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1. Metabarcoding analysis of eukaryotic microbiota in the gut of HIV-infected patients.

Author

Ibrahim Hamad, Rita Abou Abdallah, Isabelle Ravaux, Saadia Mokhtari, Hervé Tissot-Dupont, Caroline Michelle, Andreas Stein, Jean-Christophe Lagier, Didier Raoult, and Fadi Bittar

Subjects
Medicine, Science
Abstract

Research on the relationship between changes in the gut microbiota and human disease, including AIDS, is a growing field. However, studies on the eukaryotic component of the intestinal microbiota have just begun and have not yet been conducted in HIV-infected patients. Moreover, eukaryotic community profiling is influenced by the use of different methodologies at each step of culture-independent techniques. Herein, initially, four DNA extraction protocols were compared to test the efficiency of each method in recovering eukaryotic DNA from fecal samples. Our results revealed that recovering eukaryotic components from fecal samples differs significantly among DNA extraction methods. Subsequently, the composition of the intestinal eukaryotic microbiota was evaluated in HIV-infected patients and healthy volunteers through clone sequencing, high-throughput sequencing of nuclear ribosomal internal transcribed spacers 1 (ITS1) and 2 (ITS2) amplicons and real-time PCRs. Our results revealed that not only richness (Chao-1 index) and alpha diversity (Shannon diversity) differ between HIV-infected patients and healthy volunteers, depending on the molecular strategy used, but also the global eukaryotic community composition, with little overlapping taxa found between techniques. Moreover, our results based on cloning libraries and ITS1/ITS2 metabarcoding sequencing showed significant differences in fungal composition between HIV-infected patients and healthy volunteers, but without distinct clusters separating the two groups. Malassezia restricta was significantly more prevalent in fecal samples of HIV-infected patients, according to cloning libraries, whereas operational taxonomic units (OTUs) belonging to Candida albicans and Candida tropicalis were significantly more abundant in fecal samples of HIV-infected patients compared to healthy subjects in both ITS subregions. Finally, real-time PCR showed the presence of Microsporidia, Giardia lamblia, Blastocystis and Hymenolepis diminuta in different proportions in fecal samples from HIV patients as compared to healthy individuals. Our work revealed that the use of different sequencing approaches can impact the perceived eukaryotic diversity results of the human gut. We also provide a more comprehensive view of the eukaryotic community in the gut of HIV-infected patients through the complementarity of the different molecular techniques used. Combining these various methodologies may provide a gold standard for a more complete characterization of the eukaryotic microbiome in future studies.

Published
2018
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2. Reaching the Second and Third Joint United Nations Programme on Human Immunodeficiency Virus (HIV)/AIDS 90-90-90 Targets Is Accompanied by a Dramatic Reduction in Primary HIV Infection and in Recent HIV Infections in a Large French Nationwide HIV Cohort

Author

Claudine Duvivier, Clotilde Allavena, J Lippmann, P. Dellamonica, A Soria, Sandrine Pierre-François, B J Gaborit, Isabelle Poizot-Martin, Anne Frésard, Elodie Curlier, F. Biron, Eric Cua, M Saadia Mokhtari, I Luquet Besson, C Gubavu, Caroline Lions, Laurent Cotte, C. Tomei, Elina Teicher, Faouzi Souala, Karima Amazzough, C Merle de Boever, Romain Palich, C Brochier, Véronique Reliquet, Patrick Miailhes, M Priester, Samira Fafi-Kremer, Mathieu Dupont, M Piffaut, I. Schlienger, C Bernaud, A S Ritleng, F-Xavier Lescure, C Cheneau, L Lelièvre, C Biron, Adrien Le Guillou, Alexa Debard, Marc-Antoine Valantin, Gilles Peytavin, S Lariven, G Benabdelmoumen, Florence Ader, I Kmiec, I Fabre, Cyrille Delpierre, C. Longuet, François Raffi, A de Monte, M. Alvarez, David Rey, A Boucher, M. Valette, E de Mautort, Jean-Luc Berger, H Bertone, Bruno Hoen, M Poisson-Vanier, Pascal Pugliese, Virginie Ferré, M Pradier, Z Julia, Nathalie Dournon, M Baldeyrou, N Biezunski, Caroline Charlier, J Goesch, J Pasquier, M P Bouillon, Cécile Goujard, Sophie Matheron, V. Le Moing, Romain Guery, N. Viget, N Atoui, C Dhiver, A Meybeck, Fanny Lanternier, F Touam, Tristan Ferry, M Carta Padovani, G Thomas, C Ceppi, A Brunet, Alain Makinson, Isabelle Ravaux, Laurent Hocqueloux, A Maillard, Firouzé Bani-Sadr, P. Loubet, Laurent Boyer, O Deradji, I Alcaraz, T Prazuck, A Rodallec, F Lemaitre, B Lafon-Desmurs, J Turmel, A Sève, Benoit Pilmis, A Gervais, C. Augustin-Normand, D Chirio, Brigitte Montes, Cédric Arvieux, V Brodard, M Delestan, E Aïssi, C Louisin, Christian Chidiac, M Ducassou, S Leautez, Catherine Chirouze, M André, Dominique Merrien, Q Gardiennet, P Fischer, Sylvie Abel, Guillaume Martin-Blondel, Benoît Henry, H. Tissot Dupont, S Patrat-Delon, A Ménard, E. Billaud, Malikhone Chansombat, K Jidar, Karine Sauné, Colin Deschanvres, V. Gueripel, M Cavellec, K. Schepers, C Pronier, R Ouissa, P Choisy, A Cheret, A. Belkhir, P Parize, A Barrail-Tran, B. Bonnet, C Mackoumbou-Nkouka, A. Galinier, M Monclar, P Lansalot, S Bouchez, C Guennoun, N Meftah, C Brunet-Cartier, Pierre Tattevin, J. Durant, E Ressiot, T. Huleux, François Bénézit, C Boulard, M Poinot, Elisabeth André-Garnier, J Sinteff, André Cabié, Charlotte Charpentier, L Meddeb, Rodolphe Garraffo, M Batard, D. Lebrun, R Tubiana, M J Soavi, I Lamaury, Philippe Bossi, Y Quertainmont, S Galie, C Michelangeli, François Danion, N Lerolle, Y N’guyen, Amandine Gagneux-Brunon, Elisa Demonchy, Christine Katlama, C Bernard-Henry, V Mondain, S Seang, David Boutoille, P. Le Turnier, Faiza Ajana, André Boibieux, J Koffi, L. Porte, Laurence Bocket, O Bollangier, A Maka, S Sécher, Marine Morrier, T Guimard, Matthieu Revest, C Godard, C Rioux, C Etienne, M Illiaquer, O. Aubry, N Hall, Paul-Henri Consigny, C Blanc, P Morineau, K Guitteaud, T. Perpoint, G Cessot, V Baclet, Lise Cuzin, T May, E Braun, Marialuisa Partisani, Veronique Joly, Jacques Reynes, Olivier Lortholary, C Blanco-Betancourt, Philippe Van de Perre, D Lambert, Moustapha Dramé, S Ferrando, S Breaud, A Montoya Ferrer, Yazdan Yazdanpanah, M. Hentzien, Cécile Herrmann-Storck, A. Duréault, A. Ivanova, F. Lucht, Pierre Delobel, Thomas Jovelin, J. M. Chapplain, Olivier Robineau, Roland Landman, Olivier Grossi, F Louni, Elisabeth Botelho-Nevers, J Lourenco, M Lefebvre, Diane Descamps, Luminita Schneider, R Agher, M Orticoni, D Rahli, S Degroodt, CHU de la Martinique [Fort de France], Centre Hospitalier Universitaire de Nice (CHU Nice), Service de maladies infectieuses et tropicales [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Infectious Diseases [Nantes], Hôtel-Dieu de Nantes, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Infectious Diseases and Tropical Medicine Unit [Fort-de-France, Martinique], Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire de Virologie Médicale et Moléculaire - EA 4684 (CardioVir), Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Département de maladies infectieuses, and Hospices Civils de Lyon (HCL)

Subjects
0301 basic medicine, Microbiology (medical), Cart, medicine.medical_specialty, Longitudinal study, business.industry, Public health, Incidence (epidemiology), medicine.disease, 030112 virology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, Acquired immunodeficiency syndrome (AIDS), Interquartile range, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, Epidemiology, Cohort, Medicine, 030212 general & internal medicine, business
Abstract

Background In late 2013, France was one of the first countries to recommend initiation of combination antiretroviral therapy (cART) irrespective of CD4 cell count. Methods To assess the impact of achieving the second and third Joint United Nations Programme on HIV/AIDS 90-90-90 targets (ie, 90% of diagnosed people on sustained cART, and, of those, 90% virologically controlled) on human immunodeficiency virus (HIV) incidence, we conducted a longitudinal study to describe the epidemiology of primary HIV infection (PHI) and/or recent HIV infection (patients with CD4 cell count ≥500/mm3 at HIV diagnosis; (PRHI) between 2007 and 2017 in a large French multicenter cohort. To identify changes in trends in PHI and PRHI, we used single breakpoint linear segmented regression analysis. Results During the study period, 61 822 patients were followed in the Dat’AIDS cohort; 2027 (10.0%) had PHI and 7314 (36.1%) had PRHI. The second and third targets were reached in 2014 and 2013, respectively. The median delay between HIV diagnosis and cART initiation decreased from 9.07 (interquartile range [IQR], 1.39–33.47) months in 2007 to 0.77 (IQR, 0.37–1.60) months in 2017. A decrease in PHI (−35.1%) and PRHI (−25.4%) was observed starting in 2013. The breakpoints for PHI and PRHI were 2012.6 (95% confidence interval [CI], 2010.8–2014.4) and 2013.1 (95% CI, 2011.3–2014.8), respectively. Conclusions Our findings show that the achievements of 2 public health targets in France and the early initiation of cART were accompanied by a reduction of about one-third in PHI and PRHI between 2013 and 2017. Clinical Trials Registration NCT02898987.

Published
2020

3. Reaching the Second and Third Joint United Nations Programme on HIV/AIDS 90-90-90 Targets Is Accompanied by a Dramatic Reduction in Primary Human Immunodeficiency Virus (HIV) Infection and in Recent HIV Infections in a Large French Nationwide HIV Cohort

Author

Le Guillou, Adrien, Pugliese, Pascal, Raffi, Francois, Cuzin, Lise, Katlama, Christine, Allavena, Clotilde, Dramé, Moustapha, Cotte, Laurent, Bani-Sadr, Firouzé, Orticoni, M, Soavi, M, Luquet- Besson, I, Ressiot, E, Carta- Padovani, M, Ducassou, M, Bertone, H, Galie, S, Galinier, A., Monclar, M, Ritleng, A, Ivanova, A., Blanco-Betancourt, C, Lions, C., Poizot-Martin, I., Dhiver, C., Saadia Mokhtari, M, Ménard, A, Tissot Dupont, H., Tomei, C., Meddeb, L., Belkhir, A., Ravaux, I., Alvarez, M., Biezunski, N, Debard, A., Delpierre, C., Lansalot, P, Lelievre, L., Martin-Blondel, G., Piffaut, M, Porte, L., Saune, K, Delobel, P., Breaud, S., Ceppi, C, Chirio, D, Cua, E, Dellamonica, P., Demonchy, E, De Monte, A, Durant, J., Etienne, C, Ferrando, S, Garraffo, R, Michelangeli, C, Mondain, V., Bernaud, C, Billaud, E., Biron, C, Bonnet, B., Bouchez, S, Boutoille, D., Brunet-Cartier, C, Deschanvres, C, Gaborit, B., Hall, N., Le Turnier, P., Morineau, P, Reliquet, V., Sécher, S, Cavellec, M, Soria, A., Ferre, V., André-Garnier, E., Rodallec, A., Lefebvre, M, Grossi, O, Aubry, O., Amazzough, K., Benabdelmoumen, G, Bossi, P, Cessot, G, Charlier, C., Consigny, P, Danion, F., Dureault, A, Duvivier, C., Goesch, J, Guery, R., Henry, B, Jidar, K, Lanternier, F., Loubet, P., Lortholary, O., Louisin, C, Lourenco, J, Parize, P., Pilmis, B., Touam, F, Valantin, M, Tubiana, R., Agher, R, Seang, S, Schneider, L, PaLich, R, Blanc, C., Cabié, André, Abel, S., Pierre-François, S, Pasquier, J., Guitteaud, K, Turmel, J, Illiaquer, M, Fischer, P, Partisani, M., Cheneau, C., Priester, M, Batard, M, Bernard-Henry, C, de Mautort, E, Fafi-Kremer, S., Rey, D., Chirouze, C., Gardiennet, Q, Berger, J., N’Guyen, Y, Lambert, D., Hentzien, M., Lebrun, D., Brunet, A, Kmiec, I, Brodard, V, Chidiac, C., Ferry, T., Ader, F., Biron, F., Boibieux, A., Miailhes, P., Perpoint, T., Schlienger, I, Lippmann, J, Braun, E, Koffi, J, Longuet, C., Guéripel, V, Augustin-Normand, C, Brochier, C, Degroodt, S, Atoui, N, Le Moing, V., Makinson, A., Meftah, N., de Boever, C Merle, Montes, B., Montoya Ferrer, A, Reynes, J., André, M, Boyer, L., Bouillon, M, Delestan, M, May, T., Hocqueloux, L, Prazuck, T., Gubavu, C, Sève, A, Maka, A, Boulard, C., Thomas, G, Cheret, A, Goujard, C, Quertainmont, Y, Teicher, E., Lerolle, N., Deradji, O, Barrail-Tran, A, Landman, R, Joly, V, Rioux, C., Lariven, S, gervais, a, Lescure, F., Matheron, S., Louni, F, Godard, C, Julia, Z, Chansombat, M, Rahli, D, Mackoumbou-Nkouka, C, Charpentier, C., Descamps, D., Peytavin, G., Yazdanpanah, Y., Tattevin, P., Revest, M., Souala, F., Baldeyrou, M., Patrat-Delon, S, Chapplain, J, Bénézit, F., Dupont, M., Poinot, M., Maillard, A., Pronier, C., Lemaître, F., Guennoun, C, Poisson-Vanier, M, Jovelin, T., Sinteff, J, Arvieux, C., Botelho-Nevers, E., Gagneux-Brunon, A., Frésard, A., Lucht, F., Ajana, F, Aïssi, E, Alcaraz, I, Baclet, V, Bocket, L, Boucher, A., Choisy, P, Huleux, T., Lafon-Desmurs, B., Meybeck, A, Pradier, M, Robineau, O, Viget, N, Valette, M., Hoen, B., Lamaury, I, Fabre, I, Curlier, E, Ouissa, R, Schepers, K, Herrmann-Storck, C, Dournon, N, Merrien, D, Perré, P., Guimard, T, Bollangier, O, Leautez, S, Morrier, M, Service de Maladies Infectieuses [Nice], Centre hospitalier universitaire de Nantes (CHU Nantes), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), 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), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de maladies infectieuses et tropicales [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Reims (CHU Reims), Département de maladies infectieuses, Hospices Civils de Lyon (HCL), Neurobiologie, plasticité tissulaire et métabolisme énergétique (NPTME), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Space Research Institute of the Russian Academy of Sciences (IKI), Russian Academy of Sciences [Moscow] (RAS), DDSIS 76, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Institut Hospitalier Universitaire Méditerranée Infection (IHU AMU), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Istituto Nazionale di Fisica Nucleare [Sezione di Roma 1] (INFN), Istituto Nazionale di Fisica Nucleare, Service des Maladies Infectieuses et Tropicales [Hôpital de la Conception] (SMIT), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Laboratoire de Physique et Chimie Quantique [Tizi-Ouzou] (LPCQ ), Université Mouloud Mammeri [Tizi Ouzou] (UMMTO), Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, Assistance Publique - Hôpitaux de Marseille (APHM), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-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 Paris-Saclay-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)-Université d'Évry-Val-d'Essonne (UEVE), Hôpital de la Croix-Rousse [CHU - HCL], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Département Etude des Réacteurs (DER), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service des maladies infectieuses, Centre Hospitalier Universitaire de Nice (CHU Nice)-University Hospital, CHU Nice [Cimiez], Hôpital Cimiez [Nice] (CHU), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Université Clermont Auvergne (UCA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service des maladies infectieuses et tropicales [CHU Nantes], Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Plant Biomechanics Group, Botanischer Garten, Albert-Ludwigs-Universität Freiburg, Hôtel-Dieu de Nantes, Service de virologie [CHU Nantes], Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Service de rhumatologie [Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Pathogénie des infections systémiques (UMR_S 570), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Service des maladies infectieuses [CHU Pitié-Salêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Service de Maladies Infectieuses et Tropicales [Fort-de-France, Martinique], CHU de la Martinique [Fort de France]-Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France]-Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique], Weill Cornell Medicine [Qatar], 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), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de Virologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire Chrono-environnement - CNRS - UFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), service de maladies infectieuses CHU J Minjoz Besancon, Hôpital Jean Minjoz, Service de Maladies Infectieuses et Tropicales [Hôpital de la Croix-Rousse - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hosp Civils Lyon, Serv Malad Infect, Lyon, France, Equipe 15, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), 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)-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), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Universtié Yaoundé 1 [Cameroun]-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Bell Labs (BELL), Lucent Technologies, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Registre EPIMAD, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Amiens-Picardie, Centre d'Etudes Lasers Intenses et Applications (CELIA), Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB), Pharmacie de l'Hôpital Bichat, UMR CNRS 8179, Université de Lille, Sciences et Technologies-Centre National de la Recherche Scientifique (CNRS), Service des maladies infectieuses et réanimation médicale, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre de Physique des Particules de Marseille (CPPM), Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], SEV, Groupe d'Etudes et de Contrôle des Variétés et des Semences (GEVES), Service de virologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], CHU Saint-Etienne, University Hospital and University Jean Monnet, Virologie et pathogenèse virale (VPV), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Tourcoing, CHU de Fort de France, Service des maladies infectieuses et tropicales, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Saint-Jacques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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]-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 Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Universtié Yaoundé 1 [Cameroun]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Amiens-Picardie-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Aix Marseille Université (AMU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Recherches Translationnelles sur le VIH et les maladies infectieuses (TransVIHMI), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, and Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)

Subjects
cascade of care, primary HIV infection, Dat’AIDS cohort, TasP, 90-90-90 target, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background - In late 2013, France was one of the first countries to recommend initiation of combination antiretroviral therapy (cART) irrespective of CD4 cell count. Methods - To assess the impact of achieving the second and third Joint United Nations Programme on HIV/AIDS 90-90-90 targets (ie, 90% of diagnosed people on sustained cART, and, of those, 90% virologically controlled) on human immunodeficiency virus (HIV) incidence, we conducted a longitudinal study to describe the epidemiology of primary HIV infection (PHI) and/or recent HIV infection (patients with CD4 cell count ≥500/mm3 at HIV diagnosis; (PRHI) between 2007 and 2017 in a large French multicenter cohort. To identify changes in trends in PHI and PRHI, we used single breakpoint linear segmented regression analysis. Results - During the study period, 61 822 patients were followed in the Dat'AIDS cohort; 2027 (10.0%) had PHI and 7314 (36.1%) had PRHI. The second and third targets were reached in 2014 and 2013, respectively. The median delay between HIV diagnosis and cART initiation decreased from 9.07 (interquartile range [IQR], 1.39-33.47) months in 2007 to 0.77 (IQR, 0.37-1.60) months in 2017. A decrease in PHI (-35.1%) and PRHI (-25.4%) was observed starting in 2013. The breakpoints for PHI and PRHI were 2012.6 (95% confidence interval [CI], 2010.8-2014.4) and 2013.1 (95% CI, 2011.3-2014.8), respectively. Conclusions - Our findings show that the achievements of 2 public health targets in France and the early initiation of cART were accompanied by a reduction of about one-third in PHI and PRHI between 2013 and 2017. Clinical trials registration - NCT02898987.

Published
2020

4. Risk of Progressive Multifocal Leukoencephalopathy in the Combination Antiretroviral Therapy Era in the French Hospital Database on Human Immunodeficiency Virus (ANRS-C4)

Author

Jacques Gasnault, Hugues Melliez, Olivier Robineau, Véronique Joly, Pierre de Truchis, Murielle Mary-Krause, Karine Risso, Dominique Costagliola, Marie-Aude Khuong-Josses, Nathalie De Castro, Anna Canestri, Matthieu Revest, Marguerite Guiguet, Saadia Mokhtari, Guillaume Martin-Blondel, Aurelia Henn, Sophie Abgrall, Christine Katlama, and Laurence Bocket

Subjects
Adult, Male, 0301 basic medicine, Microbiology (medical), Cart, Databases, Factual, Anti-HIV Agents, Hepatitis C virus, HIV Infections, computer.software_genre, medicine.disease_cause, Men who have sex with men, Sexual and Gender Minorities, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, medicine, Humans, Prospective Studies, Homosexuality, Male, Substance Abuse, Intravenous, Prospective cohort study, Proportional Hazards Models, Database, business.industry, Incidence, Progressive multifocal leukoencephalopathy, Incidence (epidemiology), Hazard ratio, Leukoencephalopathy, Progressive Multifocal, virus diseases, medicine.disease, Hepatitis C, Hospitals, 030104 developmental biology, Infectious Diseases, Cohort, HIV-1, Drug Therapy, Combination, Female, France, business, computer, 030217 neurology & neurosurgery
Abstract

Background Risk factors for progressive multifocal leukoencephalopathy (PML) in individuals with human immunodeficiency virus (HIV) infection are poorly documented in the era of combination antiretroviral therapy (cART). Methods We studied HIV-1-infected individuals aged ≥15 years who had no history of PML and were prospectively followed up between 1997 and 2011 in the French Hospital Database on HIV (FHDH-ANRS CO4) cohort. Cox models were used to calculate adjusted hazard ratios (HRs), focusing on sub-Saharan origin, suggested to be protective, and recent cART initiation, potentially associated with an increased risk of PML. Results PML developed in 555 individuals, in 57 during the first 6 months of cART. From 1997-2000 to 2009-2011, the incidence fell from 1.15 (95% confidence interval [CI], .98-1.31) to 0.49 (.37-.61) per 1000 person-years. Sub-Saharan African origin had no clear influence (HR, 0.80; 95% CI, .58-1.11). Compared with men who have sex with men, injection drug users (IDUs) were at higher risk (HR, 1.80 [95% CI, 1.32-2.45] for male and 1.68 [1.13-2.48] for female IDUs). When IDUs were excluded, hepatitis C virus seropositivity was associated with an increased risk (HR, 1.40; 95% CI, 1.02-1.93). Compared with no cART initiation, initiation

Published
2018

5. Concentration–response model of rilpivirine in a cohort of HIV-1-infected naive and pre-treated patients

Author

Florence Gattacceca, Nadège Néant, Caroline Solas, Gilles Peytavin, Diane Descamps, Catherine Dhiver, Yazdan Yazdanpanah, Bruno Lacarelle, Naïm Bouazza, Minh Patrick Lê, Catherine Tamalet, Saadia Mokhtari, Sylvie Bregigeon, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Pharmacocinétique Toxicocinétique - [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM), Université de Montpellier (UM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Microbiology (medical), Oncology, Adult, Male, medicine.medical_specialty, Anti-HIV Agents, [SDV]Life Sciences [q-bio], Population, HIV Infections, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Emtricitabine, 030226 pharmacology & pharmacy, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, Humans, Pharmacology (medical), Trough Concentration, Computer Simulation, 030212 general & internal medicine, education, Aged, Pharmacology, education.field_of_study, business.industry, Rilpivirine, Disease Management, Middle Aged, Models, Theoretical, Viral Load, 3. Good health, CD4 Lymphocyte Count, Regimen, Infectious Diseases, chemistry, Pharmacodynamics, HIV-1, Female, Drug Monitoring, business, Viral load, Algorithms, medicine.drug
Abstract

Background Rilpivirine is widely prescribed in people living with HIV. Although trough plasma concentrations have been associated with virological response, the drug pharmacodynamics remain incompletely characterized. Objectives To develop the first pharmacodynamic model of rilpivirine in order to establish the rilpivirine concentration–response relationship for future treatment optimization. Methods A retrospective observational study was conducted in patients receiving the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. Individual rilpivirine trough plasma concentrations over time were predicted using a previous pharmacokinetic model. An established susceptible, infected, recovered model was used to describe HIV dynamics without assuming disease steady-state. Population analysis was performed with MONOLIX 2018 software. Simulations of the viral load evolution as a function of time and rilpivirine trough plasma concentration were performed. Results Overall, 60 naive and 39 pre-treated patients were included with a follow-up ranging from 2 to 37 months. The final model adequately described the data and the pharmacodynamic parameters were estimated with a good precision. The population typical value of rilpivirine EC50 was estimated at 65 ng/mL. A higher infection rate constant of CD4 cells for HIV-1 was obtained in pre-treated patients. Consequently, the time to obtain virological suppression was longer in pre-treated than in naive patients. Conclusions The concentration–response relationship of rilpivirine was satisfactorily described for the first time using an original population pharmacodynamic model. Simulations performed using the final model showed that the currently used 50 ng/mL rilpivirine trough plasma concentration efficacy target might need revision upwards, particularly in pre-treated patients.

Published
2019

6. Usefulness of therapeutic drug monitoring of rilpivirine and its relationship with virologic response and resistance in a cohort of naive and pretreated HIV-infected patients

Author

Bruno Lacarelle, Florence Gattacceca, Saadia Mokhtari, Gilles Peytavin, Caroline Solas, Naïm Bouazza, Catherine Dhiver, Diane Descamps, Minh Patrick Lê, Sylvie Bregigeon, Yazdan Yazdanpanah, Catherine Tamalet, and Nadège Néant

Subjects
Adult, Male, medicine.medical_specialty, Anti-HIV Agents, HIV Infections, Emtricitabine, 030226 pharmacology & pharmacy, Gastroenterology, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, Humans, Pharmacology (medical), Trough Concentration, 030212 general & internal medicine, Tenofovir, Aged, Retrospective Studies, Pharmacology, medicine.diagnostic_test, business.industry, Rilpivirine, Original Articles, Middle Aged, Viral Load, Regimen, chemistry, Therapeutic drug monitoring, Pharmacodynamics, Cohort, HIV-1, Female, Drug Monitoring, business, medicine.drug
Abstract

Aims The purpose of this study was to assess the antiviral activity of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination and to describe the pharmacokinetics of rilpivirine and its association with resistance in clinical routine. Methods A retrospective multicentre cohort study was performed in both naive and pretreated HIV patients receiving the once-daily rilpivirine/emtricitabine/tenofovir disoproxil fumarate regimen. Immuno-virologic and resistance data, and rilpivirine plasma trough concentrations were collected over the follow-up. Statistical analyses were performed to evaluate the relationship between rilpivirine pharmacokinetics and virological response. Receiver operating characteristic (ROC) curve analysis was performed to determine the best target rilpivirine trough concentration. Results Overall, 379 patients were included. After a median follow-up of 28 months, 26% of patients discontinued mainly due to toxicity and the virological success rate was 65.7%. Virological failure occurred in 5% of patients. A significant proportion of patients with HIV-RNA > 40 copies/mL displayed rilpivirine plasma trough concentrations below the currently used 50 ng/mL efficacy threshold at both M6 (28%) and M12 (31%), in agreement with a significant lower median rilpivirine plasma trough concentration compared with patients virologically suppressed. Half of the patients with virologic failure who acquired rilpivirine resistance mutations had at least one suboptimal rilpivirine trough concentration. The optimal target for rilpivirine trough concentration was 70 ng/mL (sensitivity 75.4%; specificity 61.5%). Conclusions This study shows the impact of rilpivirine plasma trough concentration on both virological response and the emergence of rilpivirine mutations. Moreover, our results suggest that a higher target of rilpivirine trough concentration could be proposed in clinical practice.

Published
2019

7. Safety study and therapeutic drug monitoring of the oral tablet formulation of posaconazole in patients with haematological malignancies

Author

Lemaitre, Florian, Le Guillou, Adrien, Pugliese, Pascal, Raffi, François, Cuzin, Lise, Katlama, Christine, Allavena, Clotilde, Dramé, Moustapha, Cotte, Laurent, Bani-Sadr, Firouzé, Orticoni, M, Soavi, M, Luquet- Besson, I, Ressiot, E, Carta- Padovani, M, Ducassou, M, Bertone, H, Galie, S, Galinier, A., Monclar, M, Ritleng, A, Ivanova, A., Blanco-Betancourt, C, Lions, C., Poizot-Martin, I., Dhiver, C, Saadia Mokhtari, M, Menard, A., Tissot Dupont, H, Toméi, C, Meddeb, L., Belkhir, A., Ravaux, I., Alvarez, M., Biezunski, N, Debard, A., Delpierre, C, Lansalot, P, Lelievre, L., Martin-Blondel, G., Piffaut, M, Porte, L., Saune, K, Delobel, P., Breaud, S., Ceppi, C, Chirio, D, Cua, E, Dellamonica, P., Demonchy, E, De Monte, A, Durant, J., Etienne, C, Ferrando, S, Garraffo, R, Michelangeli, C, Mondain, V., Bernaud, C, Billaud, E., Biron, C, Bonnet, B, Bouchez, S, Boutoille, D., Brunet-Cartier, C, Deschanvres, C, Gaborit, B., Hall, N, Le Turnier, P., Morineau, P, Reliquet, V., Sécher, S, Cavellec, M, Soria, A., Ferre, V., André-Garnier, E., Rodallec, A., Lefebvre, M, Grossi, O, Aubry, O., Amazzough, K., Benabdelmoumen, G, Bossi, P, Cessot, G, Charlier, C., Consigny, P, Danion, F., Dureault, A, Duvivier, C., Goesch, J, Guery, R., Henry, B., Jidar, K, Lanternier, F., Loubet, P., Lortholary, O., Louisin, C, Lourenco, J, Parize, P., Pilmis, B., Touam, F, Valantin, M, Tubiana, R., Agher, R, Seang, S, Schneider, L, PaLich, R, Blanc, C, Cabié, André, Abel, S., Pierre-François, S, Pasquier, J., Guitteaud, K, Turmel, J, Illiaquer, M, Fischer, P., Partisani, M., Cheneau, C., Priester, M, Batard, M, Bernard-Henry, C, de Mautort, E, Fafi-Kremer, S., Rey, D., Chirouze, C., Gardiennet, Q, Berger, J, N’Guyen, Y, Lambert, D., Hentzien, M., Lebrun, D., Brunet, A, Kmiec, I, Brodard, V, Chidiac, C., Ferry, T., Ader, F., Biron, F., Boibieux, A., Miailhes, P., Perpoint, T., Schlienger, I, Lippmann, J, Braun, E, Koffi, J, Longuet, C., Guéripel, V, Augustin-Normand, C, Brochier, C, Degroodt, S, Atoui, N, Le Moing, V., Makinson, A., Meftah, N., de Boever, C Merle, Montes, B, Montoya Ferrer, A, Reynes, J., Andre, M., Boyer, L, Bouillon, M, Delestan, M, May, T, Hocqueloux, L, Prazuck, T., Gubavu, C, Sève, A, Maka, A, Boulard, C., Thomas, G, Cheret, A, Goujard, C, Quertainmont, Y, Teicher, E., Lerolle, N., Deradji, O, Barrail-Tran, A, Landman, R, Joly, V, Rioux, C., Lariven, S, gervais, a, Lescure, F., Matheron, S., Louni, F, Godard, C, Julia, Z, Chansombat, M, Rahli, D, Mackoumbou-Nkouka, C, Charpentier, c, Descamps, D., Peytavin, G., Yazdanpanah, Y., Tattevin, P., Revest, M., Souala, F., Baldeyrou, M., Patrat-Delon, S, Chapplain, J, Bénézit, F., Dupont, M., Poinot, M., MAILLARD, A, Pronier, C., Guennoun, C, Poisson-Vanier, M, Jovelin, T., Sinteff, J, Arvieux, C, Botelho-Nevers, E., Gagneux-Brunon, A., Frésard, A., Lucht, F., Ajana, F, Aïssi, E, Alcaraz, I, Baclet, V, Bocket, L, Boucher, A, Choisy, P, Huleux, T., Lafon-Desmurs, B., Meybeck, A, Pradier, M, Robineau, O, Viget, N, Valette, M., Hoen, B., Lamaury, I, Fabre, I, Curlier, E, Ouissa, R, Schepers, K, Herrmann-Storck, C, Dournon, N, Merrien, D, Perré, P., Guimard, T, Bollangier, O, Leautez, S, Morrier, M, Boglione-Kerrien, C., Picard, S., Tron, C., Nimubona, S., Gangneux, J.-P., Lalanne, S., Lemaître, F., Bellissant, E., Verdier, M.-C., Petitcollin, A., Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Nice (CHU Nice), Service des maladies infectieuses et tropicales [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), 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, Immunité et Infection, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de maladies infectieuses et tropicales [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Maladies Infectieuses et Tropicales [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), 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), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), DDSIS 76, Institut national de recherche et de sécurité (Vandoeuvre lès Nancy) (INRS ( Vandoeuvre lès Nancy)), Service des Maladies Infectieuses et Tropicales [Hôpital de la Conception] (SMIT), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Laboratoire de Physique et Chimie Quantique, Université Mouloud Mamerri, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, Assistance Publique - Hôpitaux de Marseille (APHM), Département de Physique Nucléaire (ex SPhN) (DPHN), Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), 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 Paris-Saclay-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 Paris-Saclay-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut des Matériaux, de Microélectronique et des Nanosciences de Provence (IM2NP), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Département Etude des Réacteurs (DER), CEA-Direction de l'Energie Nucléaire (CEA-DEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hopital l'Archet, Centre d'Information et de Soins de I'Immunodéficience Humaine (CISIH). Hôpital l'Archet 1, Hôpital l'Archet, CHU Nice [Cimiez], Hôpital Cimiez [Nice] (CHU), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôtel-Dieu de Nantes, Service de virologie [CHU Nantes], Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Science et Technologie du Lait et de l'Oeuf (STLO), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Institut des Sciences du Mouvement Etienne Jules Marey (ISM), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Paris Descartes - Paris 5 (UPD5), Institut de Physique du Globe de Paris (IPGP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des maladies infectieuses [CHU Pitié-Salêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Système membranaires, photobiologie, stress et détoxication (SMPSD), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Weill Cornell Medicine [Qatar], Institut Rayonnement Matière de Saclay (IRAMIS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de Virologie [Strasbourg], GEOMA, Université de Vigo, Universidate de Vigo, Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Laboratoire d'aérologie (LA), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Service des Maladies Infectieuses, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France, parent, Pathogénie des Staphylocoques – Staphylococcal Pathogenesis, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hosp Civils Lyon, Serv Malad Infect, Lyon, France, Equipe 15, Centre de Recherche en Cancérologie de Lyon (CRCL), 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)-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), Recherches Translationnelles sur le VIH et les maladies infectieuses (TransVIHMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 1 (UM1)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Universtié Yaoundé 1 [Cameroun]-Université de Montpellier (UM), Faculté des Mathématiques et des Sciences de la Matière, Université Kasdi Merbah Ouargla, Laboratoire de Géochimie Isotopique Environnementale (GIS) / Université de Nîmes (GIS), Université de Nîmes (UNIMES)-Centre National de la Recherche Scientifique (CNRS), CHU UCL Namur, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des maladies infectieuses et tropicales, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre d'Etudes Lasers Intenses et Applications (CELIA), Université de Bordeaux (UB)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Pharmacie de l'Hôpital Bichat, UMR CNRS 8179, Université de Lille, Sciences et Technologies-Centre National de la Recherche Scientifique (CNRS), Service des maladies infectieuses et réanimation médicale, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Les Hôpitaux Universitaires de Strasbourg (HUS), Service de pneumologie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Unité des Rickettsies et pathogènes émergents (URPE), 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)-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), CHU Saint-Etienne, University Hospital and University Jean Monnet, Centre Hospitalier Tourcoing, CHU de Fort de France, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Saint-Jacques, Laboratoire de Génie des Procédés et Matériaux - EA 4038 (LGPM), CentraleSupélec, Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0301 basic medicine, Male, Cancer Research, Posaconazole, Antifungal Agents, [SDV]Life Sciences [q-bio], Administration, Oral, Dat’AIDS cohort, Pharmacology, 030226 pharmacology & pharmacy, Gastroenterology, 0302 clinical medicine, MESH: Drug Monitoring, Medicine, Prospective Studies, Haematological malignancies, media_common, MESH: Aged, Hematology, MESH: Middle Aged, medicine.diagnostic_test, General Medicine, Middle Aged, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 90-90-90 target, 3. Good health, Posaconazole oral tablet, Oncology, Quartile, MESH: Young Adult, Hematologic Neoplasms, MESH: Administration, Oral, Female, Drug Monitoring, Antifungal prophylaxis, Safety, medicine.drug, Tablets, Drug, Adult, medicine.medical_specialty, media_common.quotation_subject, 030106 microbiology, Therapeutic drug monitoring, 03 medical and health sciences, Young Adult, Pharmacokinetics, Invasive fungal infections, Internal medicine, Pharmacovigilance, primary HIV infection, cascade of care, Humans, Aged, MESH: Humans, business.industry, MESH: Adult, TasP, Triazoles, MESH: Antifungal Agents, MESH: Prospective Studies, MESH: Male, MESH: Triazoles, MESH: Tablets, business, Liver function tests, MESH: Female, MESH: Hematologic Neoplasms
Abstract

International audience; PurposePosaconazole is a triazole antifungal widely used for prophylaxis of invasive fungal disease (IFI). Posaconazole tablets allow reaching higher plasma levels than the oral suspension, but safety data with this formulation in real life are scarce. This study aimed at evaluating the safety profile, the pharmacokinetic variability, and the concentration–toxicity relationship of posaconazole tablets in patients with haematological malignancies.MethodsSixty neutropenic patients treated with posaconazole tablets for prophylaxis of IFI were prospectively included in the study. Adverse drug reactions (ADR) were recorded and analyzed by the Regional Pharmacovigilance Centre to assess posaconazole implication. Blood samples were drawn once a week and plasma trough concentrations (C min) were assayed by LC–MS/MS. The rates of ADR by quartile of C min were compared.ResultsEighteen patients (30%) experienced at least one ADR attributed to posaconazole. Liver function test (LFT) abnormalities were encountered in 20% of patients and resulted in four (6.7%) treatment discontinuations. Posaconazole median (range) C min was 1.36 (< 0.1–3.44) µg/mL (inter-patient CV = 43.9%). During follow-up, 28.6% of patients had at least one concentration < 0.7 µg/mL, and 35.7% had at least one concentration > 2 µg/mL. Rates of ADR by quartile of C min were not different.ConclusionsPosaconazole was well tolerated; however, LFT abnormalities were frequent. ADR occurrence was not linked to posaconazole exposure. Because posaconazole concentrations were highly variable, TDM can be helpful to avoid underexposure to the drug and increase its efficacy in preventing IFI. Conversely, a large proportion of patients was overexposed and might have benefited of a dose reduction.

Published
2018

8. Diversity of 1,213 hepatitis C virus NS3 protease sequences from a clinical virology laboratory database in Marseille university hospitals, southeastern France

Author

Jean-Marie Ruiz, Anne Motte, Natacha Tivoli, Saadia Mokhtari, Isabelle Ravaux, Christian Tourres, Hind Hajji, Philippe Colson, Sarah Aherfi, Catherine Tamalet, René Gerolami, and Isabelle Poizot-Martin

Subjects
Genetics, education.field_of_study, NS3, Sequence database, viruses, Hepatitis C virus, Population, virus diseases, Biology, medicine.disease_cause, Virology, digestive system diseases, Infectious Diseases, GenBank, Genotype, medicine, Protease inhibitor (pharmacology), education, Clinical virology
Abstract

Infection with hepatitis C virus (HCV) represents a major public health concern worldwide. Recent therapeutic advances have been considerable, HCV genotype continuing to guide therapeutic management. Since 2008, HCV genotyping in our clinical microbiology laboratory at university hospitals of Marseille, Southeastern France, has been based on NS3 protease gene population sequencing, to allow concurrent HCV genotype and protease inhibitor (PI) genotypic resistance determinations. We aimed, first, to analyze the genetic diversity of HCV NS3 protease obtained from blood samples collected between 2003 and 2013 from patients monitored at university hospitals of Marseille and detect possible atypical sequences; and, second, to identify NS3 protease amino acid patterns associated with decreased susceptibility to HCV PIs. A total of 1,213 HCV NS3 protease sequences were available in our laboratory sequence database. We implemented a strategy based on bioinformatic tools to determine whether HCV sequences are representative of our local HCV genetic diversity, or divergent. In our 2003–2012 HCV NS3 protease sequence database, we delineated 32 clusters representative of the majority HCV genetic diversity, and 61 divergent sequences. Five of these divergent sequences showed less than 85% nucleotide identity with their top GenBank hit. In addition, among the 294 sequences obtained in 2013, three were divergent relative to these 32 previously delineated clusters. Finally, we detected both natural and on-treatment genotypic resistance to HCV NS3 PIs, including a substantial prevalence of Q80K substitutions associated with decreased susceptibility to simeprevir, a second generation PI. J. Med. Virol. 87:1921–1933, 2015. © 2015 Wiley Periodicals, Inc.

Published
2015

9. Population pharmacokinetics of Rilpivirine in HIV-1-infected patients treated with the single-tablet regimen rilpivirine/tenofovir/emtricitabine

Author

Nadège Néant, Bruno Lacarelle, Catherine Dhiver, Florence Gattacceca, Caroline Solas, Diane Descamps, Saadia Mokhtari, Minh Patrick Lê, Sylvie Bregigeon, Yazdan Yazdanpanah, Catherine Tamalet, and Gilles Peytavin

Subjects
0301 basic medicine, Male, Human immunodeficiency virus (HIV), Administration, Oral, HIV Infections, medicine.disease_cause, 030226 pharmacology & pharmacy, chemistry.chemical_compound, 0302 clinical medicine, Tandem Mass Spectrometry, Pharmacology (medical), Drug Dosage Calculations, Aged, 80 and over, education.field_of_study, medicine.diagnostic_test, General Medicine, Middle Aged, Rilpivirine, Area Under Curve, Female, France, Drug Monitoring, medicine.drug, Half-Life, Tablets, Adult, medicine.medical_specialty, Anti-HIV Agents, Metabolic Clearance Rate, 030106 microbiology, Population, Emtricitabine, Models, Biological, 03 medical and health sciences, Young Adult, Pharmacokinetics, Internal medicine, medicine, Humans, Computer Simulation, education, Aged, Retrospective Studies, Pharmacology, business.industry, NONMEM, Regimen, chemistry, Nonlinear Dynamics, Therapeutic drug monitoring, HIV-1, Emtricitabine, Rilpivirine, Tenofovir Drug Combination, business, Software, Chromatography, Liquid
Abstract

Rilpivirine, prescribed for the treatment of HIV infection, presents an important inter-individual pharmacokinetic variability. We aimed to determine population pharmacokinetic parameters of rilpivirine in adult HIV-infected patients and quantify their inter-individual variability. We conducted a multicenter, retrospective, and observational study in patients treated with the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. As part of routine therapeutic drug monitoring, rilpivirine concentrations were measured by UPLC-MS/MS. Population pharmacokinetic analysis was performed using NONMEM software. Once the compartmental and random effects models were selected, covariates were tested to explain the inter-individual variability in pharmacokinetic parameters. The final model qualification was performed by both statistical and graphical methods. We included 379 patients, resulting in the analysis of 779 rilpivirine plasma concentrations. Of the observed trough individual plasma concentrations, 24.4% were below the 50 ng/ml minimal effective concentration. A one-compartment model with first-order absorption best described the data. The estimated fixed effect for plasma apparent clearance and distribution volume were 9 L/h and 321 L, respectively, resulting in a half-life of 25.2 h. The common inter-individual variability for both parameters was 34.1% at both the first and the second occasions. The inter-individual variability of clearance was 30.3%. Our results showed a terminal half-life lower than reported and a high proportion of patients with suboptimal rilpivirine concentrations, which highlights the interest of using therapeutic drug monitoring in clinical practice. The population analysis performed with data from “real-life” conditions resulted in reliable post hoc estimates of pharmacokinetic parameters, suitable for individualization of dosing regimen.

Published
2017

10. Emergence of uncommon HIV-1 non-B subtypes and circulating recombinant forms and trends in transmission of antiretroviral drug resistance in patients with primary infection during the 2013-2015 period in Marseille, Southeastern France

Author

Anne Motte, Philippe Colson, Saadia Mokhtari, Isabelle Ravaux, Christian Tourres, Catherine Tamalet, Hélène Laroche, Catherine Dhiver, Sarah Aherfi, Hervé Tissot-Dupont, Isabelle Poizot-Martin, Hervé Chaudet, Sylvie Bregigeon, Andreas Stein, Olivia Zaegel-Faucher, Philippe Brouqui, Thérèse Dieng, Amélie Menard, Christelle Tomei, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM], Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-Assistance Publique - Hôpitaux de Marseille (APHM), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), This study was supported by a grant from the French State managed by the National Research Agency under the 'Investissements d’’avenir (Investments for the Future)' program with the referenceANR‐10‐IAHU‐03 (Méditerranée Infection)., ANR-10-IAHU-0003,Méditerranée Infection,I.H.U. Méditerranée Infection(2010), COMBE, Isabelle, Instituts Hospitalo-Universitaires - I.H.U. Méditerranée Infection - - Méditerranée Infection2010 - ANR-10-IAHU-0003 - IAHU - VALID, and Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )

Subjects
0301 basic medicine, Adult, Male, resistance-associated mutations, recombinant subtypes, Genotype, Anti-HIV Agents, Period (gene), men having sex with men, Etravirine, HIV Infections, non-B subtypes, law.invention, Men who have sex with men, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, law, Virology, Drug Resistance, Viral, medicine, Prevalence, Humans, In patient, Recombination, Genetic, Transmission (medicine), business.industry, Sequence Analysis, DNA, primary HIV Infection, Middle Aged, medicine.disease, Reverse transcriptase, 3. Good health, 030104 developmental biology, Infectious Diseases, Mutation, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Recombinant DNA, HIV-1, Female, France, primary antiretroviral resistance, business, medicine.drug
Abstract

International audience; Primary HIV-1 infections (PHI) with non-B subtypes are increasing in developed countries while transmission of HIV-1 harboring antiretroviral resistance-associated mutations (RAMs) remains a concern. This study assessed non-B HIV-1 subtypes and RAMs prevalence among patients with PHI in university hospitals of Marseille, Southeastern France, in 2005-2015 (11 years). HIV-1 sequences were obtained by inhouse protocols from 115 patients with PHI, including 38 for the 2013-2015 period. On the basis of the phylogenetic analysis of the reverse transcriptase region, non-B subtypes were identified in 31% of these patients. They included 3 different subtypes (3A, 1C, 4F), 23 circulating recombinant forms (CRFs) (CRF02_AG, best BLAST hits being CRF 36\ₓpx and CRF30 in 7 and 1 cases, respectively), and 5 unclassified sequences (U). Non-B subtypes proportion increased significantly, particularly in 2011-2013 vs in 2005-2010 (P = .03). CRF02_AG viruses largely predominated in 2005-2013 whereas atypical strains more difficult to classify and undetermined recombinants emerged recently (2014-2015). The prevalence of protease, nucleos(t) ide reverse transcriptase, and first-generation nonnucleoside reverse transcriptase inhibitors-associated RAMs were 1.7% (World Health Organization [WHO] list, 2009/2.6% International AIDS Society [IAS] list, 2017), 5.2%/4.3%, and 5.2%/5.2%, respectively. Etravirine/rilpivirine-associated RAM (IAS) prevalence was 4.3%. Men who have sex with men (MSM) were more frequently infected with drug-resistant viruses than other patients (26% vs 7%; P = .011). The recent increase of these rare HIV-1 strains and the spread of drug-resistant HIV-1 among MSM in Southeastern France might be considered when implementing prevention strategies and starting therapies.

Published
2017

11. Dolutegravir and weight gain: an unexpected bothering side effect?

Author

Catherine Dhiver, Amélie Menard, Philippe Brouqui, Philippe Colson, Hervé Tissot-Dupont, Christelle Tomei, Saadia Mokhtari, Andreas Stein, Isabelle Ravaux, Line Meddeb, Service de Maladies Infectieuses, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre de Référence des Infections Ostéo-articulaires Sud-Méditerranée (CRIOA), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Service des Maladies Infectieuses et Tropicales [Hôpital de la Conception] (SMIT), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Unité de Recherche sur les Maladies Infectieuses Tropicales Emergentes (URMITE), 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, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Service des Maladies Infectieuses, Service des Maladies Infectieuses et Tropicales [CHU Hôpital Nord - Marseille] (M.I.T), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Hôpital Nord [CHU - APHM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), INSB-INSB-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, and INSB-INSB-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Cart, medicine.medical_specialty, Side effect, Pyridones, 030106 microbiology, Immunology, Weight Gain, Piperazines, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, Oxazines, medicine, Humans, Immunology and Allergy, HIV Integrase Inhibitors, 030212 general & internal medicine, Adverse effect, ComputingMilieux_MISCELLANEOUS, business.industry, virus diseases, Middle Aged, 3. Good health, Discontinuation, Infectious Diseases, chemistry, Cohort, Dolutegravir, Female, medicine.symptom, business, Heterocyclic Compounds, 3-Ring, Weight gain, Cohort study
Abstract

We recently analyzed, in our real-life cohort of 2260 HIV-infected patients, the reasons for discontinuation of dolutegravir-based combined antiretroviral therapies (cARTs) [1]. Of 517 patients, 55 (10.6%) discontinued this cART due to adverse effects. Unexpectedly, four (7%) of these adverse effect

Published
2017

12. Neuropsychiatric adverse effects on dolutegravir: an emerging concern in Europe

Author

Catherine Dhiver, Christelle Tomei, Clementine Montagnac, Philippe Colson, Amélie Menard, Saadia Mokhtari, Line Meddeb, Caroline Solas, Isabelle Ravaux, Andreas Stein, Hervé Tissot-Dupont, Service de Maladies Infectieuses, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre de Référence des Infections Ostéo-articulaires Sud-Méditerranée (CRIOA), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Service de Pharmacocinétique et de Toxicologie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Service des Maladies Infectieuses et Tropicales [Hôpital de la Conception] (SMIT), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service des Maladies Infectieuses, Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Unité de Recherche sur les Maladies Infectieuses Tropicales Emergentes (URMITE), 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)-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), Service des Maladies Infectieuses et Tropicales [CHU Hôpital Nord - Marseille] (M.I.T), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, and Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, medicine.medical_specialty, business.industry, Immunology, MEDLINE, 030112 virology, 3. Good health, Toxicology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Infectious Diseases, chemistry, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Dolutegravir, medicine, HIV Integrase Inhibitors, Immunology and Allergy, 030212 general & internal medicine, Intensive care medicine, business, Adverse effect, ComputingMilieux_MISCELLANEOUS
Abstract

International audience; no abstract

Published
2017

13. Hepatitis C virus NS3 protease genotyping and drug concentration determination during triple therapy with telaprevir or boceprevir for chronic infection with genotype 1 viruses, southeastern France

Author

Saadia Mokhtari, Jean-Marie Ruiz, Catherine Tamalet, Caroline Solas, Isabelle Portal, Philippe Brouqui, Sarah Aherfi, Anne Motte, Isabelle Ravaux, Sylvie Bregigeon, Andreas Stein, Catherine Dhiver, René Gerolami, Philippe Colson, Isabelle Poizot-Martin, Jacques Moreau, Patrick Borentain, and Danielle Botta-Fridlund

Subjects
education.field_of_study, business.industry, Ribavirin, Hepatitis C virus, Population, virus diseases, medicine.disease_cause, Virology, digestive system diseases, Telaprevir, chemistry.chemical_compound, Infectious Diseases, chemistry, Pegylated interferon, Boceprevir, Medicine, Protease inhibitor (pharmacology), education, business, Viral load, medicine.drug
Abstract

Telaprevir and boceprevir, the two first hepatitis C virus (HCV) NS3 protease inhibitors (PIs), considerably increase rates of sustained virologic response in association with pegylated interferon and ribavirin in chronic HCV genotype 1 infections. The 30 first patients treated by telaprevir or boceprevir including anti-HCV therapies since 2011 in Marseille University hospitals, France, were monitored. HCV loads and plasmatic concentrations of telaprevir and boceprevir were determined on sequential blood samples. HCV NS3 protease gene population sequencing was performed at baseline of treatment and in case of treatment failure. Fifteen patients (including 7 co-infected with HIV) received telaprevir and the other 15 patients (including 4 co-infected with HIV) received boceprevir. At baseline, HCV NS3 protease from six patients harbored amino acid substitutions associated with PI-resistance. Treatment failure occurred at week 12 for 7 patients. Amino acid substitutions associated with PI-resistance were observed in six of these cases. HCV NS3 R155K and T54A/S mutants, all of genotype 1a, were found from four patients. Median (interquartile range) plasma concentrations were 3,092 ng/ml (2,320-3,525) for telaprevir and 486 ng/ml (265-619) for boceprevir. For HIV-HCV co-infected patients, median concentrations were 3,162 ng/ml (2,270-4,232) for telaprevir and 374 ng/ml (229-519) for boceprevir. Plasma drug concentration monitoring revealed undetectable concentrations for two patients at week 4, and probable non-adherence to therapy for another patient. These findings indicate that routine HCV NS3 protease sequencing and plasma PI concentration monitoring might be helpful to characterize cases of therapy failure, at a cost dramatically low compared to that of anti-HCV therapy.

Published
2014

14. Psychiatric disorders after starting dolutegravir

Author

Saadia Mokhtari, Julie Allemand, Farid Kheloufi, and Anne Default

Subjects
Pediatrics, medicine.medical_specialty, business.industry, Immunology, MEDLINE, Antiretroviral therapy, chemistry.chemical_compound, Infectious Diseases, chemistry, Dolutegravir, Immunology and Allergy, Medicine, business, Viral load
Published
2015

15. Gut microbiota associated with HIV infection is significantly enriched in bacteria tolerant to oxygen

Author

Grégory, Dubourg, Jean-Christophe, Lagier, Sophie, Hüe, Mathieu, Surenaud, Dipankar, Bachar, Catherine, Robert, Caroline, Michelle, Isabelle, Ravaux, Saadia, Mokhtari, Matthieu, Million, Andreas, Stein, Philippe, Brouqui, Yves, Levy, and Didier, Raoult

Subjects
INFLAMMATION, INTESTINAL BACTERIA, HIV/AIDS, Intestinal Microflora, OXIDATIVE STRESS
Abstract

Objectives Gut microbiota modifications occurring during HIV infection have recently been associated with inflammation and microbial translocation. However, discrepancies between studies justified a comprehensive analysis performed on a large sample size. Design and methods In a case–control study, next-generation sequencing of the 16S rRNA gene was applied to the faecal microbiota of 31 HIV-infected patients, of whom 18 were treated with antiretroviral treatment (ART), compared with 27 healthy controls. 21 sera samples from HIV-infected patients and 7 sera samples from control participants were used to test the presence of 25 markers of inflammation and/or immune activation. Results Diversity was significantly reduced in HIV individuals when compared with controls and was not restored in the ART group. The relative abundance of several members of Ruminococcaceae such as Faecalibacterium prausnitzii was critically less abundant in the HIV-infected group and inversely correlated with inflammation/immune activation markers. Members of Enterobacteriaceae and Enterococcaceae were found to be enriched and positively correlated with these markers. There were significantly more aerotolerant species enriched in HIV samples (42/52 species, 80.8%) when compared with the control group (14/87 species, 16.1%; χ2 test, p

Published
2016

16. Toward chronic hepatitis C eradication in HIV-positive patients, including those cirrhotic and infected with genotype 3 viruses

Author

Saadia Mokhtari, Philippe Brouqui, Andreas Stein, Sarah Aherfi, Philippe Colson, Isabelle Ravaux, Hervé Tissot-Dupont, Line Meddeb, Amélie Menard, Catherine Dhiver, Service de Maladies Infectieuses, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre de Référence des Infections Ostéo-articulaires Sud-Méditerranée (CRIOA), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), 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), Service des Maladies Infectieuses et Tropicales [CHU Hôpital Nord - Marseille] (M.I.T), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Service des Maladies Infectieuses, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service des Maladies Infectieuses et Tropicales [Hôpital de la Conception] (SMIT), Unité de Recherche sur les Maladies Infectieuses Tropicales Emergentes (URMITE), INSB-INSB-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), and Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48

Subjects
0301 basic medicine, medicine.medical_specialty, Cirrhosis, Daclatasvir, Sofosbuvir, 030106 microbiology, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Chronic hepatitis, Acquired immunodeficiency syndrome (AIDS), Internal medicine, Genotype, medicine, ComputingMilieux_MISCELLANEOUS, business.industry, Ribavirin, virus diseases, medicine.disease, digestive system diseases, 3. Good health, chemistry, Cohort, 030211 gastroenterology & hepatology, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

Direct-acting agents (DAA) have proved dramatic efficiency to cure chronic hepatitis C.1 ,2 Extensive assessment of their real-life effectiveness is now required, including in cirrhotic and genotype 3 HCV-infected patients who are under-represented in real-world studies but are considered the still hard-to-cure population.1–5 We read therefore with interest the article by Welzel et al 1 about the achievement of sustained virological response (SVR) in 91% of cases in a real-world cohort treated with sofosbuvir plus daclatasvir with or without ribavirin for 12–24 weeks. Indeed, remarkably, SVR was 92% in patients infected with HCV-3 (n=102), 97% in cirrhotics (n=389), 98% in HIV-infected individuals (n=55) and 96% in case of prior HCV therapy (n=341). We analysed the efficacy and safety of DAA-based anti-HCV therapies administered during 2 years (May 2014–April 2016) to a real-world cohort of 170 HCV-HIV-coinfected …

Published
2017

17. Population Pharmacokinetics of Atazanavir in Human Immunodeficiency Virus-Infected Patients

Author

Nicolas Simon, Caroline Solas, Alain Lafeuillade, Bruno Lacarelle, Marie-Claude Gagnieu, Saadia Mokhtari, Isabelle Ravaux, and Marie-Pierre Drogoul

Subjects
Adult, Male, medicine.medical_specialty, Anti-HIV Agents, Pyridines, Atazanavir Sulfate, Population, HIV Infections, Context (language use), Pharmacology, Gastroenterology, Pharmacokinetics, Internal medicine, medicine, Humans, Pharmacology (medical), education, Aged, Retrospective Studies, Volume of distribution, education.field_of_study, business.industry, virus diseases, Middle Aged, Confidence interval, Atazanavir, NONMEM, Female, business, Oligopeptides, medicine.drug
Abstract

The aim of this study was to determine the population pharmacokinetic (PK) parameters of atazanavir in adult human immunodeficiency virus-infected patients to build up a Bayesian strategy for dosage regimen individualization. This was an observational study of patients treated with the once-daily regimen atazanavir associated with 100 mg of ritonavir. Blood samples were drawn at steady state at various times ranging from 1 to 26 hours postdose. Atazanavir plasma concentrations were determined by a validated reverse-phase high-performance liquid chromatography method. PK analysis of the atazanavir population was performed using a nonlinear mixed-effects model (NONMEM version 6). One hundred eighty-seven patients were included in the study. The atazanavir doses prescribed were 300 mg (n = 169), 400 mg (n = 12), 200 mg (n = 1), and 150 mg (n = 5). The atazanavir population PK was described using a 1-compartment model with first-order absorption. Mean PK parameter estimations (95% confidence interval, coefficients of variation %) were as follows: oral clearance (CL) = 7.6 L/h (6.9-8.3; 34%), volume of distribution (V) = 80.8 L (67.4-94; 37%), and absorption constant rate (Ka) = 1.05 hours (0.01-2.09; 156%). The mean estimated half-life (T-half) was 7.5 hours (95% confidence interval: 7.2 -7.8 hours). The estimated T-half of atazanavir was in agreement with that previously reported of 8.6 and 8.8 hours. We observed a wide interpatient variability for the PK parameters, especially for Ka. This population approach allowed us to determine atazanavir PK parameters in human immunodeficiency virus-infected patients in a real-life context and to perform Bayesian analysis to predict Ctrough from samples collected at any moment during the dosing interval. This could therefore improve therapeutic drug monitoring interpretations and provide an interesting tool for correlation with virologic data.

Published
2008

18. Diversity of 1,213 hepatitis C virus NS3 protease sequences from a clinical virology laboratory database in Marseille university hospitals, southeastern France

Author

Hind, Hajji, Sarah, Aherfi, Anne, Motte, Isabelle, Ravaux, Saadia, Mokhtari, Jean-Marie, Ruiz, Isabelle, Poizot-Martin, Christian, Tourres, Natacha, Tivoli, René, Gérolami, Catherine, Tamalet, and Philippe, Colson

Subjects
Male, Genotype, Genotyping Techniques, Molecular Sequence Data, Mutation, Missense, Genetic Variation, Sequence Homology, Hepacivirus, Sequence Analysis, DNA, Middle Aged, Viral Nonstructural Proteins, Hepatitis C, Hospitals, University, Drug Resistance, Viral, Cluster Analysis, Humans, Female, France, Phylogeny
Abstract

Infection with hepatitis C virus (HCV) represents a major public health concern worldwide. Recent therapeutic advances have been considerable, HCV genotype continuing to guide therapeutic management. Since 2008, HCV genotyping in our clinical microbiology laboratory at university hospitals of Marseille, Southeastern France, has been based on NS3 protease gene population sequencing, to allow concurrent HCV genotype and protease inhibitor (PI) genotypic resistance determinations. We aimed, first, to analyze the genetic diversity of HCV NS3 protease obtained from blood samples collected between 2003 and 2013 from patients monitored at university hospitals of Marseille and detect possible atypical sequences; and, second, to identify NS3 protease amino acid patterns associated with decreased susceptibility to HCV PIs. A total of 1,213 HCV NS3 protease sequences were available in our laboratory sequence database. We implemented a strategy based on bioinformatic tools to determine whether HCV sequences are representative of our local HCV genetic diversity, or divergent. In our 2003-2012 HCV NS3 protease sequence database, we delineated 32 clusters representative of the majority HCV genetic diversity, and 61 divergent sequences. Five of these divergent sequences showed less than 85% nucleotide identity with their top GenBank hit. In addition, among the 294 sequences obtained in 2013, three were divergent relative to these 32 previously delineated clusters. Finally, we detected both natural and on-treatment genotypic resistance to HCV NS3 PIs, including a substantial prevalence of Q80K substitutions associated with decreased susceptibility to simeprevir, a second generation PI.

Published
2015

19. First-line Highly Active Antiretroviral Regimens in 2001–2002 in the French Hospital Database on HIV: Combination Prescribed and Biological Outcomes

Author

Valérie Potard, Christian Pradier, Françoise Brun-Vézinet, Willy Rozenbaum, Véronique Frixon-Marin, Dominique Costagliola, David Rey, and Saadia Mokhtari

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Databases, Factual, First line, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, Cohort Studies, Acquired immunodeficiency syndrome (AIDS), Antiretroviral Therapy, Highly Active, Internal medicine, medicine, Humans, Pharmacology (medical), Sida, Aged, Pharmacology, biology, business.industry, HIV, Middle Aged, Viral Load, biology.organism_classification, medicine.disease, Antiretroviral therapy, Hospitals, CD4 Lymphocyte Count, Infectious Diseases, Anti-Retroviral Agents, Lentivirus, Immunology, RNA, Viral, Regression Analysis, Female, France, Viral disease, business, Viral load
Abstract

Introduction We compared biological outcomes in anti-retroviral-naive patients with viral load (VL) >5,000 copies/ml starting combivir-based, three-drug highly active antiretroviral therapy regimens in 2001–2002 according to the third component, namely abacavir (ABC), nelfinavir (NFV), indinavir/ritonavir (IDV/r), lopinavir/ritonavir (LPV/r), nevirapine (NVP) or efavirenz (EFV). Methods We evaluated virological response (HIV RNA + T-cells/u, l) separately in patients with baseline VL Results Median follow up was 19 months. EFV had better virological efficacy than NFV and IDV/r among patients with baseline VL Conclusions For first-line therapy, in this observational setting, EFV, LPV/r and NVP, when added to the combivir backbone, were more likely to drive viral load

Published
2006

20. Expression of activating receptors on natural killer cells from AIDS-related lymphoma patients

Author

Karine Baumstarck, Régis Costello, Daniel Olive, Carole Sanchez, Delphine Mercier-Bataille, Thérèse Le Treut, Nicolas Mounier, Gérard Sébahoun, Saadia Mokhtari, Céline Baier, and Caroline Besson

Subjects
Antitumor immune response, Lymphoma, HIV Positivity, business.industry, Research, Lymphocyte, Chronic lymphocytic leukemia, Myeloid leukemia, medicine.disease, NKG2D, AIDS-related lymphoma, medicine.anatomical_structure, Natural cytotoxicity receptors, hemic and lymphatic diseases, Virology, Immunology, HIV-1, medicine, Natural killer cells, Molecular Medicine, Cytotoxic T cell, Pharmacology (medical), business
Abstract

Background: Abnormal NK phenotype and cytotoxic functions have been described in acute myeloid leukemia, chronic lymphocytic leukemia, myeloma and myelodysplastic syndromes. Defective NK cytotoxicity is due to decreased expression of the Natural Cytotoxicity Receptors (NCRs), 2B4/CD244/p38, or NKG2D. This prompted us to test the expression of these molecules on circulating NK cells from patients with AIDS-related lymphomas (RL) in comparison with HIV + patients without lymphoma, healthy subjects and HIV-negative patients with lymphoma. Methods: Blood samples were analyzed by flow cytometry for NCRs, 2B4/CD244/p38 and NKG2D expression on NK cells defined as CD3-/CD56+ lymphocytes. We also analyzed by quantitative PCR specific RNA for NKp30/NCR3 and NKp46/NCR1. Results: We could not detect any defect in NKp46/NCR1 expression between all groups. NKp44/NCR2, NKp30/NCR3 and NKG2D had lower expression in AIDS-RL in comparison with HIV + patients without lymphoma when compared to patients with similar (>0.3 G/L) CD4+ lymphocyte levels. Expression of 2B4/CD244/p38 was lower in AIDS-RL than in HIV-negative lymphoma. Comparison of specific NKp30/NCR3 and NKp46/NCR1 RNA showed increased steady state levels, despite decreased surface expression for NKp30/NCR3, suggesting abnormal post-transcriptional regulatory mechanisms. Conclusions: We show a more pronounced defect in NK activating molecule when HIV infection is associated with lymphoma than when only one condition (HIV positivity or lymphoma) is present. Defective NK phenotype, in addition to CD4+ depletion and dysfunction, may participate to the increased incidence of lymphoma in HIV patients.

Published
2014

21. Hepatitis C virus NS3 protease genotyping and drug concentration determination during triple therapy with telaprevir or boceprevir for chronic infection with genotype 1 viruses, southeastern France

Author

Sarah, Aherfi, Caroline, Solas, Anne, Motte, Jacques, Moreau, Patrick, Borentain, Saadia, Mokhtari, Danielle, Botta-Fridlund, Catherine, Dhiver, Isabelle, Portal, Jean-Marie, Ruiz, Isabelle, Ravaux, Sylvie, Bregigeon, Isabelle, Poizot-Martin, Andreas, Stein, René, Gérolami, Philippe, Brouqui, Catherine, Tamalet, and Philippe, Colson

Subjects
Adult, Male, Genotype, Proline, Mutation, Missense, Interferon-alpha, Hepacivirus, Hepatitis C, Chronic, Middle Aged, Viral Load, Viral Nonstructural Proteins, Antiviral Agents, Hospitals, University, Plasma, Young Adult, Amino Acid Substitution, Drug Resistance, Viral, Ribavirin, Humans, Drug Therapy, Combination, Female, France, Treatment Failure, Oligopeptides
Abstract

Telaprevir and boceprevir, the two first hepatitis C virus (HCV) NS3 protease inhibitors (PIs), considerably increase rates of sustained virologic response in association with pegylated interferon and ribavirin in chronic HCV genotype 1 infections. The 30 first patients treated by telaprevir or boceprevir including anti-HCV therapies since 2011 in Marseille University hospitals, France, were monitored. HCV loads and plasmatic concentrations of telaprevir and boceprevir were determined on sequential blood samples. HCV NS3 protease gene population sequencing was performed at baseline of treatment and in case of treatment failure. Fifteen patients (including 7 co-infected with HIV) received telaprevir and the other 15 patients (including 4 co-infected with HIV) received boceprevir. At baseline, HCV NS3 protease from six patients harbored amino acid substitutions associated with PI-resistance. Treatment failure occurred at week 12 for 7 patients. Amino acid substitutions associated with PI-resistance were observed in six of these cases. HCV NS3 R155K and T54A/S mutants, all of genotype 1a, were found from four patients. Median (interquartile range) plasma concentrations were 3,092 ng/ml (2,320-3,525) for telaprevir and 486 ng/ml (265-619) for boceprevir. For HIV-HCV co-infected patients, median concentrations were 3,162 ng/ml (2,270-4,232) for telaprevir and 374 ng/ml (229-519) for boceprevir. Plasma drug concentration monitoring revealed undetectable concentrations for two patients at week 4, and probable non-adherence to therapy for another patient. These findings indicate that routine HCV NS3 protease sequencing and plasma PI concentration monitoring might be helpful to characterize cases of therapy failure, at a cost dramatically low compared to that of anti-HCV therapy.

Published
2014

22. Lopinavir/r no longer recommended as first line regimen: a comparative effectiveness analysis

Author

David Rey, Valérie Potard, Christian Pradier, Willy Rozenbaum, Françoise Brun-Vézinet, Dominique Costagliola, Isabelle Poizot-Martin, Saadia Mokhtari, Département Inserm Transfert, Institut Curie [Paris], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Strasbourg, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Maladies Infectieuses et Tropicales [CHU Hôpital Nord - Marseille] (M.I.T), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Service de santé publique [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7), Service de Virologie [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and HAL UPMC, Gestionnaire

Subjects
Male, HIV Infections, 030312 virology, Deoxycytidine, Lopinavir, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antiretroviral Therapy, Highly Active, Emtricitabine, Prospective Studies, Treatment Failure, 030212 general & internal medicine, 0303 health sciences, Hazard ratio, Middle Aged, Viral Load, 3. Good health, Infectious Diseases, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, France, Viral load, Research Article, medicine.drug, Adult, medicine.medical_specialty, Efavirenz, Anti-HIV Agents, antiretroviral therapy, Organophosphonates, effectiveness, 03 medical and health sciences, Internal medicine, first-line therapy, medicine, Humans, Tenofovir, propensity score, Proportional hazards model, business.industry, Adenine, Public Health, Environmental and Occupational Health, HIV infection, Confidence interval, CD4 Lymphocyte Count, Atazanavir, Surgery, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business
Abstract

on behalf of the FHDH ANRS CO4 (French Hospital Database on HIV, Agence Nationale de Recherches sur le Sida, cohort 4); International audience; Introduction: We compared the effectiveness of tenofovir/emtricitabine (TDF/FTC) combined with either lopinavir/r (LPV/r) or another recommended third drug in the 2010 French guidelines in antiretroviral-naıve patients starting combination antiretroviral therapy in 2004Á2008 in the French Hospital Database on HIV.Methods: The outcomes were stop or switch of the third component, viral load (VL) B500 copies/ml, an increase of at least 100 CD4 cells/mm 3 , AIDS-defining event and non-AIDS-defining hospitalization or death. Propensity scores were estimated by logistic regression based on the clinical centre and other confounders. In each clinical centre, each patient initiating LPV/r was matched with a patient initiating another third drug (efavirenz or atazanavir/r) and having a close propensity score. Cox's proportional hazards models were then used, with treatment as covariate. Time was right-censored at four years.Results: 1269 patients started LPV/r plus TDF/FTC, and 890 could be matched to 890 patients receiving another third drug. Baseline characteristics were well balanced between these two groups. LPV/r was associated with a higher risk of third drug stop (hazard ratio (HR): 1.69; 95% confidence interval (CI), 1.42Á2.00) and with less rapid viral suppression (HR: 0.83; 95% CI, 0.72Á 0.95). There was no difference in the time required for a CD4 cell increment of at least 100/mm 3 , or to the occurrence of an AIDS-defining event. Non-AIDS-defining hospitalizations or deaths were more frequent with LPV/r (HR: 1.79; 95% CI, 1.33Á2.39).Conclusions: For first-line therapy, in this observational setting, TDF/FTC plus LPV/r were less durable than TDF/FTC plus another recommended third drug, led to a less rapid viral suppression and were associated with a higher risk of non-AIDS morbidity.

Published
2014

23. Post-exposure prophylaxis completion and condom use in the context of potential sexual exposure to HIV

Author

Claudine Duvivier, André Cabié, Sylvie Bregigeon, Alain Makinson, David Rey, C Allavena, Jacques Reynes, Laurent Cotte, Isabelle Ravaux, Pierre Gantner, Les Hôptaux universitaires de Strasbourg (HUS), CHU Strasbourg, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôtel-Dieu de Nantes, Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris] (IP), Infection à VIH, réservoirs, diversité génétique et résistance aux antirétroviraux (ARV) (EA 7327), Université Paris Descartes - Paris 5 (UPD5), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Maladies infectieuses et tropicales dans la Caraïbe (MAITC EA 4537), CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de la Martinique [Fort de France]-Université des Antilles (UA), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Dat'AIDS Study Group: Besançon: C. Drobacheff-Thiébaut, A. Foltzer, K. Bouiller, L. Hustache-Mathieu, C. Chirouze, F. Bozon, O. Babre, P. Muret, Clermont-Ferrand: H. Laurichesse, O. Lesens, M. Vidal, N. Mrozek, C. Aumeran, O. Baud, V. Corbin, P. Letertre, S. Casanova, C. Jacomet, Guadeloupe: B. Hoen, I. Lamaury, I. Fabre, E. Curlier, R. Ouissa, K. Schepers, C. Herrmann-Storck, N. Dournon, La Roche sur Yon: D. Merrien, P. Perré, T. Guimard, O. Bollangier, S. Leautez, M. Morrier, Lyon: F. Ader, F. Biron, A. Boibieux, L. Cotte, T. Ferry, P. Miailhes, T. Perpoint, S. Roux, S. Degroodt, C. Brochier, F. Valour, C. Chidiac, Marseille (IHU): C. Dhiver, M. Saadia Mokhtari, A. Ménard, H. Tissot Dupont, C. Toméi, L. Meddeb, A.Y. Belkhir, I. Ravaux, Marseille (Ste Marguerite): S. Brégigeon, O. Zaegel-Faucher, V. Obry-Roguet, H. Laroche, M. Orticoni, M.J. Soavi, P. Geneau de Lamarlière, E. Ressiot, M.J. Ducassou, I. Jaquet, S. Galie, A. Galinier, P. Martinet, M. Landon, A.S. Ritleng, A. Ivanova, C. Debreux, C. Lions, I. Poizot-Martin, Martinique: S. Abel, R. Césaire, L. Cuzin, G. Dos Santos, L. Fagour, M. Illiaquer, F. Najioullah, D. Nguyen, M. Ouka, S. Pierre-François, J. Pasquier, M. Pircher, B. Rozé, A. Cabié, Montpellier: N. Atoui, V. Le Moing, A. Makinson, N. Meftah, C. Merle de Boever, B. Montes, A. Montoya Ferrer, J. Reynes, Nancy: M. André, L. Boyer, M.P. Bouillon, M. Delestan, T. May, Nantes: C. Allavena, C. Bernaud, E. Billaud, C. Biron, B. Bonnet, S. Bouchez, D. Boutoille, C. Brunet-Cartier, C. Deschanvres, N. Hall, T. Jovelin, P. Morineau, V. Reliquet, H. Hue, S. Sécher, M. Cavellec, A. Soria, V. Ferré, E. André-Garnier, A. Rodallec, M. Lefebvre, O. Grossi, O. Aubry, F. Raffi, Nice: P. Pugliese, S. Breaud, C. Ceppi, J. Courjon, E. Cua, J. Cottalorda, P. Dellamonica, E. Demonchy, A. De Monte, J. Durant, C. Etienne, S. Ferrando, J.G. Fuzibet, R. Garraffo, A. Joulie, K. Risso, V. Mondain, A. Naqvi, N. Oran, I. Perbost, S. Pillet, B. Prouvost-Keller, C. Pradier, S. Wehrlen-Pugliese, V. Rio, E. Rosenthal, S. Sausse, G. Zouzou, Orléans: L. Hocqueloux, T. Prazuck, C. Gubavu, A. Sève, M. Niang, C. Boulard, Paris (Bicêtre): A. Cheret, C. Goujard, Y. Quertainmont, E. Teicher, N. Lerolle, D. Vittecoq, O. Deradji, F. Fourreau, C. Pallier, A. Barrail-Tran, Paris (Bichat): R. Landman, V. Joly, C. Rioux, S. Lariven, A. Gervais, F.X. Lescure, S. Matheron, F. Louni, C. Godard, Z. Julia, M. Chansombat, D. Rahli, C. Mackoumbou-Nkouka, C. Charpentier, D. Descamps, G. Peytavin, Y. Yazdanpanah, Paris (Pasteur-Necker): P.H. Consigny, G. Cessot, P. Bossi, J. Goesch, J. Benabdelmoumen, F. Lanternier, C. Charlier, K. Amazzough, B. Henry, B. Pilmis, C. Rouzaud, M. Morgand, F. Touam, C. Louisin, C. Duvivier, O. Lortholary, R. Guery, F. Danion, J. Lourenco, P. Parize, M. Launay, V. Avettand-Fenoel, Paris (Pitié): M.A. Valantin, F. Caby, R. Tubiana, R. Agher, S. Seang, L. Schneider, R. Palich, C. Blanc, C. Katlama, Reims: J.L. Berger, Y. N'Guyen, D. Lambert, D. Lebrun, I. Kmiec, M. 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Subjects
0301 basic medicine, Male, HIV Infections, law.invention, Men who have sex with men, Condoms, 0302 clinical medicine, MESH: Tenofovir, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Emtricitabine, MESH: Sexual Partners, Emtricitabine, Pharmacology (medical), 030212 general & internal medicine, Condom use, Health Policy, MESH: HIV Infections, Infectious Diseases, Sexual Partners, Cohort, cardiovascular system, Female, France, Post-Exposure Prophylaxis, circulatory and respiratory physiology, medicine.drug, Adult, medicine.medical_specialty, Unprotected Sexual Intercourse, MESH: Unsafe Sex, Treatment discontinuation, education, Context (language use), MESH: Multivariate Analysis, Medication Adherence, MESH: Homosexuality, Male, 03 medical and health sciences, MESH: Condoms, Condom, Internal medicine, medicine, Humans, Homosexuality, Male, Tenofovir, Retrospective Studies, MESH: Humans, Unsafe Sex, business.industry, HIV, MESH: Adult, MESH: Retrospective Studies, Odds ratio, MESH: Medication Adherence, 030112 virology, MESH: Male, Discontinuation, Sexual exposure, MESH: France, Multivariate Analysis, business, MESH: Female, MESH: Post-Exposure Prophylaxis
Abstract

International audience; ObjectivesPost-exposure prophylaxis (PEP) care remains a challenge for individuals with potential sexual exposure to HIV in terms of PEP completion and ongoing risk behaviours.MethodsA retrospective analysis was carried out on data from the French Dat’AIDS prevention cohort (NCT03795376) for individuals evaluated for PEP between 2004 and 2017. A multivariable analysis was performed of predictors of both PEP completion and condom use [odds ratios (ORs)] and their associated probabilities (P, with P > 95% being clinically relevant).ResultsOverall, 29 060 sexual exposures to HIV were evaluated for PEP [36% in men who have sex with men (MSM) and 64% in heterosexuals]. Overall, 12 different PEP regimens were offered in 19 240 cases (46%). Tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) was the preferred backbone (n = 14 304; 74%). We observed a shift from boosted protease inhibitor-based regimens to nonnucleoside reverse transcriptase inhibitor- or integrase inhibitor-based regimens in recent years. Overall, 20% of PEP prescriptions were prematurely discontinued. Older age, MSM, intercourse with a sex worker, rape and intercourse with a known HIV-infected source patient were factors associated with increased rates of PEP completion (OR > 1; P > 98%). None of the 12 PEP regimens was associated with premature discontinuation. We also found 12 774 cases of unprotected sexual intercourse (48%). Condom use decreased (OR < 1; P > 99%) with the year of exposure, and was lower in MSM and rape victims. Condom use increased (OR > 1, P > 99%) with age, and was higher in those who had intercourse with a sex worker or with a female partner and in those with knowledge of the partner’s HIV status.ConclusionsWe provide new insights into how rates of condom use and PEP completion might be improved in those receiving PEP by targeting certain groups of individuals for interventions. In particular, youth and MSM at risk should be linked in a prevention-to-care continuum.

Published
2020

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