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1. SARS-CoV-2 Variants in Immunocompromised Patient Given Antibody Monotherapy

Author: Aurélie Truffot, Julien Andréani, Marion Le Maréchal, Alban Caporossi, Olivier Epaulard, Raphaele Germi, Pascal Poignard, and Sylvie Larrat
Subjects: coronavirus disease, COVID-19, severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, coronaviruses, viruses, Medicine, Infectious and parasitic diseases, RC109-216
Abstract: A 72-year-old immunocompromised man infected with severe acute respiratory syndrome coronavirus 2 received bamlanivimab monotherapy. Viral evolution was monitored in nasopharyngeal and blood samples by melting curve analysis of single-nucleotide polymorphisms and whole-genome sequencing. Rapid emergence of spike receptor binding domain mutations was found, associated with a compartmentalization of viral populations.
Published: 2021
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2. Added Value of Next-Generation Sequencing for Multilocus Sequence Typing Analysis of a Pneumocystis jirovecii Pneumonia Outbreak

Author: Elena Charpentier, Cécile Garnaud, Claire Wintenberger, Sébastien Bailly, Jean-Benjamin Murat, John Rendu, Patricia Pavese, Thibault Drouet, Caroline Augier, Paolo Malvezzi, Anne Thiébaut-Bertrand, Marie-Reine Mallaret, Olivier Epaulard, Muriel Cornet, Sylvie Larrat, and Danièle Maubon
Subjects: Pneumocystis jirovecii, pneumocystosis, pneumonia, disease outbreaks, infectious diseases, high-throughput nucleotide sequencing, Medicine, Infectious and parasitic diseases, RC109-216
Abstract: Pneumocystis jirovecii is a major threat for immunocompromised patients, and clusters of pneumocystis pneumonia (PCP) have been increasingly described in transplant units during the past decade. Exploring an outbreak transmission network requires complementary spatiotemporal and strain-typing approaches. We analyzed a PCP outbreak and demonstrated the added value of next-generation sequencing (NGS) for the multilocus sequence typing (MLST) study of P. jirovecii strains. Thirty-two PCP patients were included. Among the 12 solid organ transplant patients, 5 shared a major and unique genotype that was also found as a minor strain in a sixth patient. A transmission map analysis strengthened the suspicion of nosocomial acquisition of this strain for the 6 patients. NGS-MLST enables accurate determination of subpopulation, which allowed excluding other patients from the transmission network. NGS-MLST genotyping approach was essential to deciphering this outbreak. This innovative approach brings new insights for future epidemiologic studies on this uncultivable opportunistic fungus.
Published: 2017
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3. Diagnostic accuracy of a rapid RT-PCR assay for point-of-care detection of influenza A/B virus at emergency department admission: A prospective evaluation during the 2017/2018 influenza season.

Author: Maxime Maignan, Damien Viglino, Maud Hablot, Nicolas Termoz Masson, Anne Lebeugle, Roselyne Collomb Muret, Prudence Mabiala Makele, Valérie Guglielmetti, Patrice Morand, Julien Lupo, Virginie Forget, Caroline Landelle, and Sylvie Larrat
Subjects: Medicine, Science
Abstract: Study objectiveTo investigate the performance of a rapid RT-PCR assay to detect influenza A/B at emergency department admission.MethodsThis single-center prospective study recruited adult patients attending the emergency department for influenza-like illness. Triage nurses performed nasopharyngeal swab samples and ran rapid RT-PCR assays using a dedicated device (cobas Liat, Roche Diagnostics, Meylan, France) located at triage. The same swab sample was also analyzed in the department of virology using conventional RT-PCR techniques. Patients were included 24 hours-a-day, 7 days-a-week. The primary outcome was the diagnostic accuracy of the rapid RT-PCR assay performed at triage.ResultsA total of 187 patients were included over 11 days in January 2018. Median age was 70 years (interquartile range 44 to 84) and 95 (51%) were male. Nine (5%) assays had to be repeated due to failure of the first assay. The sensitivity of the rapid RT-PCR assay performed at triage was 0.98 (95% confidence interval (CI): 0.91-1.00) and the specificity was 0.99 (95% CI: 0.94-1.00). A total of 92 (49%) assays were performed at night-time or during the weekend. The median time from patient entry to rapid RT-PCR assay results was 46 [interquartile range 36-55] minutes.ConclusionRapid RT-PCR assay performed by nurses at triage to detect influenza A/B is feasible and highly accurate.
Published: 2019
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4. Hidden Selection of Bacterial Resistance to Fluoroquinolones In Vivo: The Case of Legionella pneumophila and Humans

Author: Lubana Shadoud, Iyad Almahmoud, Sophie Jarraud, Jérôme Etienne, Sylvie Larrat, Carole Schwebel, Jean-François Timsit, Dominique Schneider, and Max Maurin
Subjects: Legionella pneumophila, Legionellosis, Fluoroquinolone resistance, In vivo selection, Resistance detection, Next generation sequencing, Medicine, Medicine (General), R5-920
Abstract: Background: Infectious diseases are the leading cause of human morbidity and mortality worldwide. One dramatic issue is the emergence of microbial resistance to antibiotics which is a major public health concern. Surprisingly however, such in vivo adaptive ability has not been reported yet for many intracellular human bacterial pathogens such as Legionella pneumophila. Methods: We examined 82 unrelated patients with Legionnaire's disease from which 139 respiratory specimens were sampled during hospitalization and antibiotic therapy. We both developed a real time PCR assay and used deep-sequencing approaches to detect antibiotic resistance mutations in L. pneumophila and follow their selection and fate in these samples. Findings: We identified the in vivo selection of fluoroquinolone resistance mutations in L. pneumophila in two infected patients treated with these antibiotics. By investigating the mutational dynamics in patients, we showed that antibiotic resistance occurred during hospitalization most likely after fluoroquinolone treatment. Interpretation: In vivo selection of antibiotic resistances in L. pneumophila may be associated with treatment failures and poor prognosis. This hidden resistance must be carefully considered in the therapeutic management of legionellosis patients and in the control of the gradual loss of effectiveness of antibiotics.
Published: 2015
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5. Evaluation of the cobas® GT hepatitis C virus genotyping assay in G1-6 viruses including low viral loads and LiPA failures.

Author: Benjamin Némoz, Léa Roger, Vincent Leroy, Jean-Dominique Poveda, Patrice Morand, and Sylvie Larrat
Subjects: Medicine, Science
Abstract: Direct-acting antiviral (DAA) drug performances depend on the viral genotype. So international recommendations give typing of the virus a prerequisite for treatment choice and patient management. Commercially available HCV genotyping kits are scarce and this analysis is often in-house using tedious PCRs and Sanger sequencing, leading to a lack of standardization. A newly commercialized HCV genotyping assay based on real-time PCR has been developed by Roche Diagnostics (Mannheim, Germany). We compared this new assay with our in-house PCRs -sequencing technique on 101 regular samples and 81 LiPA failures or low viral load samples. No genotype or 1a/1b subtype mismatch was observed. Two samples were misidentified at the subtype level without clinical impact. Three genotype 1b and two genotype 1a samples with low viral load could not be subtyped. Nevertheless, 13 (13%) samples from the regular panel and 35 (43%) from the more difficult-to-type panels failed to give results on first pass with the Roche kit. Failures were mostly associated with genotype 3 subtype a, with genotype 4 subtype non-a, or with viral loads
Published: 2018
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6. Natural non-homologous recombination led to the emergence of a duplicated V3-NS5A region in HCV-1b strains associated with hepatocellular carcinoma.

Author: Hélène Le Guillou-Guillemette, Adeline Pivert, Elise Bouthry, Cécile Henquell, Odile Petsaris, Alexandra Ducancelle, Pascal Veillon, Sophie Vallet, Sophie Alain, Vincent Thibault, Florence Abravanel, Arielle A Rosenberg, Elisabeth André-Garnier, Jean-Baptiste Bour, Yazid Baazia, Pascale Trimoulet, Patrice André, Catherine Gaudy-Graffin, Dominique Bettinger, Sylvie Larrat, Anne Signori-Schmuck, Hénia Saoudin, Bruno Pozzetto, Gisèle Lagathu, Sophie Minjolle-Cha, Françoise Stoll-Keller, Jean-Michel Pawlotsky, Jacques Izopet, Christopher Payan, Françoise Lunel-Fabiani, and Christophe Lemaire
Subjects: Medicine, Science
Abstract: BACKGROUND:The emergence of new strains in RNA viruses is mainly due to mutations or intra and inter-genotype homologous recombination. Non-homologous recombinations may be deleterious and are rarely detected. In previous studies, we identified HCV-1b strains bearing two tandemly repeated V3 regions in the NS5A gene without ORF disruption. This polymorphism may be associated with an unfavorable course of liver disease and possibly involved in liver carcinogenesis. Here we aimed at characterizing the origin of these mutant strains and identifying the evolutionary mechanism on which the V3 duplication relies. METHODS:Direct sequencing of the entire NS5A and E1 genes was performed on 27 mutant strains. Quasispecies analyses in consecutive samples were also performed by cloning and sequencing the NS5A gene for all mutant and wild strains. We analyzed the mutant and wild-type sequence polymorphisms using Bayesian methods to infer the evolutionary history of and the molecular mechanism leading to the duplication-like event. RESULTS:Quasispecies were entirely composed of exclusively mutant or wild-type strains respectively. Mutant quasispecies were found to have been present since contamination and had persisted for at least 10 years. This V3 duplication-like event appears to have resulted from non-homologous recombination between HCV-1b wild-type strains around 100 years ago. The association between increased liver disease severity and these HCV-1b mutants may explain their persistence in chronically infected patients. CONCLUSIONS:These results emphasize the possible consequences of non-homologous recombination in the emergence and severity of new viral diseases.
Published: 2017
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7. Myasthenia Gravis Associated with Acute Hepatitis E Infection in Immunocompetent Woman

Author: Aude Belbezier, Alban Deroux, Françoise Sarrot-Reynauld, Sylvie Larrat, and Laurence Bouillet
Subjects: hepatitis E virus, myasthenia gravis, MuSK protein, antibodies, immunoglobulins, intravenous, Medicine, Infectious and parasitic diseases, RC109-216
Published: 2014
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8. Hepatitis E Virus Infection after Platelet Transfusion in an Immunocompetent Trauma Patient

Author: Emmanuelle Loyrion, Thibaut Trouve-Buisson, Patricia Pouzol, Sylvie Larrat, Thomas Decaens, and Jean-Francois Payen
Subjects: hepatitis E virus, platelet transfusion, trauma, injury, HEV, opportunistic infection, Medicine, Infectious and parasitic diseases, RC109-216
Abstract: Hepatitis E virus (HEV) infection causes acute liver disease, but severe infections are rare in immunocompetent patients. We describe a case of HEV infection in a previously healthy male trauma patient in France who received massive transfusions. Genotyping confirmed HEV in a transfused platelet pool and the donor.
Published: 2017
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9. Hepatitis E Virus Infection in Sheltered Homeless Persons, France

Author: Mamadou Kaba, Philippe Colson, Sylvie Larrat, Stéphanie Gaillard, Monique Baccard, Lionel Piroth, Patrice Cacoub, Stanislas Pol, Christian Perronne, Fabrice Carrat, and Patrice Morand
Subjects: Hepatitis E virus, homeless persons, HEV transmission, autochthonous hepatitis, injection drug use, France, Medicine, Infectious and parasitic diseases, RC109-216
Published: 2012
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10. Persistence at one year of neutralizing antibodies after SARS-CoV-2 infection: Influence of initial severity and steroid use

Author: Myriam Blanc, Sylvie Larrat, Jean-François Payen, Isabelle Pierre, Marion Le Maréchal, Pascal Poignard, Patricia Pavese, Marlyse Buisson, Olivier Epaulard, Nicolas Terzi, Raphaele Germi, Benjamin Nemoz, Laurence Grossi, Marie Froidure, Julien Lupo, Fanny Quénard, and Anne-Laure Mounayar
Subjects: Microbiology (medical), 2019-20 coronavirus outbreak, biology, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Virology, Persistence (computer science), Infectious Diseases, Steroid use, biology.protein, Medicine, Antibody, business
Published: 2022
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11. SARS-CoV-2 Variants in Immunocompromised Patient Given Antibody Monotherapy

Author: Sylvie Larrat, Pascal Poignard, Julien Andreani, Aurélie Truffot, Raphaële Germi, Alban Caporossi, Olivier Epaulard, and Marion Le Maréchal
Subjects: Microbiology (medical), Male, Epidemiology, medicine.drug_class, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.medical_treatment, viruses, Expedited, coronaviruses, selection, Infectious and parasitic diseases, RC109-216, Monoclonal antibody, Antibodies, Viral, Melting curve analysis, SARS-CoV-2 Variants in Immunocompromised Patient Given Antibody Monotherapy, respiratory infections, Immunocompromised Host, Research Letter, Medicine, Humans, Aged, Whole genome sequencing, variants, biology, business.industry, SARS-CoV-2, COVID-19, Immunocompromised patient, Immunotherapy, Virology, compartmentalization, zoonoses, Infectious Diseases, coronavirus disease, monoclonal antibody, whole-genome sequencing, Viral evolution, monotherapy, Spike Glycoprotein, Coronavirus, biology.protein, immunotherapy, bamlanivimab, Antibody, business, severe acute respiratory syndrome coronavirus 2
Abstract: A 72-year-old immunocompromised man infected with severe acute respiratory syndrome coronavirus 2 received bamlanivimab monotherapy. Viral evolution was monitored in nasopharyngeal and blood samples by melting curve analysis of single-nucleotide polymorphisms and whole-genome sequencing. Rapid emergence of spike receptor binding domain mutations was found, associated with a compartmentalization of viral populations.
Published: 2021

12. Evaluation of six commercial SARS-CoV-2 rapid antigen tests in nasopharyngeal swabs: better knowledge for better patient management?

Author: Julien Lupo, Julien Andreani, Marie Roccon, Benjamin Nemoz, Raphaële Germi, Christel Laugier, Patrice Morand, and Sylvie Larrat
Subjects: Rapid Antigen tests, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Concordance, RT-PCR, Sensitivity and Specificity, Article, Antigen, Nasopharynx, Virology, Pandemic, medicine, Humans, Viral shedding, Intensive care medicine, Antigens, Viral, Pandemics, Retrospective Studies, business.industry, SARS-CoV-2, COVID-19, Retrospective cohort study, Triage, Infectious Diseases, business
Abstract: Robust antigen point-of-care SARS-CoV-2 tests have been proposed as an efficient tool to address the COVID-19 pandemic. This requirement was raised after acknowledging the constraints that are brought by molecular biology. However, worldwide markets have been flooded with cheap and potentially underperforming lateral flow assays. Herein we retrospectively compared the overall performance of five qualitative rapid antigen SARS-CoV-2 assays and one quantitative automated test on 239 clinical swabs. While the overall sensitivity and specificity are relatively similar for all tests, concordance with molecular based methods varies, ranging from 75,7% to 83,3% among evaluated tests. Sensitivity is greatly improved when considering patients with higher viral excretion (Ct≤33), proving that antigen tests accurately distinguish infectious patients from viral shedding. These results should be taken into consideration by clinicians involved in patient triage and management, as well as by national authorities in public health strategies and for mass campaign approaches.
Published: 2021

13. Is it possible to hospitalize patients in multiple-bed room without increasing the risk of hospital-acquired influenza? Description of a pragmatic preventive strategy in a French university hospital

Author: Othmane Azzam, Caroline Landelle, Sylvie Larrat, Meghann Gallouche, Marie Reine Mallaret, Patrice Morand, Céline Giner, Fabiana Cazzorla, and Emeline Buet
Subjects: Oseltamivir, Epidemiology, Health Personnel, Detection bias, Beds, Antiviral Agents, Hospitals, University, chemistry.chemical_compound, Health care, Influenza, Human, medicine, Humans, Preventive strategy, business.industry, Health Policy, Public Health, Environmental and Occupational Health, virus diseases, Emergency department, University hospital, medicine.disease, Surgical mask, Infectious Diseases, Physical Barrier, chemistry, Medical emergency, business
Abstract: Background Large inrush of patients through Emergency Department during influenza season can be dramatic. The purpose of this study was to evaluate the impact of an emergency preventive strategy, namely admission of patients with influenza in multiple-bed room with patients free from influenza, on the occurrence of hospital-acquired influenza (HAI). Methods When a patient with an influenza RT-PCR diagnosis was hospitalized in a multiple-bed room, the emergency preventive strategy was applied: selection of non-immunocompromised neighbor, implementation of physical barriers (rigid screen pulled between beds, surgical mask for healthcare workers and visitors), preemptive Oseltamivir therapy for the neighbor. Results From 29/11/2017 to 10/05/2018 a total of 464 hospitalized influenza patients were included; 318 were placed in multiple-bed room and 141 in single room. Emergency preventive strategy was correctly applied for 75.1% of patients in multiple-bed room. A total of 8 exposed neighbors matched HAI definition despite strategy. 7 were already exposed to the case before the set-up of the strategy. Only one case of documented transmission of influenza occurred after application of an incorrect emergency preventive strategy: preventive posology of Oseltamivir was not correct. Conclusions These preliminary results suggest that the occurrence of HAI in multiple-bed rooms can be limited by the implementation of maximum precautions and urge us to promote further evaluation of the strategy. A detection bias should be considered without a systematic neighbors monitoring.
Published: 2021

14. SARS-CoV-2 nosocomial infection acquired in a French university hospital during the 1st wave of the Covid-19 pandemic, a prospective study

Author: Benjamin Nemoz, C. Giner, Meghann Gallouche, A Landoas, Sylvie Larrat, Olivier Epaulard, Patricia Pavese, M.R. Mallaret, Patrice Morand, F Cazzorla, Caroline Landelle, and M Le Maréchal
Subjects: Microbiology (medical), Male, medicine.medical_specialty, media_common.quotation_subject, Health Personnel, Infectious and parasitic diseases, RC109-216, Hospitals, University, COVID-19 Testing, Hygiene, Interquartile range, Pandemic, medicine, Infection control, Humans, Pharmacology (medical), Hand Hygiene, Prospective Studies, Healthcare-associated infection, Prospective cohort study, Pandemics, media_common, Aged, Retrospective Studies, Aged, 80 and over, Cross Infection, Infection Control, Mask, business.industry, SARS-CoV-2, Research, Public Health, Environmental and Occupational Health, Masks, COVID-19, Retrospective cohort study, Outbreak, Middle Aged, Surgical mask, Infectious Diseases, Emergency medicine, Observational study, Female, France, business
Abstract: Background In healthcare facilities, nosocomial transmissions of respiratory viruses are a major issue. SARS-CoV-2 is not exempt from nosocomial transmission. Our goals were to describe COVID-19 nosocomial cases during the first pandemic wave among patients in a French university hospital and compliance with hygiene measures. Methods We conducted a prospective observational study in Grenoble Alpes University Hospital from 01/03/2020 to 11/05/2020. We included all hospitalised patients with a documented SARS-CoV-2 diagnosis. Nosocomial case was defined by a delay of 5 days between hospitalisation and first symptoms. Hygiene measures were evaluated between 11/05/2020 and 22/05/2020. Lockdown measures were effective in France on 17/03/2020 and ended on 11/05/2020. Systematic wearing of mask was mandatory for all healthcare workers (HCW) and visits were prohibited in our institution from 13/03/2021 and for the duration of the lockdown period. Results Among 259 patients included, 14 (5.4%) were considered as nosocomial COVID-19. Median time before symptom onset was 25 days (interquartile range: 12–42). Eleven patients (79%) had risk factors for severe COVID-19. Five died (36%) including 4 deaths attributable to COVID-19. Two clusters were identified. The first cluster had 5 cases including 3 nosocomial acquisitions and no tested HCWs were positive. The second cluster had 3 cases including 2 nosocomial cases and 4 HCWs were positive. Surgical mask wearing and hand hygiene compliance were adequate for 95% and 61% of HCWs, respectively. Conclusions The number of nosocomial COVID-19 cases in our hospital was low. Compliance regarding mask wearing, hand hygiene and lockdown measures drastically reduced transmission of the virus. Monitoring of nosocomial COVID-19 cases during the first wave enabled us to determine to what extent the hygiene measures taken were effective and patients protected. Trial registration Study ethics approval was obtained retrospectively on 30 September 2020 (CECIC Rhône-Alpes-Auvergne, Clermont-Ferrand, IRB 5891).
Published: 2020

15. Screening of hepatitis E in patients presenting for acute neurological disorders

Author: Sébastien Lhomme, Chantal Dumestre-Pérard, Vincent Leroy, Lorella Minotti, Emeline Lagrange, Patrice Morand, Jean-Luc Bosson, M. Lugosi, Claire Wintenberger, Roselyne Collomb-Muret, Aude Belbézier, Maxime Maignan, Damien Viglino, Françoise Sarrot-Reynauld, Sylvie Larrat, Perrine Dumanoir, Isabelle Boccon-Gibod, Alban Deroux, Carole Schwebel, A. Bosseray, Antoine Vilotitch, Mathieu Vaillant, Julien Lupo, Laurence Bouillet, Olivier Epaulard, B. Colombe, Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre Hospitalier Universitaire [Grenoble] (CHU), Pôle Psychiatrie et Neurologie [Grenoble], Service d'immunologie [CHU Grenoble], CHU de Grenoble, Centre de Physiopathologie Toulouse Purpan (CPTP), 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), Laboratoire de Virologie [Toulouse], CHU Toulouse [Toulouse], Département de virologie [Grenoble], 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), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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), Laboratoire Virologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications Grenoble - UMR 5525 (TIMC-IMAG)
Subjects: 0301 basic medicine, Male, viruses, Neurological disorder, medicine.disease_cause, Serology, Hepatitis, 0302 clinical medicine, Hepatitis E virus, Seroepidemiologic Studies, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030212 general & internal medicine, Prospective Studies, Acute hepatitis, MESH: Acute Disease / epidemiology, Adult, Aged, Aged, 80 and over, Brachial Plexus Neuritis / epidemiology, Female, France / epidemiology, Guillain-Barre Syndrome / epidemiology, Hepatitis Antibodies / blood, Hepatitis E / blood, Hepatitis E / diagnosis, Hepatitis E / epidemiology, Hepatitis E / immunology, Hepatitis E virus / immunology, Humans Immunoglobulin M / blood, Middle Aged, Nervous System Diseases / epidemiology, Nervous System Diseases / immunology, RNA, Viral / blood, Reverse Transcriptase Polymerase Chain Reaction, Transaminases / blood, Young Adult, education.field_of_study, lcsh:Public aspects of medicine, virus diseases, General Medicine, Hepatitis E, 3. Good health, Infectious Diseases, Acute Disease, RNA, Viral, France, medicine.medical_specialty, 030106 microbiology, Population, Guillain-Barre Syndrome, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Internal medicine, medicine, Seroprevalence, Brachial Plexus Neuritis, Humans, lcsh:RC109-216, Hepatitis Antibodies, education, Transaminases, business.industry, Public Health, Environmental and Occupational Health, lcsh:RA1-1270, medicine.disease, Immunoglobulin M, Elevated transaminases, Nervous System Diseases, business
Abstract: International audience; Introduction: Hepatitis E virus (HEV) infection has been reported to be associated with neurological disor-ders. However, the real prevalence of acute hepatitis E in those diseases is still unknown. We determinedthe prevalence of anti-HEV IgM antibody in a population with acute non-traumatic, non-metabolic,non-vascular neurological injury.Method: A registry was created in Grenoble Hospital University from 2014 to 2018 to collect data onpatients with acute (
Published: 2020
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16. Baseline and Post-Treatment Hepatitis C NS5A Resistance in Relapsed Patients from a Multicentric Real-Life Cohort

Author: Philippe Halfon, Jacques Izopet, Pascale Trimoulet, Caroline Scholtes, Sofiane Mohamed, Denis Ouzan, Laurent Chiche, Victor de Ledinghen, Hacène Khiri, Marc Bourlière, M.A. Thelu, Sophie Metivier, Guillaume Penaranda, Anne Plauzolles, Laurent Alric, Vincent Leroy, Fabien Zoulim, Sylvie Larrat, Florence Abravanel, ALPHABIO - Laboratoire de biologie médicale, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut de biologie structurale (IBS - UMR 5075), 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)-Centre National de la Recherche Scientifique (CNRS), Service de virologie et d'immunologie biologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'Hépatologie et de Gastroentérologie [Lyon], Hospices Civils de Lyon (HCL), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Gastro-entérologie - Hépatologie [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Hôpital Michallon, Institut Arnault Tzanck, Service d'Hépato-Gastro-Entérologie, CHU Bordeaux [Bordeaux]-Hôpital Saint-André, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine interne [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Service d'hépatologie et de gastroentérologie [Hôpital Saint-Joseph - Marseille], Aix Marseille Université (AMU)-Hôpital Saint-Joseph [Marseille], Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen [Fondation Ambroise Paré - Marseille], Centre Hospitalier Universitaire de Lyon (CHU Lyon), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Bordeaux [Bordeaux], Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Hôpital Haut-Lévêque [CHU Bordeaux], Hôpital Saint-Joseph [Marseille], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon], 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), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de Virologie [CHU Purpan, Toulouse], Institut Fédératif de Biologie (IFB) - Hôpital Purpan, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre Léon Bérard [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), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT)
Subjects: Male, 0301 basic medicine, DNA Mutational Analysis, Viral Nonstructural Proteins / genetics, Drug Resistance, Hepacivirus, Drug resistance, Viral Nonstructural Proteins, Virological response, Viral Nonstructural Proteins / antagonists & inhibitors, 0302 clinical medicine, Medicine, Pharmacology (medical), Viral, Treatment Failure, Hepatitis C, Viral Load, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Treatment Outcome, Infectious Diseases, Antiviral Agents / pharmacology, Cohort, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, Viral load, Hepacivirus / genetics, medicine.medical_specialty, Genotype, Antiviral Agents / therapeutic use, Antiviral Agents, 03 medical and health sciences, Pharmacotherapy, Drug Therapy, Internal medicine, Drug Resistance, Viral, Humans, NS5A, Pharmacology, business.industry, medicine.disease, 030104 developmental biology, Hepatitis C / virology, Hepacivirus / drug effects, Post treatment, Hepatitis C / drug therapy, business
Abstract: Background Recent data have suggested that failure to achieve sustained virological response with direct-acting antiviral therapy is usually due to relapse and is primarily associated with the emergence of resistance-associated substitutions. The aim of this study was to investigate the prevalence and characterization of non-structural-5A resistance-associated substitutions in patients infected with HCV genotypes 1, 3 and 4 treated by direct-acting antiviral therapy, including anti-non-structural-5A, and to characterize the pre-existing resistance-associated substitutions in subjects treated with anti-non-structural-5A inhibitors. Methods From January 2014 to March 2016, 2,995 patients infected with HCV genotypes 1, 3 and 4 were exposed to non-structural-5A inhibitors. Sequencing results at the time of virological failure were available for 61 patients; sequencing at baseline was available for 35 of these patients. Results Among the 35 patients with sequencing results available at baseline, 15 had no resistance-associated substitution, 16 had only one resistance-associated substitution, and 4 had more than one resistance-associated substitution. Resistance-associated substitutions were harbored in 57% of the sequences in the non-structural-5A region. Among the 61 patients sequenced at virological failure, 50 (82%) patients presented at least one resistance-associated substitutions inducing a high level of resistance to non-structural-5A inhibitors (>10-fold resistance). Conclusions This pooled analysis suggests that non-structural-5A resistance-associated substitutions screening should be recommended when considering retreatment with a non-structural-5A inhibitor regimen in patients who have previously experienced failed non-structural-5A treatment.
Published: 2017
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17. Different precore/core mutations of hepatitis B interact with, limit, or favor liver fibrosis severity

Author: Pascal Veillon, Evelyne Schvoerer, Joël Gozlan, Hélène Le Guillou-Guillemette, Sylvie Larrat, Françoise Lunel-Fabiani, Adeline Pivert, Vincent Mackiewicz, Véronique Brodard, Véronique Loustaud-Ratti, Vincent Thibault, Emmanuel Gordien, Sophie Alain, Alexandra Ducancelle, Jérôme Boursier, Sandrine Castelain, Sandrine Bertrais, Marianne Coste-Burel, Bénédicte Roquebert, Paul Calès, Sarah Maylin, Stéphane Chevaliez, and Viorica Balan
Subjects: Hepatitis B virus, medicine.medical_specialty, HBsAg, Mutation, Hepatology, business.industry, Gastroenterology, Hepatitis B, medicine.disease, medicine.disease_cause, Virology, 3. Good health, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Fibrosis, 030220 oncology & carcinogenesis, Internal medicine, Medicine, 030211 gastroenterology & hepatology, Hepatic fibrosis, business, Viral hepatitis
Abstract: BACKGROUND AND AIM The impact of basal core promoter (BCP) and precore (PC) mutants of the hepatitis B virus (HBV) on liver disease severity remains controversial. The aim of the present study was to screen BCP and PC mutations in 252 HBV surface antigen (HBsAg) positive carriers in France and to assess relationships between these mutations and severe fibrosis. METHODS Direct sequencing of the precore/core gene was used to detect A1762T/G1764A and G1757A mutations in the BCP and G1896A and G1899A mutations in the PC region. RESULTS The prevalences of A1762T/G1764A, G1757A, G1896A, and G1899A mutations were 34.1%, 38.7%, 54.9%, and 29.3% (P
Published: 2016
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18. Hepatitis C virus whole genome sequencing: Current methods/issues and future challenges

Author: Alban Caporossi, Pauline Tremeaux, Michael G. B. Blum, Patrice Morand, Vincent Leroy, M.A. Thelu, Sylvie Larrat, Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes - UFR Médecine (UGA UFRM), Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), As Scalable As Possible: foundations of large scale dynamic distributed systems (ASAP), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SYSTÈMES LARGE ÉCHELLE (IRISA-D1), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), SYSTÈMES LARGE ÉCHELLE (IRISA-D1), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Cancer genome sequencing, Sanger sequencing, Hepatitis C virus, Clinical Biochemistry, Genome, Viral, Hepacivirus, MESH: Molecular Diagnostic Techniques, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, DNA sequencing, 03 medical and health sciences, symbols.namesake, medicine, Humans, MESH: Hepacivirus, MESH: High-Throughput Nucleotide Sequencing, Genotyping, Exome sequencing, MESH: Hepatitis C, Whole genome sequencing, Genetics, MESH: Humans, Whole Genome Sequencing, MESH: Molecular Typing, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], resistance-associated variants, Biochemistry (medical), High-Throughput Nucleotide Sequencing, Hepatitis C, 3. Good health, Molecular Typing, 030104 developmental biology, Molecular Diagnostic Techniques, genotyping, symbols, next-generation sequencing, MESH: Genome, Viral, MESH: Whole Genome Sequencing, Personal genomics
Abstract: International audience; Therapy for hepatitis C is currently undergoing a revolution. The arrival of new antiviral agents targeting viral proteins reinforces the need for a better knowledge of the viral strains infecting each patient. Hepatitis C virus (HCV) whole genome sequencing provides essential information for precise typing, study of the viral natural history or identification of resistance-associated variants. First performed with Sanger sequencing, the arrival of next-generation sequencing (NGS) has simplified the technical process and provided more detailed data on the nature and evolution of viral quasi-species. We will review the different techniques used for HCV complete genome sequencing and their applications, both before and after the apparition of NGS. The progress brought by new and future technologies will also be discussed, as well as the remaining difficulties, largely due to the genomic variability.
Published: 2016
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19. Diagnostic accuracy of a rapid RT-PCR assay for point-of-care detection of influenza A/B virus at emergency department admission: A prospective evaluation during the 2017/2018 influenza season

Author: Roselyne Collomb Muret, Anne Lebeugle, Valérie Guglielmetti, Sylvie Larrat, Virginie Forget, Prudence Mabiala Makele, Maxime Maignan, Julien Lupo, Damien Viglino, Maud Hablot, Patrice Morand, Nicolas Termoz Masson, Caroline Landelle, Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Emergency department [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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), Laboratoire de Virologie [Grenoble], Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Infection Control Unit [Grenoble], Techniques pour l'Evaluation et la Modélisation des Actions de la Santé (TIMC-IMAG-ThEMAS), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), This work was partly funded by Roche Diagnostics (http://www.roche-diagnostics.fr/), the industrial company that markets the cobas Liat system. MM received this grant., Laboratoire Hypoxie et Physiopathologies cardiovasculaires et respiratoires [Grenoble] (HP2), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Bodescot, Myriam
Subjects: 0301 basic medicine, Male, RNA viruses, Viral Diseases, Influenza Viruses, Critical Care and Emergency Medicine, Health Care Providers, Nurses, Artificial Gene Amplification and Extension, medicine.disease_cause, Roche Diagnostics, Pathology and Laboratory Medicine, Polymerase Chain Reaction, Biochemistry, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Interquartile range, Nucleic Acids, Influenza A virus, Medicine and Health Sciences, Medicine, 030212 general & internal medicine, Prospective Studies, Medical Personnel, Prospective cohort study, Aged, 80 and over, Multidisciplinary, Reverse Transcriptase Polymerase Chain Reaction, Middle Aged, 3. Good health, Professions, Infectious Diseases, Molecular Diagnostic Techniques, Medical Microbiology, Viral Pathogens, Viruses, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, France, Seasons, Pathogens, Emergency Service, Hospital, Research Article, Adult, medicine.medical_specialty, Science, Point-of-Care Systems, 030106 microbiology, Research and Analysis Methods, Microbiology, Specimen Handling, 03 medical and health sciences, Internal medicine, Virology, Influenza, Human, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology Techniques, Molecular Biology, Microbial Pathogens, Point of care, Aged, business.industry, Organisms, Biology and Life Sciences, Emergency department, Reverse Transcriptase-Polymerase Chain Reaction, Triage, Confidence interval, Influenza, Health Care, Influenza B virus, People and Places, Population Groupings, business, Orthomyxoviruses
Abstract: Study objectiveTo investigate the performance of a rapid RT-PCR assay to detect influenza A/B at emergency department admission.MethodsThis single-center prospective study recruited adult patients attending the emergency department for influenza-like illness. Triage nurses performed nasopharyngeal swab samples and ran rapid RT-PCR assays using a dedicated device (cobas Liat, Roche Diagnostics, Meylan, France) located at triage. The same swab sample was also analyzed in the department of virology using conventional RT-PCR techniques. Patients were included 24 hours-a-day, 7 days-a-week. The primary outcome was the diagnostic accuracy of the rapid RT-PCR assay performed at triage.ResultsA total of 187 patients were included over 11 days in January 2018. Median age was 70 years (interquartile range 44 to 84) and 95 (51%) were male. Nine (5%) assays had to be repeated due to failure of the first assay. The sensitivity of the rapid RT-PCR assay performed at triage was 0.98 (95% confidence interval (CI): 0.91-1.00) and the specificity was 0.99 (95% CI: 0.94-1.00). A total of 92 (49%) assays were performed at night-time or during the weekend. The median time from patient entry to rapid RT-PCR assay results was 46 [interquartile range 36-55] minutes.ConclusionRapid RT-PCR assay performed by nurses at triage to detect influenza A/B is feasible and highly accurate.
Published: 2019
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20. Hepatitis C subtype distribution in chronically infected patients with mild liver fibrosis in France: the GEMHEP study

Author: Vincent Thibault, Benjamin Nemoz, Magali Bouvier-Alias, P. Marcellin, Françoise Lunel-Fabiani, Vincent Leroy, C. Henquell, Etienne Brochot, Patrice Morand, T. Semenova, Christopher Payan, Gilles Duverlie, S. Vallet, Pascale Trimoulet, Sylvie Larrat, L. Izquierdo, Gisèle Lagathu, A. M. Roque-Afonso, Sarah Maylin, Stéphane Chevaliez, Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Pontchaillou [Rennes], Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Service de virologie et d'immunologie biologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), CHU Clermont-Ferrand, Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), Laboratoire de Virologie [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Service d'hépatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Université Grenoble Alpes (UGA), Laboratoire Microorganismes : Génome et Environnement - Clermont Auvergne (LMGE), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, Institut de biologie structurale (IBS - UMR 5075), 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)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Liver Cirrhosis, Male, Databases, Factual, Epidemiology, Hepacivirus, medicine.disease_cause, Severity of Illness Index, Tertiary Care Centers, 0302 clinical medicine, Genotype, Prevalence, ComputingMilieux_MISCELLANEOUS, education.field_of_study, [SDE.IE]Environmental Sciences/Environmental Engineering, Incidence (epidemiology), Hepatitis C, 3. Good health, Infectious Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Viral, 030211 gastroenterology & hepatology, Female, France, Viral hepatitis, Adult, treatment-naive HCV, medicine.medical_specialty, Hepatitis C virus, [SDE.MCG]Environmental Sciences/Global Changes, Population, HCV genotypes, Statistics, Nonparametric, 03 medical and health sciences, Viral Proteins, Internal medicine, medicine, Humans, education, Retrospective Studies, Hepatitis, Original Paper, business.industry, fibrosis, Hepatitis C, Chronic, medicine.disease, [SDE.ES]Environmental Sciences/Environmental and Society, 030104 developmental biology, Logistic Models, Multivariate Analysis, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, business
Abstract: Treatment options for Hepatitis C infection have greatly improved with direct-acting antiviral (DAA) combinations achieving high cure rates. Nevertheless, the cost of this treatment is still high and access to treatment in many countries has been preferentially reserved for patients with more severe fibrosis (F3 and F4). In this French nationwide study, we investigated the epidemiological characteristics and genotype distribution of hepatitis C virus (HCV) in treatment-naive patients with METAVIR fibrosis stages between F0 and F2 in order to identify patient profiles that became eligible for unrestricted treatment in a second period. Between 2015 and 2016 we collected data from nine French university hospitals on a total of 584 HCV positive patients with absent, mild or moderate liver fibrosis. The most represented genotypes were genotype 1b (159/584; 27.2%), followed by genotype 1a (150/584; 25.7%); genotype 3 (87/584: 14.9%); genotype 4 (80/584; 13.7%). Among genotype 4: 4a was predominantly encountered with 22 patients (27.5% of genotype 4). Genotypes 1b and 1a are currently the most frequent virus types present in treatment-naive patients with mild fibrosis in France. They can be readily cured using the available DAA. Nevertheless, non-a/non-d genotype 4 is also frequent in this population and clinical data on the efficacy of DAA on these subtypes is missing. The GEMHEP is the French group for study and evaluation of viral hepatitis on a national scale. Data collection on epidemiological and molecular aspects of viral hepatitis is performed on a regular basis in all main French teaching hospitals and serves as a basis for surveillance of these infections. Analysis and trends are regularly published on behalf of the GEMHEP group. Data collection was performed retrospectively over the 2015–2016 period, covering nine main university hospitals in France. A total of 584 hepatitis C positive patients were included in this study. Genotyping of the circulating viruses showed a high prevalence of genotypes 1b and 1a in our population. The epidemiology of hepatitis C is slowly changing in France, particularly as a consequence of the rise of ‘non-a non-d’ genotype 4 viruses mainly originating from African populations. More data concerning treatment efficacy of these genotypes is needed in order to guide clinical care.
Published: 2019
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21. Using high-throughput sequencing for investigating intra-host hepatitis C evolution over long retrospective periods

Author: Om Kulkarni, V. Leroy, Olivier François, Alban Caporossi, Patrice Morand, Michael G. B. Blum, Sylvie Larrat, Francois, Olivier, Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: 0301 basic medicine, Microbiology (medical), Genotype, Secondary infection, Hepatitis C virus, 030106 microbiology, Population, Hepacivirus, Viral Nonstructural Proteins, Biology, medicine.disease_cause, Microbiology, Evolution, Molecular, 03 medical and health sciences, chemistry.chemical_compound, Drug Resistance, Viral, Genetics, medicine, Humans, Selection, Genetic, education, Molecular Biology, NS5B, Phylogeny, Ecology, Evolution, Behavior and Systematics, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, education.field_of_study, Genetic diversity, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Genetic heterogeneity, Genetic Variation, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Hepatitis C, medicine.disease, 3. Good health, 030104 developmental biology, Infectious Diseases, chemistry, Host-Pathogen Interactions, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Selective sweep
Abstract: Collections of biological samples held by hospitals represent invaluable resources for conducting retrospective evolutionary studies of chronic infections. Using high-throughput sequencing, those collections permit analysis of within-host genetic diversity over long follow-up periods, and allow a better understanding of resistance to treatment regimes during disease evolution. Here, we studied the evolution of hepatitis C virus (HCV) populations in two patients with an absence of response to dual therapies. We implemented amplicon sequencing to survey genomic variation at the Core and NS5B regions of HCV over a period of 13 years from blood samples obtained at multiple time points. We observed mixed infection by multiple HCV genotypes in both patients. Genetic heterogeneity and sample composition analysis provided information about the changes in viral population over the course of clinical treatment, with NS5B experiencing an increase in diversity after treatment initiation. Secondary infections were estimated to predate treatment year, and our results pointed towards diversifying selection occurring post-treatment, acting on standing genomic variation and maintaining high genetic heterogeneity during infection. For these two patients infected with multiple HCV genotypes, the maintenance of viral diversity was explained with the hypothesis of soft selective sweep started at the same time as antiviral treatment was initiated.
Published: 2019

22. Innovative multiplexed point-of-care immunoassay applied to hepatitis B screening

Author: Paul Kauffmann, Pn Marche, Guillaume Blaire, Sarah Delshadi, Thomas Decaens, Patrice Morand, V. Masse, O. Cugat, Sylvie Larrat, Microbiology and Infectious Diseases, Sherbrooke University Hospital, Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génie Electrique de Grenoble (G2ELab), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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)-Centre National de la Recherche Scientifique (CNRS), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Chadebec, Olivier, Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: medicine.diagnostic_test, business.industry, [SPI.NRJ]Engineering Sciences [physics]/Electric power, Biochemistry (medical), Clinical Biochemistry, General Medicine, Biochemistry, Virology, 3. Good health, Hepatitis B screening, Immunoassay, medicine, business, ComputingMilieux_MISCELLANEOUS, [SPI.NRJ] Engineering Sciences [physics]/Electric power, Point of care
Abstract: International audience
Published: 2019
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23. Evaluation of the cobas® GT hepatitis C virus genotyping assay in G1-6 viruses including low viral loads and LiPA failures

Author: Sylvie Larrat, Jean-Dominique Poveda, Patrice Morand, Benjamin Nemoz, Vincent Leroy, Léa Roger, Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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), Hôpital Michallon, Laboratoire CERBA [Saint Ouen l'Aumône], Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: RNA viruses, 0301 basic medicine, Genotyping Techniques, MESH: Reagent Kits, Diagnostic, lcsh:Medicine, Artificial Gene Amplification and Extension, Hepacivirus, medicine.disease_cause, Roche Diagnostics, Polymerase Chain Reaction, MESH: Genotype, Genotype, MESH: Sequence Analysis, RNA, Medicine, MESH: Hepacivirus, lcsh:Science, Asymptomatic Infections, Pathology and laboratory medicine, Sanger sequencing, Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Hepatitis C virus, MESH: Real-Time Polymerase Chain Reaction, Viral Load, Medical microbiology, Subtyping, MESH: Hepatitis C, Chronic, 3. Good health, MESH: RNA, Viral, Viruses, symbols, RNA, Viral, Pathogens, MESH: Viral Load, Viral load, Research Article, MESH: Antiviral Agents, Genotyping, 030106 microbiology, MESH: Asymptomatic Infections, Research and Analysis Methods, Real-Time Polymerase Chain Reaction, Microbiology, Antiviral Agents, 03 medical and health sciences, symbols.namesake, Extraction techniques, Virology, MESH: Genotyping Techniques, Humans, Serologic Tests, Typing, Molecular Biology Techniques, Sequencing Techniques, Molecular Biology, Retrospective Studies, Medicine and health sciences, MESH: Humans, Flaviviruses, Sequence Analysis, RNA, business.industry, MESH: Serologic Tests, lcsh:R, Organisms, Viral pathogens, Automated Fluorescent Genotyping, Biology and Life Sciences, MESH: Retrospective Studies, Reverse Transcriptase-Polymerase Chain Reaction, Hepatitis C, Chronic, Hepatitis viruses, RNA extraction, Microbial pathogens, lcsh:Q, Reagent Kits, Diagnostic, business, Viral Transmission and Infection
Abstract: International audience; Direct-acting antiviral (DAA) drug performances depend on the viral genotype. So international recommendations give typing of the virus a prerequisite for treatment choice and patient management. Commercially available HCV genotyping kits are scarce and this analysis is often in-house using tedious PCRs and Sanger sequencing, leading to a lack of standardization. A newly commercialized HCV genotyping assay based on real-time PCR has been developed by Roche Diagnostics (Mannheim, Germany). We compared this new assay with our in-house PCRs -sequencing technique on 101 regular samples and 81 LiPA failures or low viral load samples. No genotype or 1a/1b subtype mismatch was observed. Two samples were misidentified at the subtype level without clinical impact. Three genotype 1b and two genotype 1a samples with low viral load could not be subtyped. Nevertheless, 13 (13%) samples from the regular panel and 35 (43%) from the more difficult-to-type panels failed to give results on first pass with the Roche kit. Failures were mostly associated with genotype 3 subtype a, with genotype 4 subtype non-a, or with viral loads
Published: 2018
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24. Hepatitis E Virus in Acute Non-Traumatic, Non-Vascular Neurological Injury: A French Monocentric Prospective Study

Author: Claire Wintenberger, Maxime Maignan, Damien Viglino, Olivier Epaulard, Sylvie Larrat, Carole Schwebel, Françoise Sarrot-Reynauld, B. Colombe, Chantal Dumestre-Pérard, Lorella Minotti, Emeline Lagrange, Isabelle Boccond-Gibod, Alban Deroux, Maxime Lugosi, Laurence Bouillet, Perrine Dumanoir, Patrice Morand, A. Bosseray, Roselyne Collomb-Muret, Vincent Leroy, Jean-Luc Bosson, Julien Lupo, Antoine Vilotitch, Mathieu Vaillant, and Aude Belbézier
Subjects: medicine.medical_specialty, Neurological injury, Hepatitis E virus, business.industry, Non traumatic, Internal medicine, Medicine, business, Prospective cohort study, medicine.disease_cause
Published: 2018
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25. Ultradeep Pyrosequencing of NS3 To Predict Response to Triple Therapy with Protease Inhibitors in Previously Treated Chronic Hepatitis C Patients

Author: Olivier François, Katia Fusillier, Michael G. B. Blum, Jean-Pierre Zarski, Sylvie Larrat, Pauline Tremeaux, Patrice Morand, Réjane Beugnot, Alice Marlu, Jean-Baptiste Claude, Agnès Plages, Om Kulkarni, Anne Signori-Schmuck, Julien Lupo, Hervé Duborjal, Vincent Leroy, Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF), Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Genostar, GENOME Express (GENOME Express), GENOME Express, Earth and Environmental, AMEC, Biochimie et Génétique Moléculaire, CHU Grenoble-Hôpital Michallon, Pôle Digidune, Pôle DigiDune, Unité de Biophysique, CRSSA, Département d'hépato-gastroentérologie, Université Grenoble Alpes (UGA)-CHU Grenoble, Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), CHU Grenoble-Université Grenoble Alpes (UGA), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, and Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Microbiology (medical), NS3, medicine.medical_specialty, Entropy, medicine.medical_treatment, Mutation, Missense, Salvage therapy, Viral quasispecies, Viral Nonstructural Proteins, Biology, Antiviral Agents, Peripheral blood mononuclear cell, Gastroenterology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Virology, Internal medicine, Drug Resistance, Viral, Genotype, medicine, Humans, Protease Inhibitors, Aged, 030304 developmental biology, Aged, 80 and over, Salvage Therapy, 0303 health sciences, Protease, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Genetic Variation, High-Throughput Nucleotide Sequencing, virus diseases, Odds ratio, Hepatitis C, Chronic, Middle Aged, Prognosis, digestive system diseases, Confidence interval, 3. Good health, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], HCV, Immunology, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology
Abstract: Despite the gain in sustained virological responses (SVR) provided by protease inhibitors (PIs), failures still occur. The aim of this study was to determine if a baseline analysis of the NS3 region using ultradeep pyrosequencing (UDPS) can help to predict an SVR. Serum samples from 40 patients with previously nonresponding genotype 1 chronic hepatitis C who were retreated with triple therapy, including a PI, were analyzed. Baseline UDPS of the NS3 gene was performed on plasma and peripheral blood mononuclear cells (PBMC). Mutations conferring resistance to PIs were sought. The overall diversity of the quasispecies was evaluated by calculating the Shannon entropy (SE). Resistance mutations were found in plasma and PBMC but were not discriminating enough to predict an SVR. NS3 quasispecies heterogeneity was significantly lower at baseline in patients achieving an SVR than in those not achieving an SVR (SE of 26.98 ±16.64 x10^3 versus 44.93 ±19.58 x10^3, P =0.0047). With multivariate analysis, the independent predictors of an SVR were fibrosis of stage F <2 (odds ratio [OR], 13.3; 95% confidence interval [CI], 1.25 to 141.096; P < 0.03) and SE below the median (OR, 5.4; 95% CI, 1.22 to 23.87; P < 0.03). More than the presence of minor mutations at the baseline in plasma or in PBMC, the NS3 viral heterogeneity determined by UDPS is an independent factor for an SVR in previously treated patients receiving triple therapy that includes a PI.&nbsp
Published: 2015
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26. Added Value of Next-Generation Sequencing for Multilocus Sequence Typing Analysis of a Pneumocystis jirovecii Pneumonia Outbreak1

Author: Patricia Pavese, Sébastien Bailly, Claire Wintenberger, Cécile Garnaud, Caroline Augier, Anne Thiebaut-Bertrand, Sylvie Larrat, Thibault Drouet, Marie-Reine Mallaret, Olivier Epaulard, Danièle Maubon, Eléna Charpentier, John Rendu, Paolo Malvezzi, Muriel Cornet, Jean-Benjamin Murat, Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Biochimie et Génétique Moléculaire, CHU Grenoble-Hôpital Michallon-CHU Grenoble-Hôpital Michallon, Service des Maladies Infectieuses, CHU Grenoble, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Clinique Universitaire d'Hématologie [La Tronche, Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Unité d'hygiène Hospitalière, Department of infectious diseases, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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)-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: Male, 0301 basic medicine, transplants, Epidemiology, multilocus sequence typing, Pneumocystis carinii, Pneumocystis pneumonia, Disease Outbreaks, Genotype, Pneumocystosis, high-throughput nucleotide sequencing, Child, Pneumocystis jirovecii, Phylogeny, ComputingMilieux_MISCELLANEOUS, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, biology, Pneumonia, Pneumocystis, Middle Aged, 3. Good health, Infectious Diseases, NGS, Child, Preschool, Synopsis, Female, MLST, Adult, Microbiology (medical), Adolescent, 030106 microbiology, Sensitivity and Specificity, DNA sequencing, pneumocystosis, respiratory infections, Young Adult, 03 medical and health sciences, medicine, pneumonia, Humans, Genotyping, Aged, Polymorphism, Genetic, Added Value of Next-Generation Sequencing for Multilocus Sequence Typing Analysis of a Pneumocystis jirovecii Pneumonia Outbreak, Computational Biology, Infant, Outbreak, biology.organism_classification, medicine.disease, Virology, Case-Control Studies, Multilocus sequence typing, next-generation sequencing, fungi
Abstract: Pneumocystis jirovecii is a major threat for immunocompromised patients, and clusters of pneumocystis pneumonia (PCP) have been increasingly described in transplant units during the past decade. Exploring an outbreak transmission network requires complementary spatiotemporal and strain-typing approaches. We analyzed a PCP outbreak and demonstrated the added value of next-generation sequencing (NGS) for the multilocus sequence typing (MLST) study of P. jirovecii strains. Thirty-two PCP patients were included. Among the 12 solid organ transplant patients, 5 shared a major and unique genotype that was also found as a minor strain in a sixth patient. A transmission map analysis strengthened the suspicion of nosocomial acquisition of this strain for the 6 patients. NGS-MLST enables accurate determination of subpopulation, which allowed excluding other patients from the transmission network. NGS-MLST genotyping approach was essential to deciphering this outbreak. This innovative approach brings new insights for future epidemiologic studies on this uncultivable opportunistic fungus.
Published: 2017
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27. Sequencing Assays for Failed Genotyping with the Versant Hepatitis C Virus Genotype Assay (LiPA), Version 2.0

Author: Anne Signori-Schmuck, Katia Fusillier, Jean-Dominique Poveda, Sylvie Larrat, Vincent Thibault, Nelly Magnat, Camille Coudret, and Patrice Morand
Subjects: Adult, Male, Microbiology (medical), Untranslated region, Genotype, Hepacivirus, Hepatitis C virus, Molecular Sequence Data, medicine.disease_cause, chemistry.chemical_compound, Virology, medicine, Humans, False Negative Reactions, NS5B, Genotyping, Aged, Genetics, NS3, Base Sequence, biology, Genetic Variation, Sequence Analysis, DNA, Hepatitis C, Middle Aged, medicine.disease, biology.organism_classification, Molecular Diagnostic Techniques, chemistry, Mutation, RNA, Viral, Female
Abstract: For optimal antiviral therapy, the hepatitis C virus (HCV) genotype needs to be determined, as it remains a strong predictor of sustained viral response. In this study, we assessed the number of HCV genotyping results that could not be determined using the commercially available line probe assay (LiPA) (Versant hepatitis C virus genotype 2.0 assay) in a large international panel of samples from 9,874 HCV-positive patients. In-house sequencing assays targeting the 5′ untranslated region (UTR), core region, NS3 region, and NS5B region of the HCV genome and phylogenetic analyses were used to resolve these LiPA failures. Among all cases, the genotypes of 51 samples (0.52%) could not be determined with the LiPA. These undetermined results were observed more frequently among samples from non-European regions (mainly the Arabian Peninsula). The use of sequencing assays coupled with phylogenetic analysis provided reliable genotype results for 86% of the LiPA failures, which exhibited higher rates of genotypes 4, 5, and 6 than did LiPA-resolved genotypes. As expected, the 5′ UTR was not sufficiently variable for clear discrimination between genotypes 1 and 6, but it also resulted in errors in classification of some genotype 3 and 4 cases using well-known Web-based BLAST programs. This study demonstrates the low frequency of genotyping failures with the Versant hepatitis C virus genotype 2.0 assay (LiPA) and also underlines the need for a complex combination of sequences and phylogenetic analyses in order to genotype these particular HCV strains correctly.
Published: 2013
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28. Fatal autochthonous fulminant hepatitis E early after allogeneic stem cell transplantation

Author: Anne Thiebaut-Bertrand, Sylvie Larrat, N Sturm, Sébastien Lhomme, Vincent Leroy, Martin Carre, J. Y. Cahn, Frédéric Garban, Patricia Pouzol, Patrice Morand, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: MESH: Fatal Outcome, Fatal outcome, medicine.medical_treatment, MESH: Allografts, Hematopoietic stem cell transplantation, Precursor Cell Lymphoblastic Leukemia Lymphoma, 03 medical and health sciences, 0302 clinical medicine, Fatal Outcome, medicine, MESH: Liver Failure, Acute, Humans, 030212 general & internal medicine, Fulminant hepatitis, ComputingMilieux_MISCELLANEOUS, MESH: Hematopoietic Stem Cell Transplantation, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, Transplantation, MESH: Humans, MESH: Middle Aged, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], business.industry, MESH: Hepatitis E, Liver failure, Hematopoietic Stem Cell Transplantation, Hematology, Liver Failure, Acute, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Hepatitis E, medicine.disease, Allografts, Virology, 3. Good health, Immunology, 030211 gastroenterology & hepatology, Female, Stem cell, business, MESH: Female
Abstract: International audience
Published: 2017
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29. First next-generation sequencing full-genome characterization of a hepatitis C virus genotype 7 divergent subtype

Author: M.-A. Thélu, Peter Simmonds, Katia Fusillier, N. De Castro, Maud Salmona, Séverine Mercier-Delarue, Olivier François, Jérôme LeGoff, Sarah Maylin, Marie-Laure Chaix, Alban Caporossi, Patrice Morand, Sylvie Larrat, and François Simon
Subjects: 0301 basic medicine, Microbiology (medical), Male, Genotype, Hepacivirus, Hepatitis C virus, Genome, Viral, medicine.disease_cause, Genome, DNA sequencing, Evolution, Molecular, 03 medical and health sciences, Phylogenetics, medicine, Humans, Phylogeny, Whole genome sequencing, Genetics, biology, Strain (biology), High-Throughput Nucleotide Sequencing, General Medicine, Sequence Analysis, DNA, Middle Aged, biology.organism_classification, Virology, 030104 developmental biology, Infectious Diseases
Abstract: We report the near-full-length genome sequence of a hepatitis C virus (HCV) isolate from a man originating from Democratic Republic of Congo, the genotype of which could not be determined by the routinely used sequencing technique. The near-complete genome sequence of this variant BAK1 was obtained by the association of two next-generation sequencing technologies. Evolutionary analysis indicates that this isolate, BAK1, could be the first reported strain belonging to a new HCV-7b subtype. This new subtype has been incorrectly identified as genotype 2 by the Versant HCV Genotype 2.0 assay (LiPA). The requirement of three independent isolates has been filled, and a new subtype can be assigned. More examples of HCV-7 are required to better understand its origin, its pathogenicity and its relationship with genotype 2.
Published: 2016

30. Ultradeep sequencing of B and non-B HIV-1 subtypes: Viral diversity and drug resistance mutations before and after one month of antiretroviral therapy in naive patients

Author: Michael G. B. Blum, Myriam Blanc, Om Kulkarni, Olivier Epaulard, Anne Signori-Schmuck, Katia Fusillier, Olivier François, Patrice Morand, Sylvie Larrat, and P Leclercq
Subjects: 0301 basic medicine, Adult, Male, Genotype, Anti-HIV Agents, Population, HIV Infections, Drug resistance, Biology, medicine.disease_cause, 03 medical and health sciences, Plasma, immune system diseases, Virology, Antiretroviral Therapy, Highly Active, Genetic variation, Drug Resistance, Viral, medicine, Humans, education, education.field_of_study, Mutation, virus diseases, Genetic Variation, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Middle Aged, Viral Load, Reverse transcriptase, HIV Reverse Transcriptase, CD4 Lymphocyte Count, 030104 developmental biology, Infectious Diseases, HIV-1, Pyrosequencing, RNA, Viral, Reverse Transcriptase Inhibitors, Female, Viral load
Abstract: Background Ultradeep pyrosequencing technologies permit an assessment of the genetic diversity and the presence and frequency of minority variants in a viral population. The effect of these parameters on the outcome of highly active antiretroviral therapy (HAART) in HIV-infected patients is poorly understood. Objectives The present study used the pyrosequencing Roche 454 prototype assay to determine whether antiretroviral efficacy is correlated with viral diversity and minority drug resistance mutations in HIV-infected treatment-naive patients and to compare assay performance in B and non-B subtypes. Study design The study included 30 HIV-1 infected naive patients (20 with subtype non-B and 10 with subtype B). Ultradeep pyrosequencing of protease and reverse transcriptase genes was performed at baseline and 1 month after HAART initiation. Plasma HIV VL was measured at 0 and after 1, 3, and 6 months of HAART. Results Pre-HAART minority drug resistance mutations were observed to NRTI in 4 patients, to NNRTI in 6 patients, and to PI in 1 patient; there was no difference in HAART-induced VL decay between patients. Pre-HAART diversity was significantly correlated with the time elapsed since HIV-1 infection diagnosis, but not with the subtype, VL, or CD4 count. Patients with an undetectable VL after 3 months of HAART had a higher pre-HAART diversity. Pre- and post-HAART diversities were not statistically different. There was no difference in assay performance between subtype B and non-B. Conclusions A high pre-HAART viral diversity might have a positive effect on the outcome of HAART. Pre-therapeutic minority drug resistance mutations are uncommon in naive patients.
Published: 2016

31. Prevalence and characterization of NS5A resistance associated variants (RAVs) in patients who relapsed following exposure to NS5A inhibitors

Author: Guillaume Penaranda, Philippe Halfon, Caroline Scholtès, Sofiane Mohamed, Vincent Leroy, Marc Bourlière, Denis Ouzan, Guillaume Pénaranda, Hacène Khiri, Laura Polverel, Fabien Zoulim, Marie-Ange Thélu, and Sylvie Larrat
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, business.industry, Immunology, Public Health, Environmental and Occupational Health, Microbiology, QR1-502, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Infectious Diseases, Virology, Internal medicine, medicine, In patient, 030212 general & internal medicine, Public aspects of medicine, RA1-1270, business, NS5A
Published: 2016

32. Performance of an antigen–antibody combined assay for hepatitis C virus testing without venipuncture

Author: Marie-Noelle Hilleret, Cécile Bourdon, Cécile Garnaud, Myriam Blanc, Jean-Louis Quesada, Vincent Leroy, Raphaele Germi, P Leclercq, Jean-Pierre Zarski, Monique Baccard, Sophie Mathieu, Sylvie Larrat, Patrice Morand, and Anne Signori-Schmuck
Subjects: Adult, Male, Fingerstick, Point-of-Care Systems, Hepatitis C virus, medicine.disease_cause, Sensitivity and Specificity, Young Adult, Phlebotomy, Antigen, Virology, medicine, Humans, Saliva, Dried blood, Antigens, Viral, Aged, Immunoassay, Venipuncture, biology, Clinical Laboratory Techniques, business.industry, virus diseases, Hepatitis C Antibodies, Middle Aged, Serum samples, Hepatitis C, digestive system diseases, Blood, Infectious Diseases, biology.protein, Female, Antibody, business
Abstract: Background Hepatitis C virus (HCV) is underdiagnosed and therefore increasing the opportunities for HCV testing without venipuncture may be useful. Objectives We evaluated the analytical performance of a modified, commercially available, combined HCV antigen–antibody assay (cEIA) (Monolisa ® HCV-Ag-Ab-ULTRA) and a commercially available point-of-care (POC) device (OraQuick ® HCV) on fingerstick blood (FSB) and oral mucosal transudate (OMT). Study design FSB, OMT and serum samples were collected from 113 cases of HCV-antibody-positive patients and 88 HCV-antibody-negative controls. The HCV-antibody-positive group included 63 patients with quantifiable HCV-RNA (56%) and 17 HIV/HCV co-infected patients (15%). FSB and OMT specimens were collected as dried blood spots (DBSs) or with the OraSure collection system, before testing with cEIA. Results With FSB specimens, the cEIA and the POC device exhibited 100% specificity and 98.2% and 97.4% sensitivity, respectively. The specificity of the cEIA in FSB sharply decreased if stored 3 days at room temperature. With OMT specimens, the cEIA sensitivity (71.7%) and specificity (94.3%) were significantly lower than the performance of OraQuick ® HCV (sensitivity, 94.6%; specificity, 100%). The optical densities obtained with the cEIA in FSB and OMT were lower in HIV/HCV co-infected patients compared with HCV monoinfected patients. Conclusion The cEIA using FSB specimens collected on DBSs preserved in appropriate storage conditions was a reliable alternative, equivalent to the POC assay, for HCV testing without venipuncture. The cEIA was not adapted for HCV testing on OMT.
Published: 2012
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33. Plasmacytoid dendritic cells induce efficient stimulation of antiviral immunity in the context of chronic hepatitis B virus infection

Author: Joel Plumas, Marie-Jeanne Richard, Vincent Leroy, Jérémie Martinet, Tania Dufeu-Duchesne, Fabien Zoulim, Sylvie Larrat, and Caroline Aspord
Subjects: Adult, Male, Hepatitis B virus, Cellular immunity, Mice, SCID, Adaptive Immunity, CD8-Positive T-Lymphocytes, Biology, Transfection, medicine.disease_cause, Interferon-gamma, Mice, Young Adult, Immune system, Antigen, Lysosomal-Associated Membrane Protein 1, Mice, Inbred NOD, Lysosomal-Associated Membrane Protein 2, medicine, Animals, Humans, Cytotoxic T cell, Hepatitis B Vaccines, Hepatitis B e Antigens, Aged, Hepatitis B Surface Antigens, HLA-A Antigens, Hepatology, virus diseases, hemic and immune systems, Dendritic Cells, Hep G2 Cells, Middle Aged, Viral Load, Hepatitis B, Acquired immune system, medicine.disease, Hepatitis B Core Antigens, Virology, digestive system diseases, Disease Models, Animal, HBeAg, Immunology, Hepatocytes, Leukocytes, Mononuclear, Female
Abstract: The immune control of hepatitis B virus (HBV) infection is essential for viral clearance. Therefore, restoring functional anti–HBV immunity is a promising immunotherapeutic approach to treatment of chronic infection. Plasmacytoid dendritic cells (pDCs) play a crucial role in triggering antiviral immunity through their ability to capture and process viral antigens and subsequently induce adaptive immune responses. We investigated the potential of pDCs to trigger antiviral cellular immunity against HBV. We used a human leukocyte antigen A (HLA–A)*0201+ pDC line loaded with HLA–A*0201-restricted peptides derived from hepatitis B core/hepatitis B surface (HBc/HBs) antigens to amplify specific CD8 T cells ex vivo from chronic HBV patients and established a Hepato-HuPBL mouse model to address the therapeutic potential of the strategy in vivo. Stimulation of PBMCs or liver-infiltrating lymphocytes from HLA–A*0201+ chronic HBV patients by HBc peptide-loaded pDCs elicited up to 23.1% and 76.1% HBV-specific CD8 T cells in 45.8% of cases. The specific T cells from the “responder” group secreted interferon-γ, expressed CD107 upon restimulation, and efficiently lysed HBV antigen-expressing hepatocytes. Circulating hepatitis B e antigen (HBeAg) was found to distinguish the group of patients not responding to the pDC stimulation. The therapeutic efficacy of the pDC vaccine was evaluated in immunodeficient NOD-SCID β2m−/− mice reconstituted with HBV patients' PBMCs and xenotransplanted with human HBV-transfected hepatocytes. Vaccination of Hepato–HuPBL mice with the HBc/HBs peptide–loaded pDCs elicited HBV-specific T cells able to specifically lyse the transfected hepatocytes and reduce the systemic viral load. Conclusion: pDCs loaded with HBV–derived peptides can elicit functional virus-specific T cells. HBeAg appears to be critical in determining the outcome of immunotherapies in chronic HBV patients. A pDC-based immunotherapeutic approach could be of interest in attempts to restore functional antiviral immunity, which is critical for the control of the virus in chronic HBV patients. (HEPATOLOGY 2012;56:1706–1718)
Published: 2012
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34. Inhibition of Epstein–Barr virus replication by small interfering RNA targeting the Epstein–Barr virus protease gene

Author: Patrice Morand, Solenne Vigne, Marlyse Buisson, Wim P. Burmeister, Jean-Marie Seigneurin, Sylvie Larrat, Jean-Marc Crance, Ariane Bas, Véronique Boyer, Raphaële Germi, Laurence Grossi, and Sandrine Nicod
Subjects: Pharmacology, Biology, medicine.disease_cause, biology.organism_classification, Virology, Molecular biology, Epstein–Barr virus, Herpesviridae, Virus, Infectious Diseases, Capsid, Lytic cycle, RNA interference, hemic and lymphatic diseases, medicine, Gene silencing, Gammaherpesvirinae, Pharmacology (medical)
Abstract: Background The Epstein–Barr virus (EBV) protease (PR), coded by the BVRF2 gene, is essential for the maturation of the viral capsid and viral DNA packaging during the late stage of the EBV lytic cycle. Like the other herpesvirus serine PRs, EBV PR could be a target for the inhibition of EBV replication. To date, no data have been reported on the inhibition of EBV PR messenger RNA (mRNA) by small interfering RNA (siRNA). Methods In this study, siRNAs targeting EBV PR were delivered to the epithelial 293 cell line stably transfected with the complete B95-8 EBV episome. EBV DNA and PR mRNA were quantified by real-time PCR in cells and supernatant, protein expression was assessed by immunoblotting, and production of EBV infectious particles in the culture medium was measured by Raji cell superinfection. Results The EBV PR mRNA within the cells was reduced by 73%, the PR protein by 35% and the amount of virus in the cell supernatant was drastically decreased by 86% or 95%, depending on the method. Conclusions The strong effect of the siRNA targeting EBV PR on EBV replication attests to the crucial role played by EBV PR in the production of infectious particles and suggests that targeting this enzyme can be a new strategy against EBV-associated diseases where virus replication occurs.
Published: 2008
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35. Amplification and pyrosequencing of near-full-length hepatitis C virus for typing and monitoring antiviral resistant strains

Author: Patrice Morand, Alban Caporossi, P. Trémeaux, Patrice Andre, E. Santoni, M.-A. Thélu, Sylvie Larrat, Katia Fusillier, Wim P. Burmeister, Nicolas Tarbouriech, Olivier François, C. Ramière, Vincent Leroy, L. Geneletti, Institut de Biologie et Pathologie [CHU Grenoble] (IBP), CHU Grenoble-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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), Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre d'Investigation Clinique [Grenoble] (CIC Grenoble ), CHU Grenoble-Hôpital Michallon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de Virologie [HCL, Lyon] (Institut des Agents Infectieux), Hospices civils de Lyon (HCL)-HCL Groupement Hospitalier Nord [Lyon]-Centre National de Reference des virus des Infections Respiratoires France Sud [HCL, Lyon], Service d'hépato-gastroentérologie, CHU Grenoble, Laboratoire de Virologie, Hospices Civils de Lyon (HCL), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-CHU Grenoble
Subjects: 0301 basic medicine, Microbiology (medical), Daclatasvir, Pyrrolidines, Sofosbuvir, Genotype, Genotyping Techniques, Hepatitis C virus, 030106 microbiology, Mutation, Missense, Hepacivirus, Biology, medicine.disease_cause, Recombinant virus, Antiviral Agents, 03 medical and health sciences, chemistry.chemical_compound, Drug Resistance, Viral, medicine, Humans, NS5A, Genotyping, NS5B, Genetics, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Imidazoles, Valine, General Medicine, Sequence Analysis, DNA, Hepatitis C, Chronic, Virology, 3. Good health, 030104 developmental biology, Infectious Diseases, chemistry, RNA, Viral, Carbamates, Nucleic Acid Amplification Techniques, medicine.drug
Abstract: International audience; Directly acting antivirals have contributed considerable progress to hepatitis C treatment, but they show variable activity depending on viral genotypes and subtypes. Therefore, accurate genotyping including recombinant form detection is still of major importance, as is the detection of resistance-associated mutations in case of therapeutic failure. To meet these goals, an approach to amplify the hepatitis C virus (HCV) near-complete genome with a single long-range PCR and sequence it with Roche GS Junior was developed. After optimization, the overall amplification success rate was 73% for usual genotypes (i.e. HCV1a, 1b, 3a and 4a, n = 16 of 22) and 45% for recombinant forms RF_2k/1b (n = 5 of 11). After pyrosequencing and subsequent de novo assembly, a near-full-length genomic consensus sequence was obtained for 19 of 21 samples. The genotype and subtype were confirmed by phylogenetic analysis for every sample, including the suspected recombinant forms. Resistance-associated mutations were detected in 7 of 13 samples at baseline, in the NS3 (n = 3) or NS5A region (n = 4). Of these samples, the treatment of one patient included daclatasvir and that patient experienced a relapse. Viral sequences from pre- and post-treatment samples of four patients who relapsed after sofosbuvir-based therapy were compared: the selected variants seem too far from the NS5B catalytic site to be held responsible. Although tested on a limited set of samples and with technical improvements still necessary, this assay has proved to be successful for both genotyping and resistance-associated variant detection on several HCV types.
Published: 2015
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36. Hidden Selection of Bacterial Resistance to Fluoroquinolones In Vivo: The Case of Legionella pneumophila and Humans

Author: Sophie Jarraud, Lubana Shadoud, Dominique Schneider, Jerome Etienne, Iyad Almahmoud, Sylvie Larrat, Jean-François Timsit, Max Maurin, Carole Schwebel, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Centre Nationale de Référence des Légionelles, Laboratoire de Virologie moléculaire et structurale, CHU Grenoble, Service de Réanimation Médicale [Grenoble], CHU Grenoble-Hôpital Michallon, Epidémiologie pronostique des cancers et affections graves, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Évolution des Microorganismes [?-2015] (TIMC-GEM [?-2015]), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 [2011-2015] (TIMC [2011-2015]), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-IMAG-Institut polytechnique de Grenoble - Grenoble Institute of Technology [2007-2019] (Grenoble INP [2007-2019])-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-IMAG-Institut polytechnique de Grenoble - Grenoble Institute of Technology [2007-2019] (Grenoble INP [2007-2019])-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Thérapeutique Recombinante Expérimentale [?-2015] (TIMC-TheREx [?-2015]), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Pathogenèse des légionelles- Legionella pathogenesis (LegioPath), 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)-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), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis (StaPath), Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF), Service de Réanimation Médicale [CHU Grenoble], Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), and Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Antibiotics, Colony Count, Microbial, Drug Resistance, lcsh:Medicine, Fluoroquinolone resistance, Legionella pneumophila, In vivo selection, Cohort Studies, Microbial resistance, 80 and over, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, lcsh:R5-920, Cross Infection, biology, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Bacterial, Drug Resistance, Microbial, General Medicine, Bacterial Infections, Middle Aged, 3. Good health, Human morbidity, Anti-Bacterial Agents, Hospitalization, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, lcsh:Medicine (General), Research Paper, Fluoroquinolones, DNA, Bacterial, Adult, medicine.drug_class, Microbial Sensitivity Tests, General Biochemistry, Genetics and Molecular Biology, Microbiology, Antibiotic resistance, In vivo, Next generation sequencing, Drug Resistance, Bacterial, medicine, Escherichia coli, Humans, Aged, Legionellosis, Bacteria, lcsh:R, DNA, Resistance detection, biology.organism_classification, Virology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Bacterial Load, Genes, Genes, Bacterial, Mutation, Commentary
Abstract: Background Infectious diseases are the leading cause of human morbidity and mortality worldwide. One dramatic issue is the emergence of microbial resistance to antibiotics which is a major public health concern. Surprisingly however, such in vivo adaptive ability has not been reported yet for many intracellular human bacterial pathogens such as Legionella pneumophila. Methods We examined 82 unrelated patients with Legionnaire's disease from which 139 respiratory specimens were sampled during hospitalization and antibiotic therapy. We both developed a real time PCR assay and used deep-sequencing approaches to detect antibiotic resistance mutations in L. pneumophila and follow their selection and fate in these samples. Findings We identified the in vivo selection of fluoroquinolone resistance mutations in L. pneumophila in two infected patients treated with these antibiotics. By investigating the mutational dynamics in patients, we showed that antibiotic resistance occurred during hospitalization most likely after fluoroquinolone treatment. Interpretation In vivo selection of antibiotic resistances in L. pneumophila may be associated with treatment failures and poor prognosis. This hidden resistance must be carefully considered in the therapeutic management of legionellosis patients and in the control of the gradual loss of effectiveness of antibiotics., Highlights • Legionellosis is a pneumonia caused by the inhalation of aerosols containing Legionella, mainly L. pneumophila. • Its average mortality rate is 10%, despite availability of effective antibiotics such as the macrolides and the fluoroquinolones. • Using modern molecular approaches, we identified the selection of fluoroquinolone resistance in L. pneumophila in patients under fluoroquinolone therapy. • This may lead to reduction of treatment efficacy and prognosis worsening. • Our findings should lead to revised guidelines for therapeutic management and prognosis evaluation of legionellosis.
Published: 2015
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37. Hepatitis E and neuralgic amyotrophy: Five cases and review of literature

Author: Sylvie Larrat, Françoise Sarrot-Reynauld, Anaïs Dartevel, Emmeline Lagrange, B. Colombe, Laurence Bouillet, A. Bosseray, Aude Belbézier, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Département de neurologie, and Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: Parsonage–Turner syndrome, Adult, Male, Pediatrics, medicine.medical_specialty, Usually asymptomatic, Sex Factors, MESH: Sex Factors, Virology, medicine, Brachial Plexus Neuritis, Humans, Parsonage turner syndrome, MESH: Brachial Plexus Neuritis, MESH: Developed Countries, Neuralgic amyotrophy, MESH: Humans, MESH: Middle Aged, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Acute hepatitis E, business.industry, Developed Countries, MESH: Hepatitis E, Mean age, Strong hepatitis E, MESH: Adult, Middle Aged, Hepatitis E, medicine.disease, Nervous system diseases, MESH: Immunoglobulin M, MESH: Male, 3. Good health, Surgery, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Infectious Diseases, Immunoglobulin M, Female, business, Brachial plexus, MESH: Female, Hepatitis E virus infection
Abstract: International audience; Hepatitis E virus infection - mainly genotype 3 - is increasingly common in industrialized countries. Infection is usually asymptomatic, but cases of central or peripheral neurological symptoms with hepatitis E have been described. The most frequent is Guillain-Barre but somes cases of neuralgic amyotrophy have been described. In our center, since 2010, we have identified five cases of neuralgic amyotrophy associated with acute hepatitis E in immunocompetent patients. For all these patients, neuralgic amyotrophy was diagnosed with electromyogram and positive IgM for hepatitis E, and detectable HEV RNA in 4 of the cases. Including our patients, we count 26 cases in literature. The mean age of the patients was 44 years old, with a large predominance of males (88%). The disorder is bilateral and asymmetric in 69% of cases. Peripheral nerves other than the brachial plexus were affected in 6 patients (23%). In industrialized countries, any neuralgic amyotrophy, particularly if there is bilateral, asymmetric associated with involvement of nerves outside the brachial plexus, should lead physicians to consider a diagnosis of acute hepatitis E.
Published: 2015
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38. Next-generation sequencing offers new insights into the resistance of Candida spp. to echinocandins and azoles

Author: Danièle Maubon, Christophe Hennequin, Cécile Garnaud, Marie-Elisabeth Bougnoux, Natacha Sertour, Françoise Botterel, Sylvie Larrat, Muriel Cornet, Jesús Guinea, Eric Dannaoui, Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Unité de Parasitologie-Mycologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Biologie et Pathogénicité fongiques, Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dynamic Microbiology - EA 7380 (DYNAMIC), École nationale vétérinaire d'Alfort (ENVA)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biologie structurale des interactions entre virus et cellule hôte (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie et Pathologie [CHU Grenoble] (IBP), CHU Grenoble-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Parasitologie - Mycologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Clinical Microbiology and Infectious Diseases Department, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), This work was supported by a grant from Pfizer (Prix de recherche Société Française de Mycologie Médicale—Pfizer 2012). The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript., Thérapeutique Recombinante Expérimentale ( TIMC-IMAG-THEREX ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Institut National de la Recherche Agronomique ( INRA ) -Institut Pasteur [Paris], Dynamyc Mycology - EA 7380, Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Laboratoire de biologie structurale des interactions entre virus et cellule hôte, Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie et Pathologie [CHU Grenoble] ( IBP ), CHU Grenoble-Université Grenoble Alpes ( UGA ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Universidad Complutense de Madrid [Madrid] ( UCM ), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Biologie et Pathogénicité fongiques (BPF), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris], Dynamyc- Dynamyc Mycology - EA 7380, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), CHU Grenoble-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Universidad Complutense de Madrid [Madrid] (UCM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Azoles, Antifungal Agents, MESH : Genotype, Candida parapsilosis, MESH: Genotype, chemistry.chemical_compound, MESH : Candidiasis, Echinocandins, MESH: Azoles, Pharmacology (medical), Candida albicans, MESH: High-Throughput Nucleotide Sequencing, [ SDV.MP.MYC ] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Candida, Genetics, chemistry.chemical_classification, 0303 health sciences, biology, Candidiasis, High-Throughput Nucleotide Sequencing, Caspofungin Acetate, MESH: Candidiasis, Infectious Diseases, NGS, MESH : Mutation, antifungals, medicine.drug, Microbiology (medical), MESH: Mutation, Echinocandin, Genotype, MESH : Antifungal Agents, Microbiology, MESH: Drug Resistance, Fungal, 03 medical and health sciences, Drug Resistance, Fungal, MESH: Candida, medicine, Humans, 030304 developmental biology, MESH : Echinocandins, Pharmacology, MESH: Humans, Candida glabrata, 030306 microbiology, MESH: Echinocandins, MESH : Humans, MESH : Drug Resistance, Fungal, biology.organism_classification, mutations, MESH: Antifungal Agents, MESH : Azoles, chemistry, Mutation, Azole, Caspofungin, MESH : Candida, MESH : High-Throughput Nucleotide Sequencing
Abstract: International audience; ObjectivesMDR Candida strains are emerging. Next-generation sequencing (NGS), which enables extensive and deep genome analysis, was used to investigate echinocandin and azole resistance in clinical Candida isolates.; MethodsSix genes commonly involved in antifungal resistance (ERG11, ERG3, TAC1, CgPDR1, FKS1 and FKS2) were analysed using NGS in 40 Candida isolates (18 Candida albicans, 15 Candida glabrata and 7 Candida parapsilosis). The strategy was validated using strains with known sequences. Then, 8 clinical strains displaying antifungal resistance and 23 sequential isolates collected from 10 patients receiving antifungal therapy were analysed.; ResultsA total of 391 SNPs were detected, among which 6 coding SNPs were reported for the first time. Novel genetic alterations were detected in both azole and echinocandin resistance genes. A C. glabrata strain, which was resistant to echinocandins but highly susceptible to azoles, harboured an FKS2 S663P mutation plus a novel presumed loss-of-function CgPDR1 mutation. This isolate was from a patient with deep-seated and urinary candidiasis. Another C. glabrata isolate, with an MDR phenotype, carried a new FKS2 S663A mutation and a new putative gain-of-function CgPDR1 mutation (T370I); this isolate showed mutated (80%) and WT (20%) populations and was collected after 75 days of exposure to caspofungin from a patient who underwent complicated abdominal surgery.; ConclusionsThis study shows that NGS can be used for extensive assessment of genetic mutations involved in antifungal resistance. This type of wide genome approach will become very valuable for detecting mechanisms of resistance in clinical strains subjected to multidrug pressure.
Published: 2015
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39. Hepatitis E Virus Infection after Platelet Transfusion in an Immunocompetent Trauma Patient

Author: Thomas Decaens, Thibaut Trouve-Buisson, Jean François Payen, Patricia Pouzol, Emmanuelle Loyrion, Sylvie Larrat, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Hématologie, CHU Grenoble, Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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), 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), Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Letter, Blood transfusion, Epidemiology, Opportunistic infection, MESH: Spleen, medicine.medical_treatment, viruses, opportunistic infection, lcsh:Medicine, 030204 cardiovascular system & hematology, medicine.disease_cause, jaundice, 0302 clinical medicine, Hepatitis E virus, Medicine, Platelet, MESH: Blood Platelets, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: Splenic Rupture, MESH: Cholecystitis, Acute, virus diseases, Jaundice, MESH: Ribs, 3. Good health, Infectious Diseases, trauma, 030211 gastroenterology & hepatology, medicine.symptom, Microbiology (medical), MESH: Antiviral Agents, MESH: Hepatitis E virus, injury, MESH: Shock, Septic, contaminated blood products, MESH: Blood Transfusion, hepatitis E virus, Hepatitis E Virus Infection after Platelet Transfusion in an Immunocompetent Trauma Patient, blood transfusion, MESH: Splenectomy, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Cholestasis, MESH: Ribavirin, MESH: Platelet Transfusion, lcsh:RC109-216, Letters to the Editor, Genotyping, transfusion, MESH: Humans, business.industry, MESH: Hepatitis E, lcsh:R, MESH: Blood Donors, MESH: Adult, medicine.disease, immunocompetent, MESH: Male, digestive system diseases, Platelet transfusion, HEV, Immunology, MESH: Respiratory Distress Syndrome, Adult, platelet transfusion, business, cholestasis, MESH: Antibodies, Viral
Abstract: International audience; Hepatitis E virus (HEV) infection causes acute liver disease, but severe infections are rare in immunocompetent patients. We describe a case of HEV infection in a previously healthy male trauma patient in France who received massive transfusions. Genotyping confirmed HEV in a transfused platelet pool and the donor.
Published: 2017
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40. Ribavirin Quantification in Combination Treatment of Chronic Hepatitis C

Author: Françoise Stanke-Labesque, Jean-Pierre Zarski, Sylvie Larrat, Agnès Plages, Germain Bessard, and Claude Souvignet
Subjects: Adult, viruses, Hepacivirus, Hepatitis C virus, Biological Availability, Alpha interferon, Pharmacology, medicine.disease_cause, Antiviral Agents, High-performance liquid chromatography, chemistry.chemical_compound, Pharmacokinetics, Interferon, Ribavirin, Humans, Medicine, Pharmacology (medical), Chromatography, High Pressure Liquid, Interferon alfa, Aged, Chromatography, biology, business.industry, Interferon-alpha, virus diseases, Hepatitis C, Chronic, Middle Aged, biology.organism_classification, digestive system diseases, Treatment Outcome, Infectious Diseases, chemistry, business, medicine.drug
Abstract: Ribavirin in combination with alpha 2 interferon is the consensus treatment for chronic hepatitis C. However, recent preliminary pharmacological studies have suggested that the bioavailability of ribavirin displays great interindividual variability. In order to monitor serum ribavirin levels during combination treatment, we developed and validated a quantitative assay using an approach adaptable for routine hospital laboratories. The method involved solid-phase extraction on phenyl boronic acid cartridges followed by high-performance liquid chromatography with a C 18 -bonded silica column and a mobile phase containing 10 mM ammonium phosphate buffer (with the pH adjusted to 2.5) and UV detection (207 nm). The sensitivity, recovery, linearity of the calibration curve, intra- and interassay accuracies, precision, and stability at 4°C were consistent with its use in the laboratory routine. In addition, other nucleoside analogues sometimes used with ribavirin in patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus did not interfere with the quantification of ribavirin levels. The ribavirin concentration was quantified in 24 serum samples from patients with chronic hepatitis C treated with a combination of ribavirin and alpha 2 interferon. The mean serum ribavirin concentration was 2.67 ± 1.06 μg/ml ( n = 24) at week 12 of treatment (W12) and 3.24 ± 1.35 μg/ml ( n = 24) at week 24 of treatment (W24). In addition, ribavirin concentrations displayed high interindividual variabilities: the coefficients of variation of the serum ribavirin concentrations adjusted to the administered dose were 44 and 48% at W12 and W24, respectively. Moreover, the ribavirin concentration was higher in patients with a sustained virological response ( n = 11) than in patients with treatment failure ( n = 13), with significant intergroup differences at W12 ( P = 0.030) and W24 ( P = 0.049). The present study describes a simple analytical method for the quantification of ribavirin in human serum that could be a useful tool for the monitoring of ribavirin concentrations in HCV-infected patients in order to improve the efficacy and safety of therapy with ribavirin plus interferon.
Published: 2003
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41. Identification of a duplicated V3 domain in NS5A associated with cirrhosis and hepatocellular carcinoma in HCV-1b patients

Author: Elisabeth André-Garnier, J. B. Bour, Jacques Izopet, Christophe Lemaire, S. Vallet, Adeline Pivert, Arielle R. Rosenberg, Pascale Trimoulet, Christopher Payan, E. Bouthry, Pascal Veillon, Sophie Alain, Dominique Bettinger, P. André, Alexandra Ducancelle, Catherine Gaudy-Graffin, Jean-Michel Pawlotsky, Françoise Stoll-Keller, Odile Petsaris, Cécile Henquell, Yazid Baazia, Bruno Pozzetto, Françoise Lunel-Fabiani, Florence Abravanel, Henia Saoudin, V. Thibault, Anne Signori-Schmuck, Sandrine Bertrais, Gisèle Lagathu, H. Le Guillou-Guillemette, Sylvie Larrat, S. Minjolle-Cha, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA), CHU Limoges, Service de virologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Laboratoire de Virologie [Toulouse], CHU Toulouse [Toulouse], Centre de Physiopathologie Toulouse Purpan (CPTP), 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), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Clermont-Ferrand, Hôtel-Dieu de Nantes, Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Avicenne, Service de virologie et d'immunologie biologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire de Bactériologie de l'Hôpital de la Croix-Rousse, Hospices Civils de Lyon (HCL), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF), Biologie structurale des interactions entre virus et cellule hôte (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Pontchaillou [Rennes], Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor, The authors thank A. Lefebvre, E. Muel, Y. Desille, I. Renard, A. Plages, A. Rodallec and W. Merrouche for their assistance in clinical data recording.Funding: This study was funded by the ANRS (Agence de Nationale de Recherche sur le VIH et les hépatites, appel d’offre Mars 2006)., PRES Université Nantes Angers Le Mans [UNAM], Interactions cellulaires et applications thérapeutiques (ICAT), Université d'Angers (UA) - CHU Angers - CRLCC Paul Papin - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Service de virologie, Université Pierre et Marie Curie - Paris 6 (UPMC) - Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Pitié-Salpêtrière [APHP], Centre de Physiopathologie Toulouse Purpan, Université Paul Sabatier - Toulouse 3 (UPS) - IFR30 - IFR150 - Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [APHP], Université européenne de Bretagne (UEB) - Université de Bretagne Occidentale (UBO) - IFR148 ScInBioS, Centre Hospitalier Universitaire de Dijon (CHU Dijon), CHU Bordeaux [Bordeaux] - Groupe hospitalier Pellegrin, Hospices Civils de Lyon, Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH), Institut National de la Santé et de la Recherche Médicale (INSERM) - Université François Rabelais - Tours - CHRU Tours, CHU Besançon, Université de Franche-Comté (UFC), Laboratoire de biologie structurale des interactions entre virus et cellule hôte, Université Joseph Fourier - Grenoble 1 (UJF) - Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg - Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire Virologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Henri Mondor [Créteil], and Jonchère, Laurent
Subjects: Adult, Liver Cirrhosis, Male, hepatitis C virus, Cirrhosis, Carcinoma, Hepatocellular, Hepatitis C virus, [SDV]Life Sciences [q-bio], Viral quasispecies, Hepacivirus, Biology, Viral Nonstructural Proteins, medicine.disease_cause, NS5A, Liver disease, Virology, Gene Duplication, Gene duplication, medicine, Prevalence, Humans, Aged, Hepatitis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Sequence Analysis, RNA, cirrhosis, Liver Neoplasms, Hepatitis C, hepatocellular carcinoma, Hepatitis C, Chronic, Middle Aged, medicine.disease, digestive system diseases, 3. Good health, Protein Structure, Tertiary, [SDV] Life Sciences [q-bio], Mutagenesis, Insertional, Infectious Diseases, Cross-Sectional Studies, Hepatocellular carcinoma, RNA, Viral, Female, V3 domain, France, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background The NS5A protein of the hepatitis C virus has been shown to be involved in the development of hepatocellular carcinoma. Objectives In a French multicenter study, we investigated the clinical and epidemiological features of a new HCV genotype 1b strain bearing a wide insertion into the V3 domain. Study Design We studied NS5A gene sequences in 821 French patients infected with genotype 1b HCV. Results We identified an uncharacterized V3 insertion without ORF disruption in 3.05% of the HCV sequences. The insertion comprised 31 amino-acids for the majority of patients; 3 patients had 27 amino-acids insertions and 1 had a 12 amino-acids insertion. Sequence identity between the 31 amino-acids insertions and the V3 domain ranged from 48 to 96% with E-values above 4e-5, thus illustrating sequence homology and a partial gene duplication event that to our knowledge has never been reported in HCV. Moreover we showed the presence of the duplication at the time of infection and its persistence at least during 12 years in the entire quasispecies. No association was found with extrahepatic diseases. Conversely, patients with cirrhosis were two times more likely to have HCV with this genetic characteristic (p=0.04). Moreover, its prevalence increased with liver disease severity (from 3.0% in patients without cirrhosis to 9.4% in patients with both cirrhosis and HCC, p for trend=0.045). Conclusions We identified a duplicated V3 domain in the HCV-1b NS5A protein for the first time. The duplication may be associated with unfavorable evolution of liver disease including a possible involvement in liver carcinogenesis
Published: 2015
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42. Severe Pneumocystis jirovecii pneumonia in an idiopathic CD4+ lymphocytopenia patient: case report and review of the literature

Author: Jean-Baptiste Kern, Clémence Minet, Laurence Bouillet, Pierre Flori, Marie-Pierre Brenier-Pinchart, Danièle Maubon, Hervé Pelloux, Sylvie Larrat, Bernabé F. F. Chumpitazi, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF), Unité de pneumologie, CHU Grenoble, Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: Microbiology (medical), medicine.medical_specialty, Early Relapse, Microbiology, Idiopathic CD4+ lymphocytopenia, trimethoprim-sulfamethoxazole, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, In patient, 030212 general & internal medicine, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], 030306 microbiology, business.industry, Mortality rate, Pneumocystis jirovecii Pneumonia, opportunistic infections, medicine.disease, 3. Good health, Pneumonia, Respiratory failure, Immunology, Hiv patients, Lymphocytopenia, business
Abstract: Introduction: When diagnosing Pneumocystis jirovecii pneumonia (PJP), the clinical suspicion must be confirmed by laboratory tests. PJP is rarely described in patients with idiopathic CD4+ lymphocytopenia (ICL), a rare T‐cell deficiency of unknown origin with persistently low levels of CD4+ T‐cells (
Published: 2014
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43. Recent evidence of underestimated circulation of hepatitis C virus intergenotypic recombinant strain RF2k/1b in the Rhône-Alpes region, France, January to August 2014: implications for antiviral treatment

Author: Patrice Morand, Mary-Anne Trabaud, Jean Nana, P Tremeaux, Pascal André, M.A. Thelu, Fanny Lebossé, François Bailly, C. Ramière, Vincent Leroy, Sylvie Larrat, A Caporossi, Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF), and Thomas, Frank
Subjects: MESH: Antiviral Agents, Genotype, Epidemiology, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Hepatitis C virus, Genome, Viral, Hepacivirus, Biology, Viral Nonstructural Proteins, MESH: Base Sequence, medicine.disease_cause, Antiviral Agents, law.invention, MESH: Genotype, law, Virology, medicine, Humans, MESH: Hepacivirus, Antiviral treatment, MESH: Phylogeny, Genotyping, Phylogeny, MESH: Treatment Outcome, Recombination, Genetic, MESH: Hepatitis C, MESH: Humans, Base Sequence, Strain (biology), Public Health, Environmental and Occupational Health, Hepatitis C, MESH: France, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Treatment Outcome, MESH: RNA, Viral, Recombinant DNA, RNA, Viral, MESH: Viral Nonstructural Proteins, MESH: Recombination, Genetic, France, MESH: Genome, Viral
Abstract: International audience; Since the beginning of 2014, hepatitis C virus (HCV) recombinant forms RF2k/1b have been detected in the Rhône-Alpes French region in 10 patients originating from the Caucasus area. Circulation of this particular HCV strain is very likely to be underestimated. It is also prone to be misgenotyped when using genotyping methods based on the 5' region of the viral genome, which may lead to suboptimal treatment.
Published: 2014

44. Association between hepatitis E and neurological disorders: two case studies and literature review

Author: M. Vaillant, Jean-Paul Brion, L. Hyerle, Emilie Mosnier, Aude Belbézier, A. Deroux, Patricia Pavese, Sylvie Larrat, Patrice Morand, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Molécules bioactives, conception, isolement et synthèse (MBCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Systèmes Agraires et Développement Rural - UP1102 (SADR), AgroParisTech, Service de Dermatologie et Vénérologie, Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF), Department of Infectious Diseases, and University Hospital
Subjects: Adult, Male, Parsonage–Turner syndrome, MESH: Hepatitis E virus, viruses, Disease, Serology, Virology, Hepatitis E virus, Brachial Plexus Neuritis, Humans, Medicine, In patient, Encephalitis, Viral, Viremia, MESH: Viremia, MESH: Brachial Plexus Neuritis, MESH: Humans, business.industry, MESH: Hepatitis E, virus diseases, MESH: Adult, Hepatitis E, medicine.disease, digestive system diseases, MESH: Male, 3. Good health, MESH: Encephalitis, Viral, Cytolysis, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Infectious Diseases, Immunology, business, Viral hepatitis, Encephalitis
Abstract: International audience; Hepatitis E (HEV) is an emerging disease in our developed countries, but is not routinely tested for in case of liver cytolysis. However, a growing number of extra-hepatic manifestations of HEV infection associated with acute hepatitis are reported. In this article, we discuss two cases of HEV with neurological symptoms, one with encephalitis, and the other with Parsonage Turner syndrome. All these disorders appeared concomitantly with liver cytolysis and disappeared quickly, following the viral kinetics. Only twenty cases of neurological manifestation of HEV have been described before. The use of HEV serology in patients with concurrent liver cytolysis and neurological symptoms has to be improved.
Published: 2014

45. Multicenter quality control of hepatitis C virus protease inhibitor resistance genotyping

Author: Evelyne Schvoerer, Elisabeth André-Garnier, Joël Gozlan, Etienne Brochot, Sylvie Larrat, Sébastien Hantz, Catherine Gaudy-Graffin, Hélène Le Guillou-Guillemette, Nelly Magnat, Vincent Mackiewicz, Syria Laperche, Jean-Christophe Plantier, Philippe Colson, Françoise Lunel-Fabiani, Patrick Soussan, Gisèle Lagathu, Christopher Payan, Jacques Izopet, Sylvain Rosec, S. Gouriou, Anne-Marie Roque-Afonso, Patrice Morand, Caroline Scholtes, Adeline Pivert, Sophie Vallet, Florence Legrand-Abravanel, Vincent Thibault, Sarah Maylin, Audrey Mirand, Stéphane Chevaliez, Jean-Michel Pawlotsky, Charlotte Charpentier, Valérie Giordanengo, Cécile Henquell, Françoise Bouchardeau, Lina Aguilera, Pascale Trimoulet, Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Laboratoire de virologie moléculaire et structurale (LVMS), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence Virus des hépatites B, C et Delta, Institut National de la Transfusion Sanguine [Paris] (INTS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de virologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 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), Laboratoire de Virologie [Rennes] = Virology [Rennes], CHU Pontchaillou [Rennes], Service de virologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Laboratoire de Virologie, CHU Strasbourg, Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours-EA3856, CHU Bordeaux [Bordeaux], Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, Unité de Virologie clinique et fondamentale (UVCF), CHU Amiens-Picardie-Université de Picardie Jules Verne (UPJV), Service de Bactériologie, Virologie, Hygiène [CHU Limoges], CHU Limoges, Services des Maladies Infectieuses et Tropicales [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Carcinogenèse Hépatique et Virologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de virologie [Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Département de microbiologie : Bactério, Virologie, Parasito, Hygiène-Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie [Purpan], CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université de Tours (UT)-EA3856, Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Département de microbiologie : Bactério, Virologie, Parasito, Hygiène, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), 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), Service de virologie, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Service des maladies infectieuses et tropicales [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Université Nice Sophia Antipolis (1965 - 2019) (UNS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Virologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Microbiology (medical), Quality Control, MESH: Antiviral Agents, MESH: Sequence Analysis, DNA, MESH: Mutation, Genotype, Hepatitis C virus, Hepacivirus, [SDV]Life Sciences [q-bio], MESH: Quality Control, MESH: Amino Acid Sequence, Viral Nonstructural Proteins, MESH: Base Sequence, medicine.disease_cause, Antiviral Agents, MESH: Genotype, 03 medical and health sciences, 0302 clinical medicine, Virology, Drug Resistance, Viral, medicine, Protease inhibitor (pharmacology), Protease Inhibitors, MESH: Hepacivirus, Amino Acid Sequence, Genotyping, 0303 health sciences, NS3, MESH: Drug Resistance, Viral, MESH: Protease Inhibitors, biology, Base Sequence, 030306 microbiology, Inhibitor resistance, virus diseases, Sequence Analysis, DNA, biology.organism_classification, 3. Good health, Hcv protease, Mutation, MESH: Viral Nonstructural Proteins, 030211 gastroenterology & hepatology
Abstract: Hepatitis C virus (HCV) protease inhibitor resistance-associated substitutions are selected during triple-therapy breakthrough. This multicenter quality control study evaluated the expertise of 23 French laboratories in HCV protease inhibitor resistance genotyping. A panel of 12 well-defined blinded samples comprising two wild-type HCV strains, nine transcripts from synthetic NS3 mutant samples or from clinical strains, and one HCV RNA-negative sample was provided to the participating laboratories. The results showed that any laboratory with expertise in sequencing techniques should be able to provide reliable HCV protease inhibitor resistance genotyping. Only a 0.7% error rate was reported for the amino acid sites studied. The accuracy of substitution identification ranged from 75% to 100%, depending on the laboratory. Incorrect results were mainly related to the methodology used. The results could be improved by changing the primers and modifying the process in order to avoid cross-contamination. This study underlines the value of quality control programs for viral resistance genotyping, which is required prior to launching observational collaborative multicenter studies on HCV resistance to direct-acting antiviral agents.
Published: 2013
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46. Effect of resistance-associated substitutions on retreatment of direct acting antiviral-exposed patients in the real-world setting (ANRS CO22 HEPATHER)

Author: Caroline Scholtes, Pascale Trimoulet, Céline Dorival, J.-M. Pawlotsky, Sylvie Larrat, Fabrice Carrat, Jean-François Meritet, Laurence Bocket, Stanislas Pol, Stéphane Chevaliez, Edouard Tuaillon, Laboratoire de Virologie CHU Henri Mondor, Hôpital Pellegrin Tripode, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département de virologie [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Université Catholique de Lyon (UCLy) (UCLy), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Hôpital Cochin [AP-HP], 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)-Université de Paris (UP), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Université de Montpellier (UM), Université catholique de Lille - Faculté de médecine et de maïeutique (UCL FMM), Université catholique de Lille (UCL), Service d'hépatologie médicale [CHU Cochin], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Hepatology, business.industry, viruses, [SDV]Life Sciences [q-bio], virus diseases, biochemical phenomena, metabolism, and nutrition, Virology, digestive system diseases, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Medicine, 030211 gastroenterology & hepatology, business, Direct acting
Abstract: International audience; Re-treatment of patients with decompensated chronic hepatitis C virus cirrhosis using 24 weeks of sofosbuvir and NS5A inhibitor, with or without ribavirin after failing a 12 week course
Published: 2017
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47. Case report: detection of a hepatitis B surface antigen variant emerging in an elderly patient after an ischemic cerebral vascular accident

Author: Patrice Morand, Wen Qin, Sylvie Larrat, Marie-Noëlle Hilleret, Monique Baccard, Philippe Zaoui, Alban Deroux, and Gaelle Billet
Subjects: Male, Hepatitis B virus, medicine.medical_treatment, Molecular Sequence Data, Hbv reactivation, Context (language use), Hepatitis b surface antigen, Brain Ischemia, Virology, medicine, Cytotoxic T cell, Humans, Amino Acid Sequence, Elderly patient, Aged, 80 and over, Chemotherapy, Cerebral vascular accident, Hepatitis B Surface Antigens, business.industry, virus diseases, Immunosuppression, Hepatitis B, digestive system diseases, Infectious Diseases, Amino Acid Substitution, Liver, Immunology, DNA, Viral, Virus Activation, business
Abstract: HBV reactivations are observed frequently in patients with past hepatitis B infection receiving cytotoxic and/or immunosuppressive chemotherapy for hemato-oncological malignancies or autoimmune diseases. Recent ischemic stroke was shown to induce immunodepression by misunderstood mechanisms. To our knowledge, the association between HBV reactivation and ischemic stroke has not been reported before. This study reports the case of an anti-HBs- and anti-HBc-positive patient who presented HBV reactivation in a context of recent ischemic stroke, with no other intercurrent iatrogenic phenomenon or usual immunosuppressive pathology. J. Med. Virol. 84:1897–1900, 2012. © 2012 Wiley Periodicals, Inc.
Published: 2012

48. Prevalence and impact of occult hepatitis B infection in chronic hepatitis C patients treated with pegylated interferon and ribavirin

Author: Jean-Pierre Zarski, Agnès Plages, Marie-Ange Thelu, Sylvie Larrat, Marion Levast, Patrice Morand, Sandrine Nicod, Alice Cheveau, Vincent Leroy, and Jean-Marie Seigneurin
Subjects: Adult, Male, HBsAg, Hepatitis B virus, Interferon alpha-2, medicine.disease_cause, Antiviral Agents, Polymerase Chain Reaction, Polyethylene Glycols, Liver disease, chemistry.chemical_compound, Pegylated interferon, Virology, Ribavirin, medicine, Prevalence, Humans, Hepatitis, Hepatitis B Surface Antigens, business.industry, virus diseases, Interferon-alpha, Hepatitis C, Hepatitis B, Hepatitis C, Chronic, Middle Aged, medicine.disease, digestive system diseases, Recombinant Proteins, Infectious Diseases, Blood, chemistry, Liver, Immunology, DNA, Viral, Female, France, Reagent Kits, Diagnostic, business, medicine.drug
Abstract: The prevalence of occult hepatitis B, defined by absence of HBsAg and HBV DNA, ranges widely in patients with hepatitis C. This may influence the treatment of hepatitis C and the severity of liver disease. Sensitive and specific real-time PCR techniques are available commercially and can detect more reliably low HBV DNA levels. The aim of this study was to determine the prevalence of occult hepatitis B virus infection using the COBAS Taqman assay (Roche Diagnostics, Meylan, France) in the serum and liver of HBsAg negative patients with chronic hepatitis C and to evaluate its clinical consequences on liver pathology and its impact on the response to treatment with peg-IFNα and Ribavirin. HBV DNA detection was assessed retrospectively on 140 sera and 113 liver biopsies of HCV positive/HBsAg negative patients before treatment. A 4.4% (5/113) prevalence of occult hepatitis B was recorded in liver samples and in none of the sera. Anti-HBc was not detected in one, three of whom were sustained virological responders to treatment, one was relapsed responder and one was non-responder. Furthermore, in this cohort composed of 12% anti-HBs negative/anti-HBc positive and 20% anti-HBs positive/anti-HBc positive patients, anti-HBc was not associated with pre-therapeutic viral load, ALT serum levels, and histological activity or fibrosis. Using a commercial real-time PCR assay, we observed a low prevalence of occult B hepatitis. This, just as anti-HBC status, had no clinical impact in a large cohort of hepatitis C patients. It therefore does not appear useful to screen for occult hepatitis B in these patients with this test before beginning HCV treatment. J. Med. Virol. 82: 000–000, 2010. © 2010 Wiley-Liss, Inc. J. Med. Virol. 82: 747–754, 2010. © 2010 Wiley-Liss, Inc.
Published: 2010

49. Assessment of selective real-time PCR for quantitation of lamivudine and adefovir hepatitis B virus-resistant strains and comparison with direct sequencing and line probe assays

Author: Sylvie Larrat, Vincent Leroy, Gérard Barguès, Patrice Morand, Jean-Marie Seigneurin, Sandrine Nicod, Julien Lupo, Véronique Boyer, Jean-Pierre Zarski, Marie-Noelle Hilleret, and Raphaele Germi
Subjects: Hepatitis B virus, Genotype, Population, DNA Mutational Analysis, Organophosphonates, medicine.disease_cause, Antiviral Agents, Polymerase Chain Reaction, Sensitivity and Specificity, Virology, Drug Resistance, Viral, medicine, Adefovir, Humans, Line Probe Assay, education, education.field_of_study, biology, Adenine, Lamivudine, Hepatitis B, medicine.disease, biology.organism_classification, Molecular biology, Hepadnaviridae, DNA, Viral, Mutation, Viral load, medicine.drug, Plasmids
Abstract: A selective real-time PCR (sPCR) assay has been developed to detect the rtM204V/I and rtN236T mutations of hepatitis B virus (HBV) associated with resistance to lamivudine and adefovir. Using mixtures of mutant and wild-type plasmids, this sPCR was able to detect 0.1% of mutated strain in a total plasmid population of 10(5) copies and was more sensitive in detecting resistant strains than the line probe INNO-LiPA-DR-v2 assay and a direct sequencing assay. The comparison of these methods on 20 clinical specimens from treated patients confirmed the plasmid results: the three methods were concordant for the detection of the mutant strains in 72% of the cases and the discrepant results were caused mainly by the sequencing assay's lack of sensitivity. The line probe assay was more sensitive for detecting mutations than sPCR when the viral load was less than 10(4) copies/ml; conversely, the sPCR provided a more sensitive detection when the viral load was greater than 10(4) copies/ml. Although difficult to perform in clinical practice, sPCR appears to be a reliable technique for detecting and quantifying quasi-species resistant to lamivudine (LAM) and adefovir (ADV) and can be useful to gain a better understanding of the natural history of antiviral resistance during the treatment of chronic hepatitis B (CHB).
Published: 2008

50. Prevalence and impact of GBV-C, SEN-V and HBV occult infections in HIV–HCV co-infected patients on HCV therapy

Author: Benoit Martha, Stanislas Pol, Lionel Piroth, Christopher Payan, Isabelle Goderel, Sylvie Larrat, Patrice Cacoub, Firouzé Bani-Sadr, Patrice Morand, Fabrice Carrat, Christian Perronne, Françoise Lunel-Fabiani, Département d'infectiologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Epidémiologie des maladies infectieuses et modélisation (ESIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de virologie moléculaire et structurale (LVMS), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Maladies infectieuses, Centre Hospitalier Chalon-sur-Saône William Morey, Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, [SDV]Life Sciences [q-bio], HIV Infections, Comorbidity, Gastroenterology, Polyethylene Glycols, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, Prevalence, 030212 general & internal medicine, biology, virus diseases, Hepatitis C, Hepatitis B, Flaviviridae Infections, Middle Aged, DNA Virus Infections, Recombinant Proteins, 3. Good health, Virus Diseases, Lentivirus, HCV, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Female, Viral disease, SEN-V, Adult, medicine.medical_specialty, Combination therapy, Hepatitis, Viral, Human, GB virus C, Interferon alpha-2, Antiviral Agents, 03 medical and health sciences, Pharmacotherapy, Hepatitis B, Chronic, Internal medicine, Ribavirin, medicine, Humans, GBV-C, Hepatitis, Torque teno virus, Hepatology, business.industry, Interferon-alpha, HIV, Occult hepatitis B, Hepatitis C, Chronic, medicine.disease, biology.organism_classification, Virology, digestive system diseases, business
Abstract: International audience; Background/AimsIt has been suggested that, in HIV–HCV co-infected patients, co-infections with other viruses may affect the response to HCV therapy. We aimed to assess the prevalence of GBV-C, SEN-V and occult HBV infections, their impact on HCV and HIV infections and on the response to HCV therapy in HIV–HCV co-infected patients. Methods Three-hundred and sixty eight patients were tested before starting interferon–ribavirin for the presence of occult hepatitis B DNA, GBV-C RNA and SEN-V DNA by using real time PCR. Clinical, immunological, virological, histological characteristics and response to HCV therapy were compared according to the presence or not of each viral co-infection. Results HBV DNA, GBV-C RNA and SEN-V DNA were found in 5 (1.4%, CI95%: 0.2–2.4%), 104 (29.9%, CI95%: 25.1–34.7%) and 209 patients (57.9%, CI95%: 52.8–63.0%), respectively. GBV-C positive patients had significantly higher CD4 count at baseline, during and after HCV therapy, even after stratification on antiretroviral treatment. No other significant difference was observed according to the presence or not of GBV-C or SEN-V co-infection, in particular regarding virological responses to HCV combination therapy. Conclusions There is no reason to withhold HCV therapy in HIV infected patients who have access to HAART, because of occult HBV, GBV-C or SEN-V co-infections.
Published: 2008
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