minority mutations. Conclusions UDS is more sensitive than Sanger sequencing at detecting INSTI MiRVs at treatment failure. The presence of MiRVs at failure could be important to the decision to switch to other INSTIs. However, there was no association between the presence of baseline MiRVs and the response to INSTI-based therapies in our study.
Published: 2018
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32. High virological suppression regardless of the genotypic susceptibility score after switching to a dolutegravir-based regimen: week 48 results in an observational cohort

Author: Diane Descamps, Bao Phung, Charlotte Charpentier, Yazdan Yazdanpanah, Sylvie Le Gac, Minh Patrick Lê, Marine Perrier, Roland Landman, Véronique Joly, Gilles Peytavin, and Ornella Cabras
Subjects: Male, 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Genotype, Anti-HIV Agents, Pyridones, 030106 microbiology, HIV Infections, Drug resistance, Piperazines, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, Antiretroviral Therapy, Highly Active, Internal medicine, Drug Resistance, Viral, Oxazines, medicine, Humans, Pharmacology (medical), In patient, Pharmacology, Drug Substitution, business.industry, Middle Aged, Viral Load, CD4 Lymphocyte Count, Regimen, Infectious Diseases, chemistry, Cohort, Dolutegravir, HIV-1, RNA, Viral, Female, Observational study, business, Heterocyclic Compounds, 3-Ring, Cohort study
Abstract: To assess, in a clinical cohort, the efficacy of switching current ART in virologically suppressed patients to a dolutegravir-based regimen, regardless of the genotypic susceptibility score (GSS).This was an observational single-centre study assessing ART-treated patients with plasma viral load (pVL)50 copies/mL who were switched to a dolutegravir-based regimen with 1 year of follow-up. PCR negative was defined as an undetected PCR signal. Trough plasma concentration (C24) was determined using UPLC-MS/MS.Two hundred and thirty-nine patients initiated a dolutegravir-based regimen: 12%, 29% and 59% had a total GSS of 1 or 1.5 (group 1), 2 or 2.5 (group 2) and 3 (group 3), respectively. At switch initiation, the median time since first ART and the median duration with pVL50 copies/mL were 13 years (IQR = 6-19) and 3 years (IQR = 1-6), respectively. Median times since last genotype were 9, 10 and 5 years for groups 1, 2 and 3, respectively. Twenty patients (8.4%) discontinued the dolutegravir-based regimen due to adverse events. During the study, 96.4% (n = 661/686) of all pVL were50 copies/mL. Four patients (1.7%) experienced virological failure (two pVL50 copies/mL) without emergence of resistance; these patients' GSSs were 2, 2.5, 3 and 3. The median dolutegravir C24 was 1545 ng/mL (IQR = 1150-2097). Of the patients with pVL20 copies/mL, 72% were PCR negative during the follow-up, with no difference between the three groups of patients.This observational cohort study showed a high level of virological suppression maintenance in the first year following the switch to a dolutegravir-based regimen, even in patients with GSS ≤2.
Published: 2018
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33. Placental transfer of elvitegravir and cobicistat in an ex-vivo human cotyledon double perfusion model

Author: Valentine Faure-Bardon, Chloé Dussaux, Laurent Mandelbrot, Minh Patrick Lê, Dominique Duro, and Gilles Peytavin
Subjects: 0301 basic medicine, Anti-HIV Agents, Placenta, 030106 microbiology, Immunology, Quinolones, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Pregnancy, Tandem Mass Spectrometry, medicine, Humans, Immunology and Allergy, 030212 general & internal medicine, Maternal-Fetal Exchange, Chromatography, High Pressure Liquid, Fetus, Elvitegravir, Chemistry, Cobicistat, Transplacental, Models, Theoretical, Infectious Diseases, medicine.anatomical_structure, Female, Perfusion, Ex vivo, medicine.drug
Abstract: OBJECTIVE To determine the transplacental pharmacokinetics of the HIV integrase strand transfer inhibitor elvitegravir and of cobicistat, a cytochrome P450 inhibitor used as a pharmacoenhancer in antiretroviral therapy. DESIGN AND METHODS Maternal-to-fetal transfer across the term human placenta was investigated with the ex-vivo dually perfused cotyledon model, in seven open-circuit experiments and 10 closed-circuit (recirculating) experiments. Elvitegravir and cobicistat were added to a maternal perfusate containing 2 g/l of human serum albumin and antipyrine, as a marker to validate the cotyledon's viability. Elvitegravir and cobicistat concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. RESULTS For elvitegravir, in open-circuit experiments the mean (±SD) fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90 min) was 19 ± 13% and the mean clearance index was 0.46 ± 0.21; in the closed-circuit model, after 3 h of perfusion the FTR was 20 ± 10% and the mean accumulation index was 12.28 ± 5.57. For cobicistat, in the open perfusions the FTR was 23 ± 13% and the mean clearance index was 0.63 ± 0.34; in the closed perfusions after 3 h the fetal-to-maternal ratio of cobicistat was 21 ± 11%. The mean accumulation index was 3.46 ± 2.19 CONCLUSION:: The two models concurred to show moderate placental transfer of elvitegravir and cobicistat across the placenta as well as elvitegravir accumulation in the placenta tissue. Whether this may lead to toxicities and modifications in fetal or placental metabolism requires clinical studies.
Published: 2018
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34. Failure of hydroxychloroquine pre-exposure prophylaxis in COVID-19 infection? A case report

Author: Minh Patrick Lê, Jade Ghosn, Benoit Visseaux, Marie-Paule Chauveheid, Gilles Peytavin, Juliette Kauv, Quentin Le Hingrat, Laurent Massias, Marc Veyrier, and Diane Descamps
Subjects: Pharmacology, Microbiology (medical), 2019-20 coronavirus outbreak, medicine.medical_specialty, biology, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Hydroxychloroquine, biology.organism_classification, Treatment failure, Pre-exposure prophylaxis, Infectious Diseases, Internal medicine, Research Letter, Medicine, Pharmacology (medical), business, Betacoronavirus, medicine.drug
Published: 2020
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35. Usefulness of therapeutic drug monitoring of rilpivirine and its relationship with virologic response and resistance in a cohort of naive and pretreated HIV-infected patients

Author: Bruno Lacarelle, Florence Gattacceca, Saadia Mokhtari, Gilles Peytavin, Caroline Solas, Naïm Bouazza, Catherine Dhiver, Diane Descamps, Minh Patrick Lê, Sylvie Bregigeon, Yazdan Yazdanpanah, Catherine Tamalet, and Nadège Néant
Subjects: Adult, Male, medicine.medical_specialty, Anti-HIV Agents, HIV Infections, Emtricitabine, 030226 pharmacology & pharmacy, Gastroenterology, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, Humans, Pharmacology (medical), Trough Concentration, 030212 general & internal medicine, Tenofovir, Aged, Retrospective Studies, Pharmacology, medicine.diagnostic_test, business.industry, Rilpivirine, Original Articles, Middle Aged, Viral Load, Regimen, chemistry, Therapeutic drug monitoring, Pharmacodynamics, Cohort, HIV-1, Female, Drug Monitoring, business, medicine.drug
Abstract: Aims The purpose of this study was to assess the antiviral activity of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination and to describe the pharmacokinetics of rilpivirine and its association with resistance in clinical routine. Methods A retrospective multicentre cohort study was performed in both naive and pretreated HIV patients receiving the once-daily rilpivirine/emtricitabine/tenofovir disoproxil fumarate regimen. Immuno-virologic and resistance data, and rilpivirine plasma trough concentrations were collected over the follow-up. Statistical analyses were performed to evaluate the relationship between rilpivirine pharmacokinetics and virological response. Receiver operating characteristic (ROC) curve analysis was performed to determine the best target rilpivirine trough concentration. Results Overall, 379 patients were included. After a median follow-up of 28 months, 26% of patients discontinued mainly due to toxicity and the virological success rate was 65.7%. Virological failure occurred in 5% of patients. A significant proportion of patients with HIV-RNA > 40 copies/mL displayed rilpivirine plasma trough concentrations below the currently used 50 ng/mL efficacy threshold at both M6 (28%) and M12 (31%), in agreement with a significant lower median rilpivirine plasma trough concentration compared with patients virologically suppressed. Half of the patients with virologic failure who acquired rilpivirine resistance mutations had at least one suboptimal rilpivirine trough concentration. The optimal target for rilpivirine trough concentration was 70 ng/mL (sensitivity 75.4%; specificity 61.5%). Conclusions This study shows the impact of rilpivirine plasma trough concentration on both virological response and the emergence of rilpivirine mutations. Moreover, our results suggest that a higher target of rilpivirine trough concentration could be proposed in clinical practice.
Published: 2019

36. Lack of a Clinically Significant Pharmacokinetic Interaction between Etravirine and Raltegravir Using an Original Approach Based on Drug Metabolism, Protein Binding, and Penetration in Seminal Fluid: A Pharmacokinetic Substudy of the ANRS-163 ETRAL Study

Author: Minh Patrick, Lê, Marc-Antoine, Valantin, Lambert, Assoumou, Cathia, Soulie, Soizic, Le Mestre, Laurence, Weiss, Yazdan, Yazdanpanah, Jean-Michel, Molina, Olivier, Bouchaud, François, Raffi, Jacques, Reynes, Vincent, Calvez, Anne-Geneviève, Marcelin, Dominique, Costagliola, Christine, Katlama, Gilles, Peytavin, Karima, Hamdoud, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service des maladies infectieuses et tropicales [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Service de virologie [CHU Pitié-Salpêtrière], ANRS France Recherche Nord & sud Sida-hiv hépatites, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hopital Saint-Louis [AP-HP] (AP-HP), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), and Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Male, Anti-HIV Agents, [SDV]Life Sciences [q-bio], antiretroviral, interaction, HIV Infections, dual therapy, Middle Aged, Pyridazines, Pyrimidines, Semen, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Raltegravir Potassium, Nitriles, HIV-1, Humans, Drug Interactions, Drug Therapy, Combination, Female, seminal fluid, etravirine, raltegravir, pharmacokinetics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Protein Binding
Abstract: International audience; Study objective: The ANRS163-ETRAL study showed that etravirine 200 mg/raltegravir 400 mg twice-daily dual therapy was highly effective in the treatment of human immunodeficiency virus (HIV)-infected patients older than 45 years, with virologic and therapeutic success rates at week 48 of 99.4% and 94.5%, respectively. The objective of this study was to determine whether a clinically significant pharmacokinetic interaction between etravirine and raltegravir exists by assessing steady-state total and unbound etravirine, raltegravir, and inactive raltegravir-glucuronide concentrations 12 hours after last intake (C12h ) in blood plasma (BP) and seminal plasma (SP).Design: Pharmacokinetic analysis of data from the ANRS163-ETRAL study.Patients: One hundred forty-six HIV-1-infected patients (of the 165 patients included in the ANRS-163 ETRAL study) who were receiving etravirine 200 mg and raltegravir 400 mg twice daily.Measurements and main results: Blood was collected from all 146 patients at weeks 2-4, 12, 24, and 48, and semen was collected from 21 patients at week 48. The extent of BP and SP protein binding was determined by using ultrafiltration assay. Total and unbound etravirine, raltegravir, and raltegravir-glucuronide C12h were determined by ultra high performance liquid chromatography coupled with tandem mass spectrometry and interpreted by using the in vitro calculated protein-bound 95% inhibitory concentration (PBIC95 ) for wild-type (WT) HIV: etravirine (116 ng/ml) and raltegravir (15 ng/ml). Median (interquartile range [IQR]) total BP etravirine C12h (536 ng/ml [376-719]) and raltegravir (278 ng/ml [97-690]) were adequate in 99% and 96% of patients, respectively. Median (IQR) SP:BP C12h ratio and BP unbound fraction were etravirine 0.3 (0.2-0.5) and < 1%, respectively, raltegravir 1.8 (1.3-3.3) and 12%, respectively, and raltegravir-glucuronide 12.0 (6.5-17.7) and > 99%, respectively. The BP raltegravir metabolic ratio (raltegravir glucuronide:raltegravir ratio) was 1.7, suggesting only weak induction of raltegravir glucuronidation by etravirine. Only three patients had etravirine and raltegravir C12h < PBIC95 simultaneously.Conclusion: No clinically significant pharmacokinetic interaction between etravirine and raltegravir was detected. Total etravirine and raltegravir BP concentrations were adequate in most patients, favoring virologic efficacy and confirming good treatment adherence (> 95%), despite twice-daily administration. The long half-life of etravirine and higher unbound fraction SP of raltegravir (57%) ensured adequate concentrations of dual therapy in genital compartments. Our results indicate that etravirine and raltegravir have good, complementary pharmacokinetic profiles, suggesting that they could be used in a dual-treatment strategy.
Published: 2019
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37. Once‐daily darunavir/ritonavir 400/100 mg in triple therapy: efficacy and penetration in seminal compartment in ANRS ‐165 DARULIGHT study

Author: François Raffi, Jean-Michel Molina, Christine Katlama, Marie-Laure Chaix, Juliette Saillard, Minh Patrick Lê, Gilles Peytavin, Sylvie Chevret, Sebastien Gallien, Yazdan Yazdanpanah, Pierre Delobel, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de maladies infectieuses et tropicales [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Hopital Saint-Louis [AP-HP] (AP-HP), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP, Hôpital Henri-Mondor Albert-Chenevier, Service d'Immunologie Clinique et Maladies Infectieuses 94000 Créteil, France, Service de Maladies Infectieuses et Tropicales [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Services de Maladies Infectieuses et Tropicales [CHU Bichat], ANRS France Recherche Nord & sud Sida-hiv hépatites, Service des Maladies Infectieuses et Tropicales [CHU Saint Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Pistre, Karine
Subjects: Darunavir+Ritonavir, unbound total, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], MESH: HIV Infections / drug therapy, MESH: Darunavir / pharmacokinetics, darunavir, Pharmacology, MESH: Drug Administration Schedule, MESH: HIV-1 / drug effects, seminal and blood plasma, MESH: HIV Infections / blood, MESH: Dose-Response Relationship, Drug, MESH: HIV-1 / isolation & purification, medicine, MESH: HIV Infections / virology, Pharmacology (medical), Therapy efficacy, Letter to the Editor, Darunavir, MESH: Drug Combinations, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, business.industry, MESH: Drug Therapy, Combination / methods, MESH: Adult, Penetration (firestop), MESH: Darunavir / administration & dosage, MESH: HIV-1 / genetics, [SDV] Life Sciences [q-bio], MESH: HIV Protease Inhibitors / pharmacokinetics, dose reduction, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Dose reduction, MESH: HIV Protease Inhibitors / administration & dosage, Once daily, business, medicine.drug
Abstract: International audience; A key concern for reduced-dose antiretroviral regimens in maintenance strategies in HIV-infected patients is virological efficacy, as assessed by the suppression of HIV-RNA in blood and reservoirs, such as the genital tract. The risk of minority variants emerging in reservoirs with different antiretroviral drug penetrations and immune pressures is also a matter of concern [1–4]. Thus, antiviral activity and drug penetration into deep compartments must be considered in reduced-dose strategies.
Published: 2019
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38. High efficacy of first-line ART in a West African cohort, assessed by dried blood spot virological and pharmacological measurements

Author: Boubacar Madougou, M Daou, Elisabeth Rouveix, Sahada Moussa Saley, Yacouba Nouhou, Constance Delaugerre, Pierre de Truchis, Achirou Sani, Minh Patrick Lê, Eric Adehossi, Gilles Peytavin, and Mamadou Saidou
Subjects: Adult, Male, 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Efavirenz, Nevirapine, Adolescent, Genotyping Techniques, 030106 microbiology, Etravirine, HIV Infections, Microbial Sensitivity Tests, Emtricitabine, Medication Adherence, Specimen Handling, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, Abacavir, Antiretroviral Therapy, Highly Active, Internal medicine, Humans, Medicine, Pharmacology (medical), Niger, Desiccation, Pharmacology, business.industry, HIV, Lamivudine, Middle Aged, Viral Load, Virology, Blood, Cross-Sectional Studies, Treatment Outcome, Infectious Diseases, Anti-Retroviral Agents, chemistry, Rilpivirine, Female, business, Nucleic Acid Amplification Techniques, Viral load, Blood Chemical Analysis, medicine.drug
Abstract: OBJECTIVES The objectives of this study were to determine the rate of viral success in HIV-infected patients on first-line ART by the assessment of dried blood spot (DBS) viral load (VL) and to assess the performance of DBS sampling for VL measurement, genotypic resistance and antiretroviral concentration determinations. METHODS HIV-infected patients treated for >1 year with first-line ART in Niamey, Niger were included. VL based on nucleic acid sequence-based amplification (NASBA) assay (limit of quantification 100 copies/mL); antiretroviral concentrations were interpreted using standard plasma cut-offs after extrapolation of blood to plasma results. Median (IQR) results are presented. RESULTS Two hundred and eighteen patients (61% women), aged 41 (34-46) years, with 138 (56-235) CD4 cells/mm3 at baseline were included. After 4 (2-6) years of follow-up under therapy, CD4 gain was +197 (98-372) cells/mm3; 81% had VL
Published: 2016
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39. Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C

Author: Stanislas Harent, Brigitte Bernard Chabert, Dominique Salmon, Sophie Hillaire, Alexandra Heurgué-Berlot, Adriana Pinto, Minh Patrick Lê, Diane Descamps, Gilles Peytavin, David Zucman, Yazdan Yazdanpanah, Anne-Marie Simonpoli, Patrice Muret, Anne Gervais, Achour Laradi, Lucile Larrouy, Aude Desnoyer, Dan Pospai, and Hélène Fontaine
Subjects: Ledipasvir, Simeprevir, medicine.medical_specialty, Daclatasvir, Hepatology, Sofosbuvir, business.industry, medicine.medical_treatment, 030232 urology & nephrology, Hepatitis C, medicine.disease, End stage renal disease, 03 medical and health sciences, chemistry.chemical_compound, Regimen, 0302 clinical medicine, chemistry, Internal medicine, medicine, 030211 gastroenterology & hepatology, Hemodialysis, business, Intensive care medicine, medicine.drug
Abstract: Background & Aims Hepatitis C virus (HCV) infection is an independent risk factor for chronic kidney disease and leads to faster liver disease progression in patients requiring hemodialysis than in those with normal renal function. Little is known about the use of a sofosbuvir-containing regimen for infected patients on hemodialysis. We aimed to describe the pharmacokinetics, safety and efficacy of sofosbuvir in 2 dosing regimens and associated antiviral agents in HCV-infected patients requiring hemodialysis. Methods Multicenter, prospective and observational study of patients receiving sofosbuvir, 400mg once daily (n=7) or 3 times a week (n=5), after hemodialysis with simeprevir, daclatasvir, ledipasvir or ribavirin was conducted. Drug plasma concentrations were determined by liquid chromatography-tandem mass spectrometry before and after a 4h hemodialysis and 1.5h after last drug intake at the end of hemodialysis. Results Plasma concentrations of sofosbuvir or its inactive metabolite sofosbuvir-007 did not accumulate with either regimen between hemodialysis sessions or throughout the treatment course. Sofosbuvir-007 extraction ratio (52%) was consistent with historical data. In one patient receiving the once daily regimen, sofosbuvir-007 half-life was slightly higher (38h) than for patients with normal renal function receiving a full dose. Hemodialysis did not remove any other associated anti-HCV agents. Clinical and biological tolerance was good for all patients. Two relapses occurred with the 3 times a week regimen and none with the once daily. Conclusions A regimen including sofosbuvir, 400mg once daily, could be proposed for HCV-infected patients requiring hemodialysis and should be associated with close clinical, biological, cardiovascular, and therapeutic drug monitoring. Lay summary Hepatitis C Virus (HCV) infection in hemodialysis patients is prevalent and aggressive. Effective anti-HCV treatment in these patients may stabilize their renal disease. However, sofosbuvir, the cornerstone of most anti-HCV–containing regimens, should not be administered to these patients until more data is available. In this pharmacokinetic study, sofosbuvir full dose (400mg once daily) administered every day with another direct antiviral agent did not accumulate in hemodialysis patients and was safe and effective.
Published: 2016
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40. Prediction of human fetal pharmacokinetics usingex vivohuman placenta perfusion studies and physiologically based models

Author: Naïm Bouazza, Stéphane Blanche, Minh Patrick Lê, Déborah Hirt, Frantz Foissac, Elodie Valade, Gabrielle Lui, Jean-Marc Tréluyer, Saïk Urien, Cécile Vinot, Gilles Peytavin, Maïlys De Sousa Mendes, Sihem Benaboud, and Claire Pressiat
Subjects: 0301 basic medicine, Pharmacology, Fetus, Physiologically based pharmacokinetic modelling, business.industry, 030106 microbiology, Transplacental, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Pharmacokinetics, In vivo, Placenta, medicine, Pharmacology (medical), business, Perfusion, Ex vivo
Abstract: Aims Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively. Methods Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy-physiologically based pharmacokinetic (p-PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models. Results Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo. Conclusion The integration of ex vivo human placental perfusion parameters in a p-PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.
Published: 2016
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41. Outbreak of Pneumocystis jirovecii Infection Among Heart Transplant Recipients: Molecular Investigation and Management of an Interhuman Transmission

Author: Yazdan Yazdanpanah, William Vindrios, François-Xavier Lescure, Michel Wolff, G. Nevez, Laurent Massias, Sandrine Houzé, Jean-Christophe Lucet, Minh Patrick Lê, Nicolas Argy, Solène Le Gal, Richard Dorent, Service des maladies infectieuses et tropicales, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), Laboratoire de Parasitologie et Mycologiede [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service des maladies infectieuses et tropicales [CHU Tenon], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pharmacie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Hôpital Bichat - Claude Bernard, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Mère et enfant face aux infections tropicales (MERIT - UMR_D 216), Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Groupe d'Etude des Interactions Hôte-Parasite (GEIHP)
Subjects: Adult, Male, 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Genotype, 030106 microbiology, Pneumocystis carinii, Chemoprevention, Disease Outbreaks, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Trimethoprim, Sulfamethoxazole Drug Combination, medicine, Humans, Pneumocystis jirovecii, Outpatient clinic, 030212 general & internal medicine, Genotyping, Atovaquone, ComputingMilieux_MISCELLANEOUS, Aged, Cross Infection, biology, Transmission (medicine), business.industry, Pneumonia, Pneumocystis, Outbreak, Middle Aged, biology.organism_classification, Trimethoprim, 3. Good health, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Chemoprophylaxis, Heart Transplantation, Female, business, medicine.drug
Abstract: Background An outbreak of Pneumocystis jirovecii pneumonia (PCP) occurred among heart transplant recipients (HTR) at the outpatient clinic of a university hospital, from March to September 2015. Clinical, therapeutic, biological, and molecular data were analyzed to determine its origin and control the outbreak. Methods Clinical and biological data regarding all HTR followed in the outpatient clinic were collected. PCP diagnosis was based on microscopy and real-time polymerase chain reaction (PCR). Investigations were performed by building a transmission map, completed by genotyping Pneumocystis isolates and by a control of chemoprophylaxis observance. Asymptomatic exposed patients were screened for colonization using real-time PCR. Results Among 124 HTR, 7 PCP cases were confirmed. Screening identified 3 additional patients colonized by P. jirovecii. All patients were cured, and no further cases were identified after trimethoprim-sulfamethoxazole prophylaxis was introduced in the entire cohort. Genotyping demonstrated the same strain in all PCP cases and colonized patients. All cases were linked with possible transmission chains from 2 possible index patients. Interhuman transmission was significantly associated with more frequent visits in the outpatient clinic. Six cases were receiving atovaquone as a prophylaxis. The occurrence of PCP was significantly associated with atovaquone prophylaxis. Conclusions This is the first outbreak with detailed molecular analysis in HTR so far. Genotyping and transmission chain confirmed interhuman transmission in all colonized/infected PCP cases. Outpatient clinic layout and high encounters probably caused this PCP cluster, which was controlled after systematic trimethoprim-sulfamethoxazole prophylaxis in exposed patients.
Published: 2017
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42. Population pharmacokinetics of Rilpivirine in HIV-1-infected patients treated with the single-tablet regimen rilpivirine/tenofovir/emtricitabine

Author: Nadège Néant, Bruno Lacarelle, Catherine Dhiver, Florence Gattacceca, Caroline Solas, Diane Descamps, Saadia Mokhtari, Minh Patrick Lê, Sylvie Bregigeon, Yazdan Yazdanpanah, Catherine Tamalet, and Gilles Peytavin
Subjects: 0301 basic medicine, Male, Human immunodeficiency virus (HIV), Administration, Oral, HIV Infections, medicine.disease_cause, 030226 pharmacology & pharmacy, chemistry.chemical_compound, 0302 clinical medicine, Tandem Mass Spectrometry, Pharmacology (medical), Drug Dosage Calculations, Aged, 80 and over, education.field_of_study, medicine.diagnostic_test, General Medicine, Middle Aged, Rilpivirine, Area Under Curve, Female, France, Drug Monitoring, medicine.drug, Half-Life, Tablets, Adult, medicine.medical_specialty, Anti-HIV Agents, Metabolic Clearance Rate, 030106 microbiology, Population, Emtricitabine, Models, Biological, 03 medical and health sciences, Young Adult, Pharmacokinetics, Internal medicine, medicine, Humans, Computer Simulation, education, Aged, Retrospective Studies, Pharmacology, business.industry, NONMEM, Regimen, chemistry, Nonlinear Dynamics, Therapeutic drug monitoring, HIV-1, Emtricitabine, Rilpivirine, Tenofovir Drug Combination, business, Software, Chromatography, Liquid
Abstract: Rilpivirine, prescribed for the treatment of HIV infection, presents an important inter-individual pharmacokinetic variability. We aimed to determine population pharmacokinetic parameters of rilpivirine in adult HIV-infected patients and quantify their inter-individual variability. We conducted a multicenter, retrospective, and observational study in patients treated with the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. As part of routine therapeutic drug monitoring, rilpivirine concentrations were measured by UPLC-MS/MS. Population pharmacokinetic analysis was performed using NONMEM software. Once the compartmental and random effects models were selected, covariates were tested to explain the inter-individual variability in pharmacokinetic parameters. The final model qualification was performed by both statistical and graphical methods. We included 379 patients, resulting in the analysis of 779 rilpivirine plasma concentrations. Of the observed trough individual plasma concentrations, 24.4% were below the 50 ng/ml minimal effective concentration. A one-compartment model with first-order absorption best described the data. The estimated fixed effect for plasma apparent clearance and distribution volume were 9 L/h and 321 L, respectively, resulting in a half-life of 25.2 h. The common inter-individual variability for both parameters was 34.1% at both the first and the second occasions. The inter-individual variability of clearance was 30.3%. Our results showed a terminal half-life lower than reported and a high proportion of patients with suboptimal rilpivirine concentrations, which highlights the interest of using therapeutic drug monitoring in clinical practice. The population analysis performed with data from “real-life” conditions resulted in reliable post hoc estimates of pharmacokinetic parameters, suitable for individualization of dosing regimen.
Published: 2017

43. Darunavir/ritonavir monotherapy at a low dose (600/100 mg/day) in HIV-1-infected individuals with suppressed HIV viraemia

Author: Ruxandra Calin, Fabienne Caby, Gilles Peytavin, Marc-Antoine Valantin, Lambert Assoumou, Luminita Schneider, Sophie Seang, Minh Patrick Lê, Thuy Van Nguyen, A G Marcelin, Cathia Soulié, Roland Tubiana, and Christine Katlama
Subjects: 0301 basic medicine, Microbiology (medical), Male, medicine.medical_specialty, Sustained Virologic Response, Anti-HIV Agents, 030106 microbiology, Human immunodeficiency virus (HIV), HIV Infections, Drug resistance, medicine.disease_cause, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Drug Resistance, Viral, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Dose Reduced, Darunavir, Pharmacology, Ritonavir, business.industry, virus diseases, Lopinavir, Middle Aged, Viral Load, Atazanavir, Infectious Diseases, Treatment Outcome, HIV-1, Female, business, Viral load, medicine.drug
Abstract: Background Darunavir/ritonavir is a potent PI with a high genetic barrier and pharmacological robustness favourably investigated as monotherapy. Whether darunavir could be dose reduced in the context of monotherapy deserves investigation. Methods Patients with HIV suppressed viraemia (plasma viral load
Published: 2017

44. Penetration and antiviral efficacy of total and unbound maraviroc, raltegravir and rilpivirine in both female and male genital fluids from HIV-positive patients receiving regimens containing these antiretrovirals

Author: Dominique Salmon, Gilles Peytavin, Nadia Mahjoub, Jade Ghosn, Odile Launay, Jean-Paul Viard, Linda Belarbi, Emmanuel Dulioust, Marie-Laure Chaix, Minh Patrick Lê, and Claudine Duvivier
Subjects: 0301 basic medicine, Microbiology (medical), Adult, Male, medicine.medical_specialty, Anti-HIV Agents, 030106 microbiology, HIV Infections, Cervix Uteri, Gastroenterology, Maraviroc, 03 medical and health sciences, chemistry.chemical_compound, Cyclohexanes, Semen, Internal medicine, Raltegravir Potassium, Blood plasma, Medicine, Humans, Pharmacology (medical), Sex organ, Prospective Studies, Prospective cohort study, Pharmacology, business.industry, Rilpivirine, Middle Aged, Triazoles, Viral Load, Raltegravir, Body Fluids, Infectious Diseases, medicine.anatomical_structure, chemistry, Vagina, HIV-1, Female, business, Viral load, medicine.drug
Abstract: Background Sub-optimal penetration of antiretroviral drugs in genital compartments might promote local HIV persistence and increase the risk of HIV transmission. Objectives To describe the penetration of maraviroc, raltegravir, raltegravir glucuronide and rilpivirine in seminal plasma and cervico-vaginal secretions (CVS) and to assess local antiretroviral efficacy in HIV-1-positive patients. Methods This was a prospective, multicentre study. Inclusion criteria were HIV-1 positive, age >18 years, receiving regimens containing maraviroc and/or raltegravir and/or rilpivirine for >1 month, and good self-reported adherence. Paired blood and genital samples were collected 12 h (raltegravir and maraviroc) or 24 h (rilpivirine) post-dose. These concentrations were determined (UPLC-MS/MS) in blood and seminal plasma (total and unbound) and CVS (total, dried spots) and HIV-RNA was quantified in paired blood and genital samples. Results Among the 54 enrolled patients, 15 received maraviroc (6 men), 27 received raltegravir (14 men) and 20 received rilpivirine (10 men), corresponding to 54 total and 52 unbound plasma concentrations, 29 total CVS samples and 23 total and 18 unbound seminal plasma samples. Maraviroc and raltegravir displayed a ratio of genital fluids/plasma concentrations >0.5 in both male and female genital tracts. Conversely, rilpivirine displayed a low ratio. Antiretroviral free fractions were consistent with historical data. Nine patients had blood plasma HIV-RNA >50 copies/mL (2/9 had sub-optimal antiretroviral blood plasma exposure) and two other patients had detectable HIV-RNA in genital fluids. Conclusions Maraviroc and raltegravir demonstrated good penetration in genital compartments, yielding good local virological response in genital compartments, whereas rilpivirine presented a low penetration profile but good local response.
Published: 2017

45. Impact of obesity on antiretroviral pharmacokinetics and immuno-virological response in HIV-infected patients: a case-control study

Author: Patrick Yeni, Gilles Peytavin, Vincent Madelain, Minh Patrick Lê, Véronique Joly, Karen Champenois, Charlotte Charpentier, Roland Landman, Diane Descamps, and Yazdan Yazdanpanah
Subjects: 0301 basic medicine, Microbiology (medical), Adult, Male, medicine.medical_specialty, Efavirenz, Nevirapine, Anti-HIV Agents, 030106 microbiology, HIV Infections, Pharmacology, Emtricitabine, Article, Body Mass Index, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Abacavir, Internal medicine, Drug Resistance, Viral, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Obesity, 2. Zero hunger, Dose-Response Relationship, Drug, business.industry, virus diseases, Lopinavir, HIV Protease Inhibitors, Middle Aged, Viral Load, Raltegravir, 3. Good health, Atazanavir, CD4 Lymphocyte Count, Infectious Diseases, Logistic Models, chemistry, Case-Control Studies, HIV-1, RNA, Viral, Ritonavir, Female, business, medicine.drug
Abstract: Background: Obesity has a large prevalence among HIV-infected patients. Increased adipose tissue mass affects the pharmacokinetics of numerous drugs, but only a few data are available for antiretroviral drugs. Objective: In this study, we aimed to explore the pharmacokinetics of antiretroviral drugs and the immune-virological response in obese patients with HIV infection. Patients and methods: We examined data from 2009 to 2012 in our hospital’s database for HIV-1-infected patients who received an antiretroviral drug among abacavir, emtricitabine, lamivudine, tenofovir, efavirenz, etravirine, nevirapine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir and raltegravir. Obese patients were defined with body mass index (BMI) ≥30 kg/m2 and normal-weight patients with BMI 19–25 kg/m2. Plasma concentrations (C12/24h) were compared for each antiretroviral using Mann-Whitney test. Suboptimal dosing and virological outcome were assessed by logistic regression, adjusting on covariates. Results: We enrolled 291 obese and 196 normal-weight patients. Among the 12 analyzed antiretroviral drugs, tenofovir, efavirenz and lopinavir C12h were significantly lower in obese than normal-weight patients: 66 versus 86 ng/mL, 1,498 versus 2,034 ng/mL and 4,595 versus 6,420 ng/mL respectively (P < 0.001). Antiretroviral C12/24h were more frequently below efficacy thresholds for obese than normal-weight patients after adjustment for other covariates (P < 0.001). Although obese patients showed higher CD4 count than normal-weight (510 vs 444 cells/µL, P < 0.001), the groups did not differ in virological failure rate. Conclusion: This study highlights the impact of obesity on antiretroviral plasma exposure, but identifies no consequence of this suboptimal exposure on the immuno-virological control in this population.
Published: 2017

46. Plasma concentrations of atovaquone given to immunocompromised patients to prevent Pneumocystis jirovecii

Author: Catherine Cordonnier, Rabah Redjoul, Giovanna Melica, Christine Robin, Nihel Khoudour, Minh Patrick Lê, Anne Hulin, Mathieu Leclerc, Laurent Massias, Sébastien Maury, and Florence Beckerich
Subjects: 0301 basic medicine, Microbiology (medical), Male, medicine.medical_specialty, Antifungal Agents, 030106 microbiology, Cmax, Biological Availability, HIV Infections, Pneumocystis carinii, Gastroenterology, 03 medical and health sciences, Cmin, Immunocompromised Host, 0302 clinical medicine, Internal medicine, medicine, Pneumocystis jirovecii, Humans, Pharmacology (medical), 030212 general & internal medicine, Atovaquone, Aged, Pharmacology, biology, medicine.diagnostic_test, business.industry, Pneumonia, Pneumocystis, Middle Aged, biology.organism_classification, Trimethoprim, Regimen, Infectious Diseases, Therapeutic drug monitoring, Chemoprophylaxis, Female, business, medicine.drug
Abstract: Objectives Atovaquone is one of the alternatives to trimethoprim/sulfamethoxazole for prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients. In volunteers, there was wide inter-individual variability in atovaquone bioavailability. The aim of this study was to assess the plasma concentrations of atovaquone in immunocompromised patients under PCP prophylaxis. Methods Adult haematology or HIV-positive patients receiving atovaquone (750 mg oral suspension twice a day) for PCP prophylaxis were included. Plasma concentrations were assessed using UV-HPLC, around 12 h after the evening dose (Cmin) and 1-5 h after the morning dose (Cmax). Results A total of 82 measurements were performed in 33 patients. This included 19 HSCT recipients, 7 haematology non-transplant patients and 7 HIV-positive patients. The median Cmin (IQR) was 11.3 μg/mL (6.2-27.8) and the median Cmax was 13.4 μg/mL (6.0-28.3). The Cmin and Cmax of atovaquone were not different between HIV-negative and HIV-positive patients, or between HSCT and non-HSCT patients. Atovaquone concentrations were not influenced by the co-administration of valaciclovir (n = 20) or ciclosporin (n = 11), by gut graft-versus-host disease (n = 7) or by the intake of atovaquone with food. Nineteen of the 33 (58%) patients had Cmin
Published: 2017

47. Pharmacokinetics, Safety and Efficacy of Ritonavir-Boosted Atazanavir (300/100 mg Once Daily) in HIV-1-Infected Pregnant Women

Author: P. Faucher, Patricia Bourse, Florence Damond, Gilles Peytavin, Sylvie Lariven, Sylvie Legac, Marc Dommergues, Françoise Meier, Roland Landman, Agnès Bourgeois-Moine, Roland Tubiana, Vincent Calvez, Minh Patrick Lê, Sophie Matheron, Diane Descamps, Houria Ichou, Emmanuel Mortier, Cathia Soulié, Dominique Duro, Laurent Mandelbrot, and Marc-Antoine Valantin
Subjects: Adult, Atazanavir Sulfate, Human immunodeficiency virus (HIV), Pharmacology, medicine.disease_cause, Drug Administration Schedule, Pharmacokinetics, Pregnancy, medicine, Humans, Pharmacology (medical), Protease inhibitor (pharmacology), Pregnancy Complications, Infectious, Hyperbilirubinemia, Ritonavir, Transmission (medicine), business.industry, Infant, Newborn, HIV Protease Inhibitors, Viral Load, medicine.disease, CD4 Lymphocyte Count, Atazanavir, Drug Combinations, Cross-Sectional Studies, Infectious Diseases, HIV-1, Female, Once daily, business, medicine.drug
Abstract: Background Atazanavir/ritonavir (ATV/r) is a boosted protease inhibitor recommended to minimize the risk of mother-to-child HIV-1 transmission (MTCT). We aimed to assess the pharmacokinetics, safety and efficacy of ATV/r in HIV-1-infected pregnant women and their neonates. Methods A multicentre, cross-sectional, non-interventional cohort of HIV-1-infected pregnant women receiving ATV/r (300/100 mg once daily) who delivered in three Paris hospitals from 2006 to 2013 was designed. We determined antiretroviral trough plasma concentrations using liquid chromatography–mass spectrometry at each of the three trimesters, delivery and post-partum. ATV concentrations at 24 h (C24h) were interpreted by the 150–850 ng/ml efficacy–tolerance thresholds. Safety data and newborn HIV status were recorded. A mother's virological failure was defined as two successive measurements of plasma HIV-1 RNA>50 copies/ml within the 2 months before delivery. Results 103 pregnant women were included, mostly from sub-Saharan Africa (88%). ATV C24h at each of the three trimesters and delivery remained similar to post-partum values. No dose adjustment was needed during pregnancy. The median plasma ratio of fetal/ maternal ATV level was 0.19 ( n=28). Only three patients showed two successive detectable viral loads but Conclusions In this population, an ATV/r-containing anti-retroviral regimen demonstrated good pharmacokinetics, virological efficacy and safety. No significant impact of pregnancy on ATV C24h was found. No dose adjustment was required.
Published: 2014
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48. HIV-1 diagnosis with unquantifiable viraemia: don't be naive, look for antiretroviral drugs

Author: Yazdan Yasdanpanah, Minh Patrick Lê, Christine Katlama, Diane Descamps, François Pichon, Sie Dionou, Nathalie Désiré, Roland Tubiana, Marc Antoine Valantin, Anne-Geneviève Marcelin, Vincent Calvez, Charlotte Charpentier, Gilles Peytavin, Marc Wirden, HAL UPMC, Gestionnaire, Service de Virologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Maladies Infectieuses et Tropicales [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Microbiology (medical), Adult, Male, [SDV]Life Sciences [q-bio], Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, 03 medical and health sciences, Medicine, Humans, Pharmacology (medical), Viremia, Aged, Retrospective Studies, Pharmacology, business.industry, Clinical Laboratory Techniques, Middle Aged, Viral Load, CD4 Lymphocyte Count, [SDV] Life Sciences [q-bio], 030104 developmental biology, Infectious Diseases, Anti-Retroviral Agents, Immunology, HIV-1, Female, business
Abstract: International audience; No abstract available
Published: 2016
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49. Plasma concentrations of maraviroc and raltegravir after dual therapy in patients with long-term suppressed viraemia: ROCnRAL ANRS 157 study

Author: B. Hoen, P. Bourse, P. Leclercq, Lambert Assoumou, X. Rey-Coquais, J. P. Aboulker, P. Morlat, L. Chablais, J. M. Molina, C. Blanc, Claudine Duvivier, J. Reynes, V. Calvez, M. Shoai-Tehrani, F. Durand, P. Mercié, A. Makinson, F. Raffi, A. Canestri, C. Katlama, S. Gerberon, Gilles Peytavin, A. Cheret, A. Simon, S. Dominguez, C. Brochier, S. Scerra, J.-P. Bastard, Y. Dudoit, A.-S. Ritleng, I. Poizot Martin, S. Kolta, C. Soulié, S. Caldato, C. Lupin, Marc-Antoine Valantin, F. Touam, Y. Levy, N. Velazquez, O. Faucher, Minh Patrick Lê, S. Couffin Cadiergues, A G Marcelin, G. Pialoux, S. Bonne, V. Thoirain, J. Saillard, P. Geneau de la Marliere, Diane Ponscarme, Christine Katlama, C. Debreux, J. Capeau, M.-C. Marien, C. Crisol, K. Koffi, Vincent Calvez, H. Hue, H. Fisher, Cathia Soulié, L. Schneider, C. Lemarchand, L. Cotte, M.-J. Dulucq, C. Chesnel, D. Ponscarme, Anne-Geneviève Marcelin, L. Assoumou, Julie Chas, C. Haffner-Mauvais, C. Duvivier, L. Cuzin, Dominique Costagliola, J. Chas, and Marc Antoine Valantin
Subjects: Pharmacology, Microbiology (medical), medicine.medical_specialty, business.industry, Raltegravir, Gastroenterology, Term (time), chemistry.chemical_compound, Infectious Diseases, chemistry, Internal medicine, Plasma concentration, medicine, Pharmacology (medical), In patient, Dual therapy, business, Maraviroc, medicine.drug
Published: 2015
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50. Switch as maintenance to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate: week 48 results in a clinical cohort

Author: Diane Descamps, Roland Landman, V Joly, Louis Blondel, Benoit Visseaux, Marine Perrier, Charlotte Charpentier, Adriana Pinto, Gilles Peytavin, Yazdan Yazdanpanah, Minh Patrick Lê, and Sophie Matheron
Subjects: 0301 basic medicine, Microbiology (medical), Adult, Male, medicine.medical_specialty, Anti-HIV Agents, 030106 microbiology, HIV Infections, Pharmacology, Quinolones, Emtricitabine, Gastroenterology, Polymerase Chain Reaction, Maintenance Chemotherapy, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antiretroviral Therapy, Highly Active, Medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Viremia, Adverse effect, Tenofovir, Elvitegravir/cobicistat/emtricitabine/tenofovir, business.industry, Elvitegravir, Cobicistat, Middle Aged, Viral Load, CD4 Lymphocyte Count, Regimen, Infectious Diseases, HIV-1, RNA, Viral, Female, business, Viral load, medicine.drug, Cohort study, Tablets
Abstract: 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 ).This was an observational single-centre study enrolling antiretroviral-treated patients with pVL50 copies/mL initiating elvitegravir-based STR. PCRneg was defined as an undetected PCR signal.One hundred and fifty-one patients were enrolled. At STR baseline, the median time since first ART and time of virological suppression were 5 years (IQR 3-9) and 24 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 pVL50 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 pVL20 copies/mL had a PCRneg, respectively. The median elvitegravir plasma C 24 value was 648 ng/mL (IQR 348-989; n = 237), with 84% of elvitegravir C 24 values45 ng/mL, the protein-adjusted IC 95 .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.
Published: 2016

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