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1. Association between SARS‐CoV‐2 viral kinetics and clinical score evolution in hospitalized patients

Author: Nadège Néant, Guillaume Lingas, Alexandre Gaymard, Drifa Belhadi, Maya Hites, Thérèse Staub, Richard Greil, Jose‐Artur Paiva, Julien Poissy, Nathan Peiffer‐Smadja, Dominique Costagliola, Yazdan Yazdanpanah, Maude Bouscambert‐Duchamp, Amandine Gagneux‐Brunon, Florence Ader, France Mentré, Florent Wallet, Charles Burdet, Jérémie Guedj, and the DisCoVeRy study group
Subjects: Therapeutics. Pharmacology, RM1-950
Abstract: Abstract The role of antiviral treatment in coronavirus disease 2019 hospitalized patients is controversial. To address this question, we analyzed simultaneously nasopharyngeal viral load and the National Early Warning Score 2 (NEWS‐2) using an effect compartment model to relate viral dynamics and the evolution of clinical severity. The model is applied to 664 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020‐000936‐23) randomly assigned to either standard of care (SoC) or SoC + remdesivir. Then we use the model to simulate the impact of antiviral treatments on the time to clinical improvement, defined by a NEWS‐2 score lower than 3 (in patients with NEWS‐2
Published: 2023
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2. The psychological syndrome associated with Long-COVID: A study protocol

Author: Raquel Gómez Bravo, Alexandre Infanti, Joël Billieux, Mark Ritzen, Psy-Long-COVID Consortium, Claus Vögele, Charles Benoy, Steffen Mortiz, Angelika Erhardt, Thérèse Staub, Christian Huber, Undine Lang, Steffi Weidt, Kira Wolff, and Juliane Müller
Subjects: Long-COVID, COVID-19, persistent COVID-19 symptoms, post-COVID-19 syndrome, mental health, Infectious and parasitic diseases, RC109-216
Abstract: IntroductionChronic post-viral syndromes, including Long-COVID, are characterized by a range of persistent symptoms that occur following a viral infection. Psychological symptoms are prevalent in Long-COVID patients and can have a significant impact on their quality of life. However, the specific patterns of psychological symptoms, their associations with physical symptoms, and the factors predicting their severity remain poorly understood.AimsThis study aims to explore and systematically assess psychological symptoms in Long-COVID, to identify syndrome clusters based on these symptoms, to examine their relationship with physical symptoms, and to investigate the influence of pandemic-related variables.MethodsDescriptive, cross-sectional study with data collected through an online questionnaire across several EU countries, from February 2020 to December 2022. Participants were recruited using public relations, the social media and information campaigns directed at the public and health professionals using snowball sampling.ResultsThe findings will allow to phenotype Long-COVID related psychological symptom clusters based on self-reports. facilitating improved assessment and treatment approaches.ConclusionsThe results will provide important knowledge for the public health management of the public healh management of Long COVID. The findings will contribute to a better understanding of the psychological symptoms associated with Long-COVID and the development of specific treatment guidelines for psychological burden associated with Long-COVID, thereby supporting management strategies to combat the after-effects of the COVID-19 pandemic, enhancing their overall well-being and quality of life.
Published: 2023
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3. Management of pharmacovigilance during the COVID‐19 pandemic crisis by the safety department of an academic sponsor: Lessons learnt and challenges from the EU DisCoVeRy clinical trial

Author: Noémie Mercier, Drifa Belhadi, Aline DeChanet, Christelle Delmas, Juliette Saillard, Marina Dumousseaux, Soizic Le Mestre, Claire Fougerou‐Leurent, Assia Ferrane, Charles Burdet, Hélène Espérou, Florence Ader, Maya Hites, Nathan Peiffer‐Smadja, Julien Poissy, Claire Andrejak, José Artur Paiva, Evelina Tacconelli, Thérèse Staub, Richard Greil, Dominique Costagliola, France Mentre, Yazdan Yazdanpanah, Alpha Diallo, and the DisCoVeRy Safety Working group
Subjects: adverse event, COVID‐19, EU‐RESPONSE, pandemic crisis, pharmacovigilance, Therapeutics. Pharmacology, RM1-950
Abstract: Abstract The current COVID‐19 pandemic was an exceptional health situation, including for drug use. As there was no known effective drug for COVID‐19 at the beginning of the pandemic, different drug candidates were proposed. In this article, we present the challenges for an academic Safety Department to manage the global safety of a European trial during the pandemic. The National Institute for Health and Medical Research (Inserm) conducted a European multicenter, open‐label, randomized, controlled trial involving three repurposed and one‐in development drugs (lopinavir/ritonavir, IFN‐β1a, hydroxychloroquine, and remdesivir) in adults hospitalized with COVID‐19. From 25 March 2020 to 29 May 2020, the Inserm Safety Department had to manage 585 Serious Adverse Events (SAEs) initial notification and 396 follow‐up reports. The Inserm Safety Department's staff was mobilized to manage these SAEs and to report Expedited safety reports to the competent authorities within the legal timeframes. More than 500 queries were sent to the investigators due to a lack of or incoherent information on SAE forms. At the same time, the investigators were overwhelmed by the management of patients suffering from COVID‐19 infection. These particular conditions of missing data and lack of accurate description of adverse events made evaluation of the SAEs very difficult, particularly the assessment of the causal role of each investigational medicinal product. In parallel, working difficulties were accentuated by the national lockdown, frequent IT tool dysfunctions, delayed implementation of monitoring and the absence of automatic alerts for SAE form modification. Although COVID‐19 is a confounding factor per se, the delay in and quality of SAE form completion and the real‐time medical analysis by the Inserm Safety Department were major issues in the quick identification of potential safety signals. To conduct a high‐quality clinical trial and ensure patient safety, all stakeholders must take their roles and responsibilities.
Published: 2023
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4. Changes in body mass index and clinical outcomes after initiation of contemporary antiretroviral regimens

Author: Wendy P. Bannister, T. Christopher Mast, Stéphane de Wit, Jan Gerstoft, Lothar Wiese, Ana Milinkovic, Vesna Hadziosmanovic, Amanda Clarke, Line D. Rasmussen, Karine Lacombe, Philipp Schommers, Thérèse Staub, Alexandra Zagalo, Joseba J. Portu, Luba Tau, Alexandra Calmy, Matthias Cavassini, Martin Gisinger, Elena Borodulina, Amanda Mocroft, Joanne Reekie, and Lars Peters
Subjects: Male, Adult, Adolescent, Immunology, HIV Infections, Middle Aged, Overweight, Body Mass Index, Infectious Diseases, Anti-Retroviral Agents, Cardiovascular Diseases, Risk Factors, Neoplasms, Diabetes Mellitus, Humans, Immunology and Allergy, Female, Obesity
Abstract: Weight gain is becoming increasingly prevalent amongst people with HIV (PWH) receiving contemporary antiretroviral treatment. We investigated BMI changes and clinical impact in a large prospective observational study.PWH aged ≥18 years were included who started a new antiretroviral (baseline) during 2010-2019 with baseline and ≥1 follow-up BMI assessment available. Rates of clinical outcomes (cardiovascular disease [CVD], malignancies, diabetes mellitus [DM] and all-cause mortality) were analysed using Poisson regression to assess effect of time-updated BMI changes (gt;1 kg/m 2 decrease, ±1 kg/m 2 stable,gt;1 kg/m 2 increase), lagged by 1-year to reduce reverse causality. Analyses were adjusted for baseline BMI plus key confounders including antiretroviral exposure.6721 PWH were included; 72.3% were male, median age 48 years (interquartile range [IQR] 40-55). At baseline, 8.4% were antiretroviral-naive, and 5.0% were underweight, 59.7% healthy weight, 27.5% overweight, and 7.8% were living with obesity. There was an 8.2% increase in proportion of overweight and 4.8% in obesity over the study period (median follow-up 4.4 years [IQR 2.6-6.7]).100 CVDs, 149 malignancies, 144 DMs, and 257 deaths were observed with incidence rates 4.4, 6.8, 6.6, 10.6 per 1000 person-years of follow-up, respectively. Compared to stable BMI,gt;1 kg/m 2 increase was associated with increased risk of DM (adjusted incidence rate ratio [IRR]: 1.96, 95% confidence interval [CI]: 1.36-2.80) andgt;1 kg/m 2 decrease with increased risk of death (adjusted IRR: 2.33, 95% CI: 1.73-3.13). No significant associations were observed between BMI changes and CVD or malignancies.A BMI increase was associated with DM and a decrease associated with death.
Published: 2022
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5. Injection of cocaine is associated with a recent HIV outbreak in people who inject drugs in Luxembourg.

Author: Vic Arendt, Laurence Guillorit, Alain Origer, Nicolas Sauvageot, Michel Vaillant, Aurélie Fischer, Henri Goedertz, Jean-Hugues François, Ivailo Alexiev, Thérèse Staub, and Carole Seguin-Devaux
Subjects: Medicine, Science
Abstract: BackgroundAn outbreak of HIV infections among people who inject drugs (PWID) started in 2014 in Luxembourg.ObjectivesWe conducted phylogenetic and epidemiological analyses among the PWID infected with HIV in Luxembourg or attending the supervised drug consumption facility (SDCF) to understand the main causes of the outbreak.MethodsBetween January 2013 and December 2017, analysis of medical files were performed from all PWID infected with HIV at the National Service of Infectious Diseases (NSID) providing clinical care nationwide. PWID were interviewed at NSID and SDCF using a standardized questionnaire focused on drug consumption and risk behaviours. The national drug monitoring system RELIS was consulted to determine the frequency of cocaine/heroin use. Transmission clusters were analysed by phylogenetic analyses using approximate maximum-likelihood. Univariate and multivariate logistic regression analyses were performed on epidemiological data collected at NSID and SDCF to determine risk factors associated with cocaine use.ResultsFrom January 2013 to December 2017, 68 new diagnosis of HIV infection reported injecting drug use as the main risk of transmission at NSID. The proportion of female cases enrolled between 2013-2017 was higher than the proportion among cases enrolled prior to 2013. (33% vs 21%, p < 0.05). Fifty six viral sequences were obtained from the 68 PWID newly diagnosed for HIV. Two main transmission clusters were revealed: one HIV-1 subtype B cluster and one CRF14_BG cluster including 37 and 9 patients diagnosed since 2013, respectively. Interviews from 32/68 (47%) newly diagnosed PWID revealed that 12/32 (37.5%) were homeless and 27/32 (84.4%) injected cocaine. Increased cocaine injection was indeed reported by the RELIS participants from 53 to 63% in drug users with services contacts between 2012 and 2015, and from 5 to 22% in SDCF users between 2012 and 2016. Compared with PWID who injected only heroin (n = 63), PWID injecting cocaine and heroin (n = 107) were younger (mean of 38 vs 44 years, p≤0.001), reported more frequent piercing (≤0.001), shared and injected drugs more often (p≤0.01), and were more frequently HIV positive (pConclusionsInjecting cocaine is a new trend of drug use in Luxembourg associated with HIV infection in this recent outbreak among PWID.
Published: 2019
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6. Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial

Author: Bruno Mourvillier, François-Xavier Lescure, Dominique Costagliola, Alain Makinson, Valérie Pourcher, Odile Launay, Clément Dubost, Saad Nseir, Emmanuel Faure, Yazdan Yazdanpanah, Jean-Christophe Richard, Lila Bouadma, Kevin Bouiller, Juliette Saillard, Jean Reignier, Claire Andrejak, Alpha Diallo, Lionel Piroth, Jean-Philippe Lanoix, Violaine Tolsma, Christelle Delmas, Gilles Peytavin, André Cabié, Marion Noret, Karine Lacombe, Elisabeth Botelho-Nevers, Thérèse Staub, Johan Courjon, Florence Ader, Nathan Peiffer-Smadja, Jean-Christophe Navellou, Maya Hites, Jean Reuter, Noemie Mercier, Maude Bouscambert-Duchamp, François Danion, S. Gallien, Julien Poissy, Florent Wallet, Guillaume Martin-Blondel, Raphaël Clere-Jehl, Bruno Lina, Amandine Gagneux-Brunon, Antoine Kimmoun, Rostane Gaci, Olivier Epaulard, Axelle Dupont, François Raffi, Aline Dechanet, François Goehringer, Joy Mootien, Stéphane Jauréguiberry, Sylvie Leroy, Charles Burdet, Toni Alfaiate, Drifa Belhadi, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Lille, 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), Hospices Civils de Lyon (HCL), Virology and human respiratory Pathologies - Virology and human respiratory Pathologies (VirPath), 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), 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), ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Santé Publique, Université de Médecine Carol Davila, 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, Département d'Epidemiologie, Biostatistique et Recherche Clinique (DEBRC), 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), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), and Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie
Subjects: medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Hospitalized patients, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Lopinavir, Hydroxychloroquine, Odds ratio, law.invention, Randomized controlled trial, law, Internal medicine, medicine, Ritonavir, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: BackgroundLopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking.ObjectiveTo determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients.DesignOpen-label, randomized, adaptive, controlled trial.SettingMulti-center trial with patients from France.Participants583 COVID-19 inpatients requiring oxygen and/or ventilatory supportInterventionStandard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-ß-1a (44 μg of subcutaneous IFN-ß-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days).MeasurementsThe 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 and safety analyses.ResultsAdjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavirversuscontrol, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-β-1aversuscontrol, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquineversuscontrol, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE.LimitationsNot a placebo-controlled, no anti-inflammatory agents tested.ConclusionNo improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings.RegistrationNCT04315948.FundingPHRC 2020, Dim OneHealth, REACTing
Published: 2023

7. 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

8. 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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9. Effect of Remdesivir on Viral Dynamics in COVID-19 Hospitalized Patients: A Modelling Analysis of the Randomized, Controlled, Open-Label DisCoVeRy Trial

Author: Guillaume Lingas, Nadège Néant, Alexandre Gaymard, Drifa Belhadi, Gilles Peytavin, Maya Hites, Thérèse Staub, Richard Greil, Jose-Artur Paiva, Julien Poissy, Nathan Peiffer-Smadja, Dominique Costagliola, Yazdan Yazdanpanah, Florent Wallet, Amandine Gagneux-Brunon, France Mentré, Florence Ader, Charles Burdet, Jérémie Guedj, Maude Bouscambert-Duchamp, 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), Hospices Civils de Lyon (HCL), Virology and human respiratory Pathologies - Virology and human respiratory Pathologies (VirPath), 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), 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, Institut des Agents Infectieux [Lyon] (IAI), Centre National de Référence des Virus des Infections Respiratoires (dont la Grippe) [Lyon] (CNR - laboratoire associé), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université libre de Bruxelles (ULB), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Centro Hospitalar Universitário São João - Faculty of Medicine - University of Porto - Grupo de Infecção e Sepsis, Porto, 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), Services de Maladies Infectieuses et Tropicales [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imperial College London, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Emergence de la résistance bactérienne in vivo (EA3964), and Université Paris Diderot - Paris 7 (UPD7)
Subjects: Pharmacology, Microbiology (medical), Alanine, Infectious Diseases, SARS-CoV-2, Humans, Pharmacology (medical), Antiviral Agents, Adenosine Monophosphate, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, COVID-19 Drug Treatment
Abstract: Background The antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. Objectives To estimate the effect of remdesivir in blocking viral replication. Methods We analysed nasopharyngeal normalized viral loads from 665 hospitalized patients included in the DisCoVeRy trial (NCT 04315948; EudraCT 2020-000936-23), randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in blocking viral replication. Additional analyses were conducted stratified on time of treatment initiation (≤7 or >7 days since symptom onset) or viral load at randomization (< or ≥3.5 log10 copies/104 cells). Results In our model, remdesivir reduced viral production by infected cells by 2-fold on average (95% CI: 1.5–3.2-fold). Model-based simulations predict that remdesivir reduced time to viral clearance by 0.7 days compared with SoC, with large inter-individual variabilities (IQR: 0.0–1.3 days). Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average (95% CI: 2.8–25-fold) and the median time to viral clearance by 2.4 days (IQR: 0.9–4.5 days). Conclusions Remdesivir halved viral production, leading to a median reduction of 0.7 days in the time to viral clearance compared with SoC. The efficacy was larger in patients with high viral load at randomization.
Published: 2022
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10. Modeling remdesivir antiviral efficacy in COVID-19 hospitalized patients of the randomized, controlled, open-label DisCoVeRy trial

Author: Maude Bouscambert-Duchamp, Drifa Belhadi, Guillaume Lingas, Yazdan Yazdanpanah, Maya Hites, Florent Wallet, Thérèse Staub, José Artur Paiva, Richard Greil, Julien Poissy, Charles Burdet, Amandine Gagneux-Brunon, Alexandre Gaymard, Nadège Néant, Jeremie Guedj, Dominique Costagliola, Gilles Peytavin, Florence Ader, and Nathan Peiffer-Smadja
Subjects: medicine.medical_specialty, Randomization, Coronavirus disease 2019 (COVID-19), business.industry, Hospitalized patients, Internal medicine, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine, In patient, Symptom onset, Open label, business, Viral load
Abstract: Despite several clinical studies, the antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. We analyzed nasopharyngeal normalized viral loads collected in the 29 days following randomization from 665 hospitalized patients included in the DisCoVeRy trial, allocated to either standard of care (SoC, N=329) or SoC + remdesivir for 10 days (N=336). We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in reducing viral production. To identify factors associated with viral kinetics, additional analyses were conducted stratified either on time of treatment initiation (≤ or > 7 days since symptom onset) or viral load at randomization (< or ≥ 3.5 log10 copies/104 cells). In our model, remdesivir reduced viral production by 2-fold on average (95%CI: 1.5-3.2). Using the estimated parameter of the model, simulations predict that remdesivir reduces time to viral clearance by 0.7 day compared to SoC, with large inter-individual variabilities (Inter-Quartile Range, IQR: 0.0-1.3 days). Exploratory analyses suggest that remdesivir had a larger impact in patients with a high viral load at randomization, reducing viral production by 5-fold on average (95%CI: 2.8-25), leading to a predicted median reduction in the time to viral clearance of 2.4 days (IQR: 0.9-4.5 days).In summary, our model shows that remdesivir reduces viral production from infected cells by a factor 2, leading to a median reduction of 0.7 days in the time to viral clearance compared to SoC. The efficacy was larger in patients with high level of viral load at treatment initiation.One sentence summaryRemdesivir reduces the time to SARS-CoV-2 clearance by 1 day in hospitalized patients, and up to 3 days in those with high viral load at admission.
Published: 2021
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11. 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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12. 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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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

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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14. 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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15. Case series of four re-infections with a SARS-CoV-2 B.1.351 variant, Luxembourg, February 2021

Author: Thérèse Staub, Michel Kohnen, Tamir Abdelrahman, Vic Arendt, Jean-Hugues François, Esther Calvo Lasso de la Vega, Chantal Tsobo, Christian Michaux, Pierre Braquet, and Anke K. Wienecke-Baldacchino
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Epidemiology, Luxembourg, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Hospital unit, health care facilities, manpower, and services, Health Personnel, education, Disease cluster, 03 medical and health sciences, Health personnel, 0302 clinical medicine, Virology, medicine, Humans, 030212 general & internal medicine, re-infection, outbreak, business.industry, healthcare workers, SARS-CoV-2, Public Health, Environmental and Occupational Health, Outbreak, virus diseases, COVID-19, Europe, 030104 developmental biology, PCR, variant, Reinfection, France, business, Rapid Communication, Re infection
Abstract: We describe four SARS-CoV-2 re-infections with a B.1.351 variant in 2021, in healthcare workers (HCWs) previously infected in 2020, before detection of this variant in Europe. Cases live in France, near the border with Luxembourg, where variants B.1.351 and B.1.1.7 circulated. All work in the same hospital unit where a cluster of COVID 19 with B1.351 variant occurred, affecting patients and HCWs. Before the cluster onset, HCWs used surgical masks, as per recommendations. After cluster onset, HCWs used FFP2 masks.
Published: 2021

16. Modeling remdesivir antiviral efficacy in COVID-19 hospitalized patients of the randomized, controlled, open-label DisCoVeRy trial

Author: Guillaume Lingas, Nadège Néant, Alexandre Gaymard, Drifa Belhadi, Gilles Peytavin, Maya Hites, Thérèse Staub , Richard Greil, Jose-Artur Paiva, Julien Poissy, Nathan Peiffer-Smadja, Dominique Costagliola, Yazdan Yazdanpanah, Florent Wallet, Amandine Gagneux-Brunon, France Mentré, Florence Ader Charles Burdet, Jérémie Guedj, Maude Bouscambert-Duchamp and the DisCoVeRy study group
Published: 2021

17. Clinical Outcomes of 2-Drug Regimens vs 3-Drug Regimens in Antiretroviral Treatment-Experienced People Living With Human Immunodeficiency Virus

Author: Felipe Rogatto, Lene Ryom, Christian Pradier, Anders Sönnerborg, Vincenzo Spagnuolo, Annegret Pelchen-Matthews, Jolie Hutchinson, Ferdinand W. N. M. Wit, Huldrych F. Günthard, Antonella Castagna, Jan-Christian Wasmuth, Michael Skoll, Alexandra U. Scherrer, Coca Valentina Necsoi, Vani Vannappagari, Nikoloz Chkhartishvili, Alexandra Calmy, Bastian Neesgaard, Claudine Duvivier, Lauren Greenberg, Natalia Bolokadze, Matthew Law, Lars Peters, Jennifer F Hoy, Alain Volny Anne, Antonella d'Arminio Monforte, José M. Miró, Margaret A. Johnson, Stéphane De Wit, Amanda Mocroft, Martin Gisinger, Cristina Mussini, Clara Lehmann, Jens D Lundgren, Christoph Stephan, Thérèse Staub, Josep M. Llibre, Colette Smith, Mark Bloch, Loveleen Bansi-Matharu, Heiner C. Bucher, and Gilles Wandeler
Subjects: 0301 basic medicine, Microbiology (medical), antiretroviral treatment, medicine.medical_specialty, Anti-HIV Agents, 030106 microbiology, HIV Infections, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Acquired immunodeficiency syndrome (AIDS), Interquartile range, Internal medicine, medicine, Humans, 030212 general & internal medicine, Online Only Articles, business.industry, 2-drug regimens, Incidence (epidemiology), Lamivudine, HIV, dual therapy, Raltegravir, medicine.disease, clinical outcomes, Regimen, Infectious Diseases, chemistry, Anti-Retroviral Agents, Pharmaceutical Preparations, Dolutegravir, Cohort, business, medicine.drug
Abstract: Background Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus. Methods Antiretroviral treatment–experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012–1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. Results Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7–59.0] vs 47.7 [39.7–54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU; 95% confidence interval [CI]: 20.7–24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8–38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5–8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9–6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI: .72–1.19; P = .53). Conclusions This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed.
Published: 2021
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18. Influence of hepatitis C virus co-infection and hepatitis C virus treatment on risk of chronic kidney disease in HIV-positive persons

Author: Christoph Boesecke, Eric Florence, Janez Tomažič, Karine Lacombe, Andri Rauch, Janos Szlavik, Qiuju Li, Helen Sambatakou, Amanda Mocroft, Inka Aho, Gordana Dragovic, Lars Peters, Nikoloz Chkhartishvili, Josep M. Llibre, Lars N Nielsen, Hila Elinav, Clifford Leen, Lene Ryom, Dalibor Sedláček, Cristiana Oprea, V. Uzdaviniene, Montse Laguno, and Thérèse Staub
Subjects: medicine.medical_specialty, Hepatitis C virus, Immunology, HIV Infections, Hepacivirus, medicine.disease_cause, Rate ratio, Gastroenterology, Antiviral Agents, 03 medical and health sciences, symbols.namesake, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Immunology and Allergy, Humans, 030212 general & internal medicine, Poisson regression, Prospective Studies, Renal Insufficiency, Chronic, Creatinine, business.industry, Coinfection, Incidence (epidemiology), virus diseases, Hepatitis C, Hepatitis C, Chronic, medicine.disease, digestive system diseases, 3. Good health, Infectious Diseases, chemistry, symbols, Albuminuria, 030211 gastroenterology & hepatology, medicine.symptom, business, Kidney disease
Abstract: BACKGROUND Hepatitis C virus (HCV) infection has been associated with increased risk of chronic kidney disease (CKD). We investigated the impact of HCV cure on CKD in HIV-positive persons in the EuroSIDA study. METHODS HIV-positive persons with known HCV status and at least three serum creatinine measurements after 1/1/2004 were compared based on time-updated HCV-RNA and HCV treatment: anti-HCV-negative, spontaneously cleared HCV, chronic untreated HCV, successfully treated HCV, and HCV-RNA positive after HCV treatment. Poisson regression compared incidence rates of CKD [confirmed (>3 months apart) eGFR
Published: 2020
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19. Isolation of an HIV-1 neutralizing peptide mimicking the CXCR4 and CCR5 surface from the heavy-chain complementary determining region 3 repertoire of a viremic controller

Author: Andy Chevigné, Thérèse Staub, Carole Seguin-Devaux, Sabrina Deroo, Arkadiusz Rybicki, Nadia Beaupain, Sylvie Delhalle, Charlène Verschueren, Jean-Claude Schmit, and Manuel Counson
Subjects: 0301 basic medicine, Program evaluation, Receptors, CXCR4, medicine.medical_specialty, Receptors, CCR5, Anti-HIV Agents, Cost effectiveness, Impact evaluation, Immunology, Psychological intervention, HIV Infections, HIV Antibodies, HIV Long-Term Survivors, Men who have sex with men, law.invention, 03 medical and health sciences, Condom, Neutralization Tests, Peptide Library, law, Environmental health, medicine, Humans, Immunology and Allergy, Young adult, Psychiatry, business.industry, Virus Internalization, Antibodies, Neutralizing, Complementarity Determining Regions, 030104 developmental biology, Infectious Diseases, Immunoglobulin M, Immunoglobulin G, HIV-1, Peptides, business
Abstract: BACKGROUND Despite the high-profile support for combination prevention programmes (CPPs) since 2008, there is little rigorous evidence on their impact and cost-effectiveness. In 2010, Mexico received funds from the Global Fund to implement a series of behavioural, biomedical, and structural interventions over 3 years targeted to men who have sex with men. The aims of the study were to estimate the impact of the programme across a range of outcomes and cost-effectiveness. METHODS A quasi-experiment was designed before the implementation of the CPP, in which 24 cities were randomly selected for impact evaluation and 12 pairs of cities were matched. In practice, though, implementation of the programme was staggered over 1 year. Therefore, we used two different approaches to estimate impact: a difference-in-difference estimation comparing both groups and a dose-response approach using time exposure to the programme at the city level. FINDINGS Results from the difference-in-difference estimation showed modest impact on condom use. However, the dose–response findings revealed a 7.5% increase in HIV testing per additional year exposed to the programme, relative to baseline coverage; an increase in awareness of HIV status among HIV-positive individuals of 6.3%; a 6.7% increase in HIV-positive individuals on treatment; and a 7% reduction in the perception of stigma/discrimination from healthcare personnel. The cost per person not exposed to an untreated HIV-positive individual was gauged to be US$400. CONCLUSIONS The study provides evidence of the effectiveness and cost of a CPP along the HIV treatment cascade: access to HIV tests, awareness of HIV status, and antiretroviral therapy initiation.
Published: 2016
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20. Persistent disparities in antiretroviral treatment (ART) coverage and virological suppression across Europe, 2004 to 2015

Author: Thérèse Staub, Robert Zangerle, Tatiana Trofimova, Elena Kuzovatova, Anders Blaxhult, Cristina Mussini, Leah Shepherd, Kamilla Laut, Igor Karpov, Fernando Maltez, Dorthe Raben, Roxana Radoi, Kai Zilmer, Miłosz Parczewski, Jens D Lundgren, Amanda Mocroft, Helen Kovari, Hila Elinav, Marcelo H. Losso, Nikoloz Chkhartishvili, Ole Kirk, and Malgorzata Inglot
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Continuity of patient care, Epidemiology, Europe, HIV infection, Surveillance, Treatment outcome, Public Health, Environmental and Occupational Health, Virology, Sustained Virologic Response, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, Logistic regression, Odds, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Antiretroviral treatment, Medicine, Humans, 030212 general & internal medicine, Treatment Failure, Healthcare Disparities, business.industry, Environmental and Occupational Health, Middle Aged, Viral Load, 030112 virology, Confidence interval, 3. Good health, CD4 Lymphocyte Count, Anti-Retroviral Agents, Western europe, RNA, Viral, Female, Public Health, business, Demography, Research Article
Abstract: Background: Direct comparisons between countries in core HIV care parameters are often hampered by differences in data collection. Aim: Within the EuroSIDA study, we compared levels of antiretroviral treatment (ART) coverage and virological suppression (HIV RNA
Published: 2018
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21. Changing utilization of Stavudine (d4T) in HIV-positive people in 2006-2013 in the EuroSIDA study

Author: Massimo Galli, Vincent Soriano, Manuel Battegay, E. Mularska, AM Johnson, Viktar Mitsura, Bernard Hirschel, E. Simons, François Dabis, Josip Begovac, M. Gargiulo, Luigia Elzi, P. Vernazza, Thérèse Staub, Antoni Jou, Dan Turner, Fiona Mulcahy, Gatell Jm, Kamal Mansinho, G. Mateo, V. Ormaasen, Boron-Kaczmarska A. Boron-Kaczmarska, M. H. Losso, A Horban, Sonia Moreno, Rainer Weber, Christian Pradier, I. Bravo, Gianpiero D’Offizi, I. Yust, Michael Burke, Jens Nielsen, Magnus Gottfredsson, J Weber, Juergen K. Rockstroh, Juan González-Lahoz, Philippe Vanhems, N. Chentsova, G. Kyselyova, Markus Bickel, Christine Katlama, Nicola Gianotti, Irina Khromova, Roberto Esposito, Dalibor Sedláček, Gerd Fätkenheuer, Ladislav Machala, J. Kosmidis, Anders Sönnerborg, Anders Blaxhult, Francesco Mazzotta, S. Chaplinskas, Lars Østergaard, Cristina Tural, Anna Grzeszczuk, Shimon Pollack, Martin Fisher, E. Kravchenko, Marie-Luce Delforge, Claudine Duvivier, N. Vetter, Bruno Ledergerber, A. Vassilenko, Cristina Mussini, K. Kostov, E. Boffi, I. Zeltina, Danica Staneková, Pierre-Marie Girard, Robert Hemmer, L Caldeira, Robert Zangerle, Jan Gerstoft, Smidt Jelena Smidt, [No Value] Schmidt, Elżbieta Jabłonowska, M. Haouzi, G. Hassoun, P Francioli, Dénes Bánhegyi, M. Gutiérrez, Hans-Jürgen Stellbrink, Roger Paredes, A d'Arminio Monforte, O. Suetnov, T. Katzenstein, Robert Flisiak, Brygida Knysz, K. Wojcik, Jordi Puig, Baiba Rozentale, A. Gabbuti, Antonella Castagna, Olaf Degen, J van Lunzen, S. Servitskiy, D. Neau, Court Pedersen, Miłosz Parczewski, Jean-Paul Viard, Fernando Maltez, M. Kundro, D Podlekareva, Nathan Clumeck, G. Scullard, Leo Flamholc, Thomas Benfield, M. Larsen, Hansjakob Furrer, M. Mokráš, A. Thalme, M. Beniowski, I. Mazeu, G. Kutsyna, S De Wit, Peter Reiss, Vincenzo Vullo, Pere Domingo, Igor Karpov, Panagiotis Gargalianos, Ulrik Bak Dragsted, David Jilich, Elena Kuzovatova, Miriam Lichtner, E. Malolepsza, Anastasiia Kuznetsova, S. Buzunova, Matthias Cavassini, Pablo Labarga, A. B E Hansen, A. Maeland, Margaret A. Johnson, Djordje Jevtovic, J. Bruun, A Rakhmanova, Chloe Orkin, M. Pynka, V. Frolov, D. Duiculescu, AN Phillips, J Gasiorowski, Ole Kirk, V. Hadziosmanovic, P. Skinhøj, J. Tomazic, Maria A. Sambeat, R. Pristera, J. W. Goethe, G. Kronborg, Daniel Grint, Elzbieta Bakowska, L. N. Nielsen, A. Rakmanova, Claudio Arici, C. Taibi, Matti Ristola, J. M. Rodriguez, Miró Jm, Amanda Mocroft, H. Trocha, Jd Lundgren, Hila Elinav, Clifford Leen, E. Montesarchio, Eric Florence, Linos Vandekerckhove, Adriano Lazzarin, Jose Medrano, J. Perdios, Manuela Doroana, Brian Gazzard, Antonio Chirianni, Annalisa Ridolfo, A. Antinori, Johannes R. Bogner, Kai Zilmer, G. Xylomenos, Bonaventura Clotet, and H. Sambatakou
Subjects: Cart, Rate ratio, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, parasitic diseases, medicine, Pharmacology (medical), 030212 general & internal medicine, Poisson regression, 0303 health sciences, 030306 microbiology, business.industry, Health Policy, Stavudine, medicine.disease, Confidence interval, 3. Good health, Infectious Diseases, HIV-positive people, Cohort, symbols, Lipodystrophy, business, Demography, medicine.drug
Abstract: OBJECTIVES: The long-term side effects of stavudine (d4T) led to recommendations in 2009 to phase out use of this drug. We aimed to describe temporal patterns of d4T use across Europe. METHODS: Patients taking combination antiretroviral therapy (cART) in EuroSIDA with follow-up after 1 January 2006 were included in the study. cART was defined as d4T-containing [d4T plus at least two other antiretrovirals (ARVs) from any class] or non-d4T-containing (at least three ARVs from any class, excluding d4T). Poisson regression was used to describe temporal changes in the prevalence of d4T use and factors associated with initiating d4T. RESULTS: A total of 5850 patients receiving cART on 1 January 2006 were included in the current analysis, rising to 7768 patients on January 1 2013. During this time, the prevalence of d4T use fell from 11.2% to 0.7%, with an overall decline of 19% per 6 months [95% confidence interval (CI) 19-20%]. d4T use declined fastest in Northern Europe [26% (95% CI 23-29%) per 6 months], and slowest in Eastern Europe [17% (95% CI 16-19%) per 6 months]. In multivariable Poisson regression models, new d4T initiations decreased by 14% per 6 months [adjusted incidence rate ratio (aIRR) 0.86; 95% CI 0.80-0.91]. Factors associated with initiating d4T were residence in Eastern Europe (aIRR 4.31; 95% CI 2.17-9.98) versus other European regions and HIV RNA > 400 copies/mL (aIRR 3.11; 95% CI 1.60-6.02) versus HIV RNA < 400 copies/mL. CONCLUSIONS: d4T use has declined sharply since 2006 to low levels in most regions; however, a low but persistent level of d4T use remains in Eastern Europe, where new d4T initiations post 2006 are also more common. The reasons for the regional differences may be multifactorial, but it is important to ensure that all clinicians treating HIV-positive patients are aware of the potential harmful effects associated with d4T.
Published: 2015
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22. Antiretrovirals, Fractures, and Osteonecrosis in a Large International HIV Cohort

Author: Eric Florence, Jens D Lundgren, P. Gargalianos-Kakolyris, Court Pedersen, Fernando Maltez, V. Uzdaviniene, Thérèse Staub, for EuroSIDA, Jennifer F Hoy, Leo Flamholc, G. Kyselyova, Hans Jürgen Stellbrink, Rainer Weber, J Tomazic, Chloe Orkin, Anna Lisa Ridolfo, Fiona Mulcahy, Christian Pradier, Patrick Schmid, Dalibor Sedláček, Álvaro H. Borges, Amanda Mocroft, and Clifford Leen
Subjects: Male, 0301 basic medicine, Bone density, Femoral Fractures / etiology, HCC INF, Tenofovir / therapeutic use, Avascular necrosis, HIV Infections / complications, Cohort Studies, HIV Infections / epidemiology, 0302 clinical medicine, Risk Factors, Medicine, 030212 general & internal medicine, Osteonecrosis / virology, HIV Infections / virology, Fractures, Bone / epidemiology, Data Collection, Incidence (epidemiology), Middle Aged, Infectious Diseases, Cohort, Coinfection, Regression Analysis, Female, Europe / epidemiology, Anti-HIV Agents / adverse effects, Fractures, Bone / virology, Cohort study, Adult, Anti-HIV Agents / therapeutic use, Microbiology (medical), medicine.medical_specialty, Tenofovir / adverse effects, Fractures, Bone / etiology, Bone Density / drug effects, Femoral Fractures / epidemiology, Femoral Fractures / virology, Fractures, Bone / ethnology, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), Osteonecrosis / etiology, Internal medicine, Journal Article, Humans, Risk factor, Osteonecrosis / epidemiology, Coinfection / epidemiology, business.industry, medicine.disease, 030112 virology, HIV Infections / drug therapy, CD4 Lymphocyte Count, Surgery, business, Anti-HIV Agents / administration & dosage
Abstract: Background: Antiretrovirals (ARVs) affect bone density and turnover, but their effect on risk of fractures and osteonecrosis of the femoral head is less understood. We investigated if exposure to ARVs increases the risk of both bone outcomes. Methods: EuroSIDA participants were followed to assess fractures and osteonecrosis. Poisson regression identified clinical, laboratory and demographic predictors of either bone outcome. Ever, current, and cumulative exposures to ARVs were assessed. Results: During 86118 PYFU among 11820 included persons (median age 41y, 75% male, median baseline CD4 440/mm3, 70.4% virologically suppressed), there were 619 fractures (incidence/1000 PYFU 7.2; 95% CI 6.6-7.7) and 89 osteonecrosis (1.0; 0.8-1.3). Older age, white race, lower BMI, IV drug use, lower baseline CD4, HCV coinfection, prior osteonecrosis, prior fracture, cardiovascular disease, and recent non-AIDS cancer (last 12 months) were associated with fractures. After adjustment, persons who had ever used tenofovir disoproxil fumarate (TDF) (1.40; 1.15-1.70) or who were currently on TDF (1.25; 1.05-1.49) had higher incidence of fractures. There was no association between cumulative exposure to TDF and fractures (1.08/5 y exposure; 0.94-1.25). No other ARV was associated with fractures (all P > .1). Risk of osteonecrosis was associated with white race, lower nadir CD4, prior osteonecrosis, prior fracture, and prior AIDS. After mutual adjustment, no ARV was associated with osteonecrosis. Conclusions: In human immunodeficiency virus (HIV) infection, host factors, HIV-specific variables, and comorbidities contribute to risk of fractures and osteonecrosis. Exposure to TDF, but not other ARVs, was an independent risk factor for fractures. info:eu-repo/semantics/publishedVersion
Published: 2017
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23. 1986-2016: 30 years of pregnancy outcomes surveillance in HIV-Positive women in Luxembourg

Author: Thérèse Staub, A Fischer, M Gantenbein, Robert Hemmer, Etienne, C Michaux, JC Schmit, A Chioti, and Arendt
Subjects: medicine.medical_specialty, business.industry, Obstetrics, Public Health, Environmental and Occupational Health, Human immunodeficiency virus (HIV), Medicine, business, Pregnancy outcomes, medicine.disease_cause
Published: 2016
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24. Regional differences in the risk of triple class failure in European patients starting combination antiretroviral therapy after 1 January 1999

Author: Johannes R. Bogner, Amanda Mocroft, Jens D Lundgren, P Aldins, Thérèse Staub, Christine Katlama, B Clotet, A d'Arminio Monforte, A Horban, and F Antunes
Subjects: medicine.medical_specialty, Reverse-transcriptase inhibitor, business.industry, Health Policy, Incidence (epidemiology), Antiretroviral therapy, Confidence interval, Regimen, Infectious Diseases, Internal medicine, Immunology, Medicine, Pharmacology (medical), Protease inhibitor (pharmacology), business, Viral load, Regional differences, medicine.drug
Abstract: Regional differences across Europe in triple class failure (TCF; the failure of each of the three separate main classes of antiretrovirals (ARVs) with a viral load >1000 HIV-1 RNA copies/mL for >4 months) have not been described. A total of 1956 patients started combination ARV therapy after 1 January 1999, of whom 123 patients developed TCF [6.3%; incidence 16.7 per 1000 person-years of follow-up; 95% confidence interval (CI) 13.7–19.6]. After adjustment, patients from Eastern Europe had a significantly increased incidence of TCF compared with patients from Southern Europe/Argentina (3.05; 95% CI 1.36–6.82; P=0.0067) while patients taking either a boosted protease inhibitor regimen (0.33; 95% CI 0.15–0.74; P=0.0072) or a nonnucleotide reverse transcriptase inhibitor (NNRTI)-based regimen (0.59; 95% CI 0.37–0.94; P=0.026) had a reduced incidence of TCF.
Published: 2008
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25. The role of antiretroviral therapy in the incidence of pancreatitis in HIV-positive individuals in the EuroSIDA study

Author: Thérèse Staub, Anders Blaxhult, Schlomo Staszewski, Colette J Smith, Christian Holkmann Holkmann Olsen, George Panos, Jean Paul Viard, N. Vetter, Amanda Mocroft, and Jens D Lundgren
Subjects: Adult, CD4-Positive T-Lymphocytes, Male, medicine.medical_specialty, Pancreatic disease, Immunology, Argentina, Cumulative Exposure, HIV Infections, Pharmacotherapy, Risk Factors, Lymphopenia, Internal medicine, medicine, Humans, Immunology and Allergy, Israel, Didanosine, Reverse-transcriptase inhibitor, business.industry, Incidence, Incidence (epidemiology), Stavudine, HIV, Middle Aged, medicine.disease, Europe, Infectious Diseases, Anti-Retroviral Agents, Pancreatitis, Case-Control Studies, Reverse Transcriptase Inhibitors, Drug Therapy, Combination, Female, business, medicine.drug
Abstract: Aim This study investigated the incidence of pancreatitis and its association with antiretroviral therapy (ART), focussing on stavudine and didanosine. Methods EuroSIDA has collected information on pancreatitis since Summer 2001. All identified cases have been verified by the coordinating centre. Individuals were followed from June 2001 or the date of entry into EuroSIDA (whichever occurred later) until a diagnosis of pancreatitis or the last study visit. Factors associated with pancreatitis were investigated using Poisson regression. Cumulative lengths of exposure to didanosine without stavudine, stavudine without didanosine, stavudine with didanosine, and other ART were time-updated variables. Treatment variables were fitted with a 6-month time lag. Results There were 43 (nine presumptive) pancreatic events in 9678 individuals during 33 742 person-years (incidence 1.27/1000 person-years). The incidence among those with no, 2 or less and over 2 years' exposure to ART including stavudine and didanosine was 1.24, 1.73 and 0.78/1000 person-years, respectively. In multivariable analysis, higher baseline CD4 cell counts were associated with a decreased risk of pancreatitis. There was no evidence of an association of pancreatitis with cumulative exposure to didanosine and stavudine, didanosine without stavudine, stavudine without didanosine, or other ART. Conclusion We observed a low overall rate of pancreatitis in the years 2001-2006, and did not find an association of an increased incidence of pancreatitis with cumulative exposure to antiretroviral agents generally, and to didanosine and stavudine in particular.
Published: 2008
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26. Simple DNA Extraction Method for Dried Blood Spots and Comparison of Two PCR Assays for Diagnosis of Vertical Human Immunodeficiency Virus Type 1 Transmission in Rwanda

Author: N. Makombe, C. Lejczak, Jean-Claude Schmit, Robert Hemmer, Christine Lambert, Vic Arendt, François Schneider, J. Rusine, Thérèse Staub, A Fischer, and Jean Servais
Subjects: Microbiology (medical), Biology, Polymerase Chain Reaction, Sensitivity and Specificity, Peripheral blood mononuclear cell, Virus, law.invention, chemistry.chemical_compound, Pregnancy, law, Virology, Humans, Polymerase chain reaction, Acquired Immunodeficiency Syndrome, Infant, Newborn, DNA extraction, Infectious Disease Transmission, Vertical, chemistry, DNA, Viral, HIV-1, Female, Viral disease, Indeterminate, Nested polymerase chain reaction, Filtration, DNA
Abstract: Dried blood spots (DBS) on filter paper facilitate the collection, transport, and storage of blood samples for laboratory use. A rapid and simple DNA extraction procedure from DBS was developed and evaluated for the diagnosis of human immunodeficiency virus type 1 (HIV-1) infection in children by an in-house nested-PCR assay on three genome regions and by the Amplicor HIV-1 DNA prototype assay version 1.5 (Roche Molecular Systems). A total of 150 samples from children born to HIV-1-infected mothers were collected in Kigali, Rwanda, in parallel as DBS and as peripheral blood mononuclear cell (PBMC) pellets. The results obtained on DBS by the two PCR assays were compared to the results of nested PCR on PBMCs. Of 150 PBMC samples, 10 were positive, 117 were negative, and 23 were indeterminate for HIV-1 infection. In DNA extracted from filter papers and amplified by using the in-house nested PCR, 9 of these 10 positive samples (90%) were found to be positive, and 1 was found to be indeterminate (only the pol region could be amplified). All of the negative samples and all of the 23 indeterminate samples tested negative for HIV-1 infection. When we used the Amplicor DNA test on DBS, all of the 10 PBMC-positive samples were found to be positive and all of the 23 indeterminate samples were found to be negative. Of the PBMC-negative samples, 115 were found to be negative and 2 were found to be indeterminate. We conclude that this simple rapid DNA extraction method on DBS in combination with both detection methods gave a reliable molecular diagnosis of HIV-1 infection in children born to HIV-infected mothers.
Published: 2004
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27. Uncommon Mutations at Residue Positions Critical for Enfuvirtide (T-20) Resistance in Enfuvirtide-Naive Patients Infected With Subtype B and Non-B HIV-1 Strains

Author: François Roman, Sabrina Deroo, Jean-Claude Schmit, Robert Hemmer, Aurélie Fischer, Ronan Boulmé, Thérèse Staub, Therese Baurith, Dimitri Gonzalez, Vic Arendt, Christine Lambert, and François Schneider
Subjects: Time Factors, Enfuvirtide, Anti-HIV Agents, Molecular Sequence Data, HIV Infections, medicine.disease_cause, Gp41, Virus, Cohort Studies, Drug Resistance, Viral, Genotype, medicine, Humans, Pharmacology (medical), Mutation, biology, biology.organism_classification, Virology, HIV Envelope Protein gp41, Peptide Fragments, Heptad repeat, Infectious Diseases, Lentivirus, HIV-1, Viral disease, Sequence Alignment, medicine.drug
Abstract: Summary: Enfuvirtide (T-20) is the lead compound of the new class of antiretroviral drugs called fusion inhibitors. T-20 resistance-associated mutations located in the heptad repeat 1 (HR-1) domain of gp41 have been described in vitro and in clinical trials. In this study, the authors investigated the primary genotypic T-20 resistance in subtype B and non-B HIV-1 strains from patients at the beginning of their follow-up in the Luxembourg HIV Cohort as well as the emergence of primary resistance to T-20 in patients who had long-term infection with subtype B HIV-1 strains. HR-1 fragments including the gp41 amino acid 36-45, T-20-sensitive region were screened for amino acid variation. No classic T-20 resistance-associated mutations were identified in subtype B or non-B isolates. However, several uncommon mutations were found at residues 37, 39, and 42 for subtype B isolates and at residue 42 for a subtype non-B isolate. The results indicate that primary genotypic T-20 resistance seems to be rare in HIV-1, regardless of subtype or prior antiretroviral therapy (excluding fusion inhibitors). However, episodic variation within HR-1 can occur and needs further phenotypic evaluation in accurate fusion inhibitor resistance assays.
Published: 2003
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28. Longitudinal Use of a Line Probe Assay for Human Immunodeficiency Virus Type 1 Protease Predicts Phenotypic Resistance and Clinical Progression in Patients Failing Highly Active Antiretroviral Therapy

Author: François Schneider, Thérèse Staub, Elodie Fontaine, Jean-Marc Plesséria, Robert Hemmer, Christine Lambert, Jean Servais, Jean-Claude Schmit, Isabelle Robert, and Vic Arendt
Subjects: medicine.medical_treatment, HIV Infections, Biology, Antiviral Agents, Nucleoside Reverse Transcriptase Inhibitor, HIV Protease, Predictive Value of Tests, Indinavir, Antiretroviral Therapy, Highly Active, medicine, Humans, HIV Protease Inhibitor, Pharmacology (medical), Protease inhibitor (pharmacology), Treatment Failure, Retrospective Studies, Pharmacology, Protease, Drug Resistance, Microbial, HIV Protease Inhibitors, Viral Load, Virology, Phenotype, Infectious Diseases, Nelfinavir, Mutation, Disease Progression, Ritonavir, Saquinavir, medicine.drug
Abstract: An observational study assessed the longitudinal use of a new line probe assay for the detection of protease mutations. Probe assays for detection of reverse transcriptase (Inno-LiPA HIV-1 RT; Innogenetics) and protease (prototype kit Inno-LiPA HIV Protease; Innogenetics) mutations gave results for 177 of 199 sequential samples collected over 2 years from 26 patients failing two nucleoside reverse transcriptase inhibitors and one protease inhibitor (first line: indinavir, n = 6; ritonavir, n = 10; and saquinavir, n = 10). Results were compared to recombinant virus protease inhibitor susceptibility data ( n = 87) and to clinical and virological data. Combinations of protease mutations (M46I, G48V, I54V, V82A or -F, I84V, and L90M) predicted phenotypic resistance to the protease inhibitor and to nelfinavir. The sum of protease mutations was associated with virological and clinical outcomes from 6 and 3 months on, respectively. Moreover, a poorer clinical outcome was linked to the sum of reverse transcriptase mutations. In conclusion, despite the limited number of patients studied and the restricted number of codons investigated, probe assay-based genotyping correlates with phenotypic drug resistance and predicts new Centers for Disease Control and Prevention stage B and C clinical events and virological outcome. Line probe assays provide additional prognostic information and should be prospectively investigated for their potential for treatment monitoring.
Published: 2002
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29. Response to Antiretroviral Therapy among Patients Exposed to Three Classes of Antiretrovirals: Results from the Eurosida Study

Author: Andrew N. Phillips, Anne M Johnson, Jens D Lundgren, Nina Friis-Møller, Robert Colebunders, Thérèse Staub, Bernard Hirschel, T. Saint-Marc, Amanda Mocroft, B Clotet, and EuroSIDA Study Group
Subjects: medicine.medical_specialty, Salvage therapy, Effectiveness, Viral diseases, Acquired immunodeficiency syndrome (AIDS), Interquartile range, Antiretroviral Therapy, Highly Active, Internal medicine, medicine, Humans, Pharmacology (medical), Protease inhibitor (pharmacology), Prospective Studies, Sida, ddc:616, Pharmacology, Acquired Immunodeficiency Syndrome, biology, Reverse-transcriptase inhibitor, business.industry, Acquired Immunodeficiency Syndrome/ drug therapy/immunology/virology, HIV, Antiretrovirals, Viral Load, biology.organism_classification, medicine.disease, CD4 Lymphocyte Count, Surgery, AIDS, Treatment, Infectious Diseases, Drug Therapy, Combination, Viral disease, business, Viral load, medicine.drug
Abstract: This is the author’s version of a work accepted for publication by International Medical Press. Changes resulting from the publishing process, including peer review, editing and formatting, might not be reflected in this document. A definitive version was published in Antiviral Therapy, [7, 1], 2002, © 2002 International Medical Press, There is an increasing proportion of HIV-positive patients exposed to all licensed classes of antiretrovirals, and the response to salvage regimens may be poor. Among over 8500 patients in EuroSIDA, the proportion of treated patients exposed to nucleosides, protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitor (NNRTI) increased from 0% in 1996 to 47% in 2001. Four-hundred-and-thirteen patients, who had failed virologically two highly active antiretroviral therapy (HAART) regimens and experienced all three main drug classes, started a salvage regimen of at least three drugs, in which at least one new PI or NNRTI was included. Median viral load was 4.7 log copies/ml [Interquartile range (IQR) 4.2-5.2], CD4 lymphocyte count 150/mm3 (IQR 60-274/mm3) and follow-up 14 months. Of these patients, 283 (69%) subsequently experienced at least a 1 log decline in viral load and 202 (49%) achieved a viral load < 500 copies/ml. Conversely, the CD4 count halved from the baseline value in 88 (21%), and 45 (11%) experienced a new AIDS-defining disease. In multivariable analyses, a 1 log viral load reduction was related to baseline viral load [relative hazard (RH) 1.27 per 1 log higher; P = 0.008], a previous viral load of less than 500 copies/ml (RH 1.69; P = 0.002), more recent initiation of the regimen (RH 1.36 per year more recent; P = 0.02), number of new drugs in the regimen (RH 1.20 per drug; P = 0.02), time since start of antiretroviral therapy (RH 0.94 per extra year; P = 0.035) and time spent on HAART with viral load > 1000 copies/ml (RH 0.96 per extra month; P = 0.0001). Analysis of factors associated with CD4 count decline and new AIDS disease also indicated improved outcomes in more recent times and a tendency for a better response in those starting more new drugs, but no relationship with the total number of drugs. Outcomes in people starting salvage regimens appear to depend on the number of new drugs started but not on the total number of drugs being used.
Published: 2002
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30. Variant Human Immunodeficiency Virus Type 1 Proteases and Response to Combination Therapy Including a Protease Inhibitor

Author: Elodie Fontaine, Vic Arendt, Robert Hemmer, Jean Servais, Jean-Marc Plesséria, Isabelle Robert, Guy Burtonboy, Christine Lambert, Jean-Claude Schmit, François Schneider, and Thérèse Staub
Subjects: Adult, Male, Proteases, medicine.medical_treatment, HIV Infections, Antiviral Agents, Virus, HIV Protease, Indinavir, medicine, Humans, HIV Protease Inhibitor, Pharmacology (medical), Longitudinal Studies, Pharmacology, Polymorphism, Genetic, Protease, biology, Genetic Variation, HIV Protease Inhibitors, biology.organism_classification, Virology, Infectious Diseases, Multivariate Analysis, Lentivirus, HIV-1, Drug Therapy, Combination, Female, Ritonavir, Saquinavir, medicine.drug
Abstract: The objective of this observational study was to assess the genetic variability in the human immunodeficiency virus (HIV) protease gene from HIV type 1 (HIV-1)-positive (clade B), protease inhibitor-naı̈ve patients and to evaluate its association with the subsequent effectiveness of a protease inhibitor-containing triple-drug regimen. The protease gene was sequenced from plasma-derived virus from 116 protease inhibitor-naı̈ve patients. The virological response to a triple-drug regimen containing indinavir, ritonavir, or saquinavir was evaluated every 3 months for as long as 2 years ( n = 40). A total of 36 different amino acid substitutions compared to the reference sequence (HIV-1 HXB2) were detected. No substitutions at the active site similar to the primary resistance mutations were found. The most frequent substitutions (prevalence, >10%) at baseline were located at codons 15, 13, 12, 62, 36, 64, 41, 35, 3, 93, 77, 63, and 37 (in ascending order of frequency). The mean number of polymorphisms was 4.2. A relatively poorer response to therapy was associated with a high number of baseline polymorphisms and, to a lesser extent, with the presence of I93L at baseline in comparison with the wild-type virus. A71V/T was slightly associated with a poorer response to first-line ritonavir-based therapy. In summary, within clade B viruses, protease gene natural polymorphisms are common. There is evidence suggesting that treatment response is associated with this genetic background, but most of the specific contributors could not be firmly identified. I93L, occurring in about 30% of untreated patients, may play a role, as A71V/T possibly does in ritonavir-treated patients.
Published: 2001
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31. Le paludisme d'importation à Strasbourg: une étude épidémiologique, clinique, biologique et thérapeutique

Author: Thérèse Staub‐Schmidt, Yves Hansmann, and Daniel Christmann
Subjects: Quinine, Pediatrics, medicine.medical_specialty, biology, business.industry, Public Health, Environmental and Occupational Health, Plasmodium falciparum, medicine.disease, Haemolysis, biology.organism_classification, Very frequent, Infectious Diseases, Cerebral Malaria, parasitic diseases, Chemoprophylaxis, medicine, Parasitology, Chills, medicine.symptom, business, Malaria, medicine.drug
Abstract: In a retrospective study, we registered 210 patients hospitalized in Strasbourg for malaria from 1984 to 1995. The diagnosis was always confirmed by presence of the parasite on blood smears. We analysed the epidemiological, clinical, biological and therapeutic data. The number of cases rose each year, with a maximum in 1995. The majority of cases occurred in January and from August to October, these periods corresponding with the return of travelers. In most cases, infection took place in Africa. In this region, Plasmodium falciparum is the most frequent species of the parasite. The mean age of the patients was 33 years. The clinical manifestations were polymorphic: fever, chills, sweating, and headache were very frequent. We noted 15 serious infections (with the WHO's definition) and two cases of cerebral malaria. All cases had a favorable outcome. Five cases occurred in pregnant women; two of them had a severe form of malaria. Among the biological abnormalities, we found thrombopenia, haemolysis, hypocholesterolaemia and hypertriglyceridaemia. The significance of disturbance of the lipid metabolism is not known. Hypocholesterolaemia is very frequent, and hypertriglyceridaemia seems to be associated with severe malaria. Most malaria attacks occurred in patients without adequate chemoprophylaxis. This confirms the importance of prophylactic information given to patients by their physicians. Resistance develops against each new medication that is available; among these quinine remains the drug of choice to cure severe malaria.
Published: 1997
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32. P1243 : Birth cohort distribution and screening of viremic HCV infections in luxembourg

Author: Thérèse Staub, D. Struck, Carole Seguin-Devaux, J. Mossong, Vic Arendt, S. Blach, P. Hoffmann, and H. Razavi
Subjects: medicine.medical_specialty, Hepatology, business.industry, Fatty liver, Disease, medicine.disease, Asymptomatic, Liver disease, Internal medicine, medicine, Abnormal Liver Function Test, Mass index, Metabolic syndrome, medicine.symptom, business
Abstract: Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of liver disease in children, with an estimated prevalence of 5–10%. The majority of published data has involved Caucasians. Data is lacking regarding the phenotypic differences of NAFLD in children of Asian origin. Methods: We performed a retrospective review of children consecutively diagnosed with NAFLD at a tertiary referral hepatology service in the UK, between 2003 and 2014. Patients had been referred from either primary care physicians or general paediatricians with incidental asymptomatic abnormal liver function tests (LFTs) and/or fatty liver on ultrasound scan (USS). Patients with inadequate data or with secondary fatty liver disease were excluded. Patients were divided by ethnicity into Asian and Caucasian. All values are (±SD), unless stated. Results: 100 patients with primary NAFLD were identified. 59/100 were Caucasian and 41/100 were of Asian origin, of whom, 73% (30/41) were Pakistani. There was male predominance in both groups, 73% (43/59) in Caucasian and 78% (32/41) in Asians. Mean ages at presentation were 12.6±2.5 and 11.7±2.8 years in Caucasian and Asian groups, respectively. Asian patients had a significantly lower body mass index (BMI) centile than Caucasian (91.2±9.5 vs. 96.1±5.1, p < 0.05). There were no differences in LFTs between Asian and Caucasian patients, ALT (87.8±60.9 vs. 94.3±84.5 IU/L) and bilirubin (9.4±7.6 vs. 9±6.5mmol/L). 61% (25/41) Asian patients had an elevated gamma glutamyl transferase, compared to 60% (35/59) Caucasian patients. Markers of the metabolic syndrome were similar in both groups: total cholesterol 4.4±1 vs. 4.4±1mg/L, triglycerides 2.0±1.4 vs. 2.2±1.4mg/L, and HbA1c 38.6 vs. 39.1±7.4mmol/mol. 20 patients had undergone biopsy. 33% (2/6) demonstrated moderate-severe fibrosis in Asian patients, compared to 21% (3/14) Caucasian patients (p =0.61). Conclusions: Asian children with NAFLD have similar disease severity as their Caucasian counterparts, despite a significantly lower BMI centile at presentation. Referring clinicians and risk stratification scores require a greater awareness of ethnic differences in adiposity in paediatric NAFLD. EU Public health
Published: 2015
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33. HIV-1 subtypes in Luxembourg, 1983-2000

Author: Sabrina Deroo, Robert Hemmer, Thérèse Staub, Jean-Claude Schmit, Elodie Fontaine, François Schneider, Vic Arendt, Christine Lambert, Isabelle Robert, and Jean-Marc Plesséria
Subjects: Adult, Male, Genotype, Luxembourg, medicine.medical_treatment, Immunology, HIV Infections, Biology, Virus, HIV Protease, Antiretroviral Therapy, Highly Active, Drug Resistance, Viral, medicine, Prevalence, Immunology and Allergy, HIV Protease Inhibitor, Humans, Genotyping, Aged, Retrospective Studies, Protease, Polymorphism, Genetic, HIV Protease Inhibitors, Middle Aged, biology.organism_classification, Virology, Reverse transcriptase, HIV Reverse Transcriptase, Infectious Diseases, Lentivirus, Mutation, HIV-1, Reverse Transcriptase Inhibitors, Female, Viral disease, HIV drug resistance
Abstract: Objectives: To study the prevalence of HIV-1 subtypes in Luxembourg between 1983 and 2000. To compare the drug susceptibility of non-B and B clade viruses and the prevalence of resistance-associated mutations and polymorphisms before antiretroviral treatment. Design: A retrospective study on plasma samples of HIV-infected patients registered at the National Service of Infectious Diseases, Luxembourg, between 1983 and 2000. Methods: Genotyping was performed by sequencing of the reverse transcriptase (RT) and protease coding region of the pol gene. Drug susceptibility was assessed in a recombinant virus assay. Results: A total of 20.1% of the HIV-positive patients were infected with non-B subtypes, and since 1990 the proportion of non-B viruses has increased ninefold. Eleven out of 14 F1 subtypes occurred in patients native to Luxembourg. Major resistance mutations related to protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) occurred in less than 3% of treatment-naive viruses; however, 87% of the viruses had at least one PI-associated mutation. Natural polymorphism of the protease and RT coding region was observed more frequently among non-B than B viruses. Significantly more B viruses displayed resistance to the tested PI, NRTI and NNRTI (P= 0.044). Conclusion: The proportion of non-B viruses has increased dramatically since 1990. Non-B subtypes showed no decreased susceptibility to antiretroviral drugs, but displayed minor mutations and polymorphisms at higher frequency in their protease and RT coding region. In contrast, a significantly higher proportion of B viruses showed resistance to a range of antiretroviral drugs.
Published: 2002

34. Longitudinal use of phenotypic resistance testing to HIV-1 protease inhibitors in patients developing HAART failure

Author: Jean, Servais, Jean-Marc, Plesséria, Christine, Lambert, Elodie, Fontaine, Isabelle, Robert, Vic, Arendt, Thérèse, Staub, François, Schneider, Robert, Hemmer, and Jean-Claude, Schmit
Subjects: Phenotype, Predictive Value of Tests, Antiretroviral Therapy, Highly Active, Drug Resistance, Viral, HIV-1, Humans, HIV Infections, HIV Protease Inhibitors, Longitudinal Studies, Microbial Sensitivity Tests, Treatment Failure
Abstract: An "in-house" recombinant virus protease inhibitor susceptibility assay was carried out (median of 3 per patient) retrospectively in 26 patients failing HIV protease inhibitor based therapy at regular intervals to the initiation of the first protease inhibitor. Patients were treated with either indinavir (N = 6), ritonavir (N = 10), or saquinavir (N = 10) and two nucleoside analogues. Second line therapy was based on single or dual protease inhibitor regimens occasionally containing nelfinavir. Clinically relevant resistance cut-offs associated with a poorer virological outcome from 6 months on and the clinical outcome from 3 months on were determined tentatively as 4- to 8-fold resistance for indinavir and ritonavir and 2.5- to 8-fold to saquinavir. In addition, the degree of cross-resistance at the time of the change of protease inhibitor was associated with the response in viral load at 6 months to the second line therapy (P = 0.018). Cross-resistance (or = 8-fold) between ritonavir and indinavir was common (78 and 100%). Cross-resistance between indinavir or ritonavir and saquinavir was less frequent (75 and 60% respectively) than the opposite (100%, P = 0.004). Cross-resistance to nelfinavir was encountered more frequently (70%) than to amprenavir (9%). The magnitudes of resistance were correlated between each other. In summary, the protease inhibitor susceptibility carried out longitudinally appears to be an earlier prognostic marker than viral load in a context of cross-resistance. The magnitude of resistance, as a marker of cross-resistance, should be useful to guide second line therapy.
Published: 2002

35. Genotypic correlates of resistance to HIV-1 protease inhibitors on longitudinal data: the role of secondary mutations

Author: Christine Lambert, Isabelle Robert, Elodie Fontaine, Jean-Marc Plesséria, Jean Servais, Thérèse Staub, François Schneider, Jean-Claude Schmit, Robert Hemmer, and Vic Arendt
Subjects: Adult, Male, Longitudinal study, Genotype, medicine.disease_cause, Virus, HIV-1 protease, HIV Protease, Drug Resistance, Viral, medicine, Humans, Pharmacology (medical), Protease inhibitor (pharmacology), Longitudinal Studies, Pharmacology, Genetics, Mutation, Acquired Immunodeficiency Syndrome, biology, HIV Protease Inhibitors, Middle Aged, Viral Load, biology.organism_classification, Virology, CD4 Lymphocyte Count, Infectious Diseases, Cross-Sectional Studies, Enzyme inhibitor, Lentivirus, biology.protein, Female
Abstract: Direct sequencing of the pol gene was assessed retrospectively with protease inhibitor susceptibility in a longitudinal study. A total of 134 samples from 26 patients were analysed at regular intervals up to 2 years. Patients were included in virological failure despite indinavir, ritonavir or saquinavir based triple-drug therapy. Both the type and number of certain secondary protease mutations modulated the effect of primary mutations on phenotypic resistance. This was notably applicable to L10I/V, and to lesser extents to A71V/T. However, combinations of primary mutations, including I54V could predict resistance to the drug used and nelfinavir in more than 80%. In contrast, in vitro cross-resistance to amprenavir was rarely encountered. In addition, there was a relationship between a higher number of key mutations and poorer virological and clinical outcomes, respectively, from 6 and 3 months on. The key mutations were the protease mutations independently conferring phenotypic resistance and/or the reverse transcriptase mutations predicting treatment outcome. This relationship was independent from drug history, viral load and CD4 cell count measurements. In summary, even on a small sample size, sequence-based genotyping seems to be a good prognostic marker when performed longitudinally. In the context of primary resistance mutations, including additional secondary mutations, it may be useful in the prediction of phenotypic and clinical resistance. This should be assessed to optimize treatment monitoring before emergence of broadly cross-resistant virus.
Published: 2002

36. HIV-associated hematologic disorders are correlated with plasma viral load and improve under highly active antiretroviral therapy

Author: Jean-Claude Schmit, Dieudonné Nkoghe, François Schneider, Isabelle Robert, Vic Arendt, Michel Moutschen, Jean Servais, Robert Hemmer, and Thérèse Staub
Subjects: Adult, Male, Cross-sectional study, HIV Infections, Virus Replication, Virus, Blood cell, Antiretroviral Therapy, Highly Active, medicine, Humans, Pharmacology (medical), Platelet, Longitudinal Studies, biology, HIV Protease Inhibitors, Viral Load, biology.organism_classification, Hematologic Diseases, Infectious Diseases, medicine.anatomical_structure, Cross-Sectional Studies, Viral replication, Lentivirus, Immunology, HIV-1, Female, Hemoglobin, Viral load
Abstract: The relationship between HIV-1 replication and hematologic parameters was examined in two separate studies. The first study was a cross-sectional evaluation of 207 untreated patients. In this study, the proportion of patients with hematologic disorders increased with disease progression. There was a significant inverse correlation between HIV-1 plasma viral load and all hematologic values (r = -0.266 to -0.331). The second study was a longitudinal evaluation of patients on combination antiretroviral therapy (HAART) with hematologic alterations before treatment ( N = 27 with platelets150,000/microl, 24 with hemoglobin12 g/dl, 36 with neutrophils2000/microl and 29 with leukocytes3000/microl). Samples were analyzed every 3 months for 2 years. At 2 years,50% of patients experienced a sustained virologic response, with viral loads500 RNA copies/ml. Hematologic reconstitution occurred progressively for all blood cell lineages and became statistically significant after the sixth month of therapy ( p.001). Mean values increased from 110 to 180 x 10(3)/microl for platelets, from 10.7 to 12.3 g/dl for hemoglobin (stabilizing finally at 11.4 g/dl), from 1,260 to 2,240/microl for neutrophils, and from 2,260 to 3,600/microl for leukocytes. In conclusion, hematologic disorders are corrected by combination antiretroviral therapy. This suggests a causative role of HIV-1 in hematologic disorders.
Published: 2001

37. Indinavir hair concentration in highly active antiretroviral therapy-treated patients: association with viral load and drug resistance

Author: Jean-Claude Schmit, Gilles Peytavin, Jean Servais, Thérèse Staub, Vic Arendt, Guy Burtonboy, François Schneider, and Robert Hemmer
Subjects: medicine.medical_treatment, Immunology, HIV Infections, Indinavir, Drug resistance, Acquired immunodeficiency syndrome (AIDS), Immunopathology, Antiretroviral Therapy, Highly Active, medicine, Immunology and Allergy, Humans, Longitudinal Studies, Sida, Chemotherapy, biology, business.industry, Drug Resistance, Microbial, HIV Protease Inhibitors, Viral Load, biology.organism_classification, medicine.disease, Infectious Diseases, DNA, Viral, HIV-1, RNA, Viral, Viral disease, business, Viral load, medicine.drug, Hair
Published: 2001

38. Comparison of DNA sequencing and a line probe assay for detection of human immunodeficiency virus type 1 drug resistance mutations in patients failing highly active antiretroviral therapy

Author: Thérèse Staub, Robert Hemmer, Jean-Marc Plesséria, Jean Servais, François Schneider, Jean-Claude Schmit, Guy Burtonboy, Isabelle Robert, Vic Arendt, Elodie Fontaine, and Christine Lambert
Subjects: Microbiology (medical), Adult, Male, Genotype, HIV Infections, Indinavir, Drug resistance, Biology, Polymerase Chain Reaction, Virus, HIV Protease, Antiretroviral Therapy, Highly Active, Virology, medicine, HIV Protease Inhibitor, Humans, Protease inhibitor (pharmacology), Treatment Failure, Saquinavir, Retrospective Studies, Acquired Immunodeficiency Syndrome, Ritonavir, Drug Resistance, Microbial, HIV Protease Inhibitors, Reverse transcriptase, HIV Reverse Transcriptase, Mutation, HIV-1, RNA, Viral, Female, medicine.drug
Abstract: The resistance of human immunodeficiency virus type 1 (HIV-1) to drugs is a major cause of antiretroviral treatment failure. We have compared direct sequencing to a line probe assay (LiPA) for the detection of drug resistance-related mutations in 197 clinical samples, and we have investigated the sequential appearance of mutations under drug pressure. For 26 patients with virological failure despite the use of two nucleoside analogues and one protease inhibitor (indinavir [ n = 6], ritonavir [ n = 10], and saquinavir [ n = 10]), genotypic resistance assays were carried out retrospectively every 3 months for up to 2 years by using direct sequencing (TruGene; Visible Genetics) and a LiPA for detection of mutations in the reverse transcriptase (INNO-LiPA HIV-1 RT; Innogenetics) and the protease (INNO-LiPA HIV Protease, prototype version; Innogenetics) genes. Comparison of the results from both assays found rare major discrepancies (
Published: 2001

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