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1. Decreased darunavir concentrations during once-daily co-administration with maraviroc and raltegravir: OPTIPRIM-ANRS 147 trial

Author

Pressiat, Claire, Hirt, Déborah, Treluyer, Jean-Marc, Zheng, Yi, Morlat, Philippe, Naqvi, Alice, Tran, Laurent, Viard, Jean-Paul, Avettand-Fenoel, Véronique, Rouzioux, Christine, Meyer, Laurence, Cheret, Antoine, Hoen, B, Bourdeaux, C, Delfraissy, J, Goujard, C, Amri, I, Fourn, E, Quertainmont, Y, Môle, M, Rami, A, Durel, A, Diemer, M, Parrinello, M, Allègre, T, Lafeuillade, A, Hittinger, G, Lambry, V, Carrerre, M, Philip, G, Duvivier, C, Consigny, P, Charlier, C, Shoai, M, Touam, F, Pialoux, G, Slama, L, l'Yavanc, T, Mathurin, P, Adda, A, Berrebi, V, Salmon, D, Chakvetadze, E, Tassadit, T, Ousseima, E, Pietri, M, Levy, Y, Lascaux, A, Lelievre, J, Giovanna, M, Dominguez, S, Dumont, C, Katlama, C, Valentin, M, Seang, S, Schneider, L, Kiorza, N, Chermak, A, Ben Abdallah, S, Simon, A, Pichon, F, Pauchard, M, Molina, J, Lascoux, C, Ponscarme, D, Colin de Verdiere, N, Scemla, A, de Castro, N, Rachline, A, Garrait, V, Rozenbaum, W, Ferret, S, Balkan, S, Clavel, F, Tourdjman, M, Lafaurie, M, Aslan, A, Goguel, J, Thierry, S, de Lastours, V, Gallien, S, Pavie, J, Delgado, J, Mededji, C, Veron, R, Abel, S, Pierre-François, S, Baringhton, C, Chennebault, J, Vandamme, Y, Fialaire, P, Rehaiem, S, Rabier, V, Abgueguen, P, Vandenhende, M, Bernard, N, Lacoste, D, Michaux, C, Paccalin, F, Receveur, M, Caldato, S, Delaune, J, Ragnaud, J, Neau, D, Lacaze-Buzy, L, Livrozet, J, Jeanblanc, F, Makhloufi, D, Brunel Dalmas, F, Jourdain, J, Chiarello, P, Yeni, P, Phung, B, Rioux, C, Godard, C, Louni, F, El Alami Talbi, N, Catalano, G, Guiroy, F, Reynes, J, Jacquet, J, Fauchere, V, Merle, C, Lemoine, V, Loriette, M, Morquin, D, Makinson, A, Atoui, N, Tramoni, C, Raffi, F, Allavena, C, Bonnet, B, Bouchez, S, Feuillebois, N, Brunet-François, C, Reliquet, V, Mounoury, O, Morineau-Le-Houssine, P, Billaud, E, Brosseau, D, Hüe, H, Dellamonica, P, Vassallo, M, Leplatois, A, Durant, J, Joulié, A, Souala, F, Michelet, C, Arvieux, C, Tattevin, P, Leroy, H, Revest, M, Fily, F, Chapplain, J, Ratajczak, C, Gras, G, Bernard, L, Dailloux, J, Laplantine, V, Cuzin, L, Marchou, B, Larrigue, S, Chauveau, M, Balsarin, F, Obadia, M, Bonne, S, Huleux, T, Ajana, F, Alcaraz, I, Baclet, V, Melliez, H, Viget, N, de la Tribonniere, X, Aissi, E, Poissy, J, Ravaux, I, Vallon, A, Varan, M, May, T, Letranchant, L, Burty, C, Briaud, A, Wassoumbou, S, Stenzel, M, Bouillon, M, Debab, Y, Caron, F, Gueit, I, Chapuzet, C, Borsa Lebas, F, Etienne, M, Miailhes, P, Perpoint, T, Senechal, A, Schlienger, I, Cotte, L, Augustin Normand, C, Boibieux, A, Ferry, T, Corsini, N, Braun, E, Lippran, J, Biron, F, Chidiac, C, Pailhes, S, Lipman, J, Koffi, J, Thoirain, V, Brochier, C, Greder Belan, A, Therby, A, Monnier, S, Ruquet, M, Richier, L, Prevoteau Du Clary, F, Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine interne et maladies infectieuses [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, Service de Maladies Infectieuses [CHU Nice], Hôpital l'Archet - CHU de Nice, 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) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Diagnostic et de Thérapeutique, Hôpital de l’Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection à VIH, réservoirs, diversité génétique et résistance aux antirétroviraux (ARV) (EA 7327), Laboratoire de Virologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de Médecine Interne - Immunologie Clinique [AP-HP Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Stratégies thérapeutiques contre l'infection VIH et les maladies virales associées [iPLesp] (THERAVIR), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and CHU Pontchaillou [Rennes]

Subjects
Male, 0301 basic medicine, MESH: Raltegravir Potassium, [SDV]Life Sciences [q-bio], HIV Infections, Pharmacology, Maraviroc, MESH: HIV-1, Plasma, chemistry.chemical_compound, Pharmacology (medical), MESH: Anti-HIV Agents, MESH: Maraviroc, Darunavir, MESH: Darunavir, education.field_of_study, MESH: Middle Aged, MESH: HIV Infections, Middle Aged, Viral Load, Infectious Diseases, MESH: Young Adult, Female, MESH: Viral Load, Viral load, medicine.drug, Adult, Microbiology (medical), Anti-HIV Agents, 030106 microbiology, Population, Emtricitabine, Young Adult, 03 medical and health sciences, Pharmacokinetics, Raltegravir Potassium, medicine, Humans, education, MESH: Plasma, Models, Statistical, Ritonavir, MESH: Humans, business.industry, MESH: Adult, Raltegravir, MESH: Male, 030104 developmental biology, chemistry, HIV-1, MESH: Ritonavir, business, MESH: Female, MESH: Models, Statistical
Abstract

International audience; BackgroundThe OPTIPRIM-ANRS 147 trial compared intensive combination ART (darunavir/ritonavir, tenofovir disoproxil fumarate/emtricitabine, raltegravir and maraviroc) started early during primary HIV-1 infection with standard tritherapy with darunavir/ritonavir, tenofovir disoproxil fumarate and emtricitabine. From month 6 to 18, the percentage of viral load values

Published
2018

2. Ritonavir-boosted darunavir combined with raltegravir or tenofovir–emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial

Author

Michal Odermarsky, Andrea Antinori, Nina Friis-Moller, Jean-michel Molina, Manuel Marquez, Magnus Gisslen, Mili Estee Torok, Clifford Leen, CARLO FEDERICO PERNO, Vicente Soriano, Mark Boyd, Pythia Nieuwkerk, Linos Vandekerckhove, Anne-Laure Knellwolf, Juan González-García, MAURIZIO MASSELLA, Elizabeth C George, STEFANO VELLA, André Cabié, Laura Richert, Juan Berenguer, Hernando Knobel, Jose Arribas, Julie Fox, Joaquín Portilla, Maladies infectieuses et tropicales, Fonctions et dysfonctions épithéliales - UFC (EA 4267) (FDE), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Inserm, Service des Maladies Infectieuses et Tropicales [CHU Saint Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Development and Differentiation, Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Stockholm University Library (SUB), Stockholm University, Service de maladies infectieuses et tropicales [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de médecine interne et maladies infectieuses, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Aménagement, Développement, Environnement, Santé et Sociétés (ADES), Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Bordeaux Montaigne, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), DARMIGNY, Sandrine, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Rennes-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Université Bordeaux Segalen - Bordeaux 2-Université Bordeaux Montaigne-Centre National de la Recherche Scientifique (CNRS), Raffi, Franã§oi, Babiker, Abdel G., Richert, Laura, Molina, Jean michel, George, Elizabeth C., Antinori, Andrea, Arribas, Jose R., Grarup, Jesper, Hudson, Fleur, Schwimmer, Christine, Saillard, Juliette, Wallet, Cã©drick, Jansson, Per O., Allavena, Clotilde, Van Leeuwen, Remko, Delfraissy, Jean franã§oi, Vella, Stefano, Chãªne, Geneviãve, Pozniak, Anton, Neat001/anrs143 Study, Group, Castagna, Antonella, Global Health, Amsterdam institute for Infection and Immunity, Infectious diseases, Amsterdam Public Health, Medical Psychology, Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, and Université Bordeaux Segalen - Bordeaux 2-Université Bordeaux Montaigne (UBM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: CD4 Lymphocyte Count, [SDV]Life Sciences [q-bio], MESH: Sulfonamides, Lopinavir/ritonavir, HIV Infections, Kaplan-Meier Estimate, Pharmacology, Deoxycytidine, MESH: HIV-1, Emtricitabine, MESH: Anti-HIV Agents, MESH: Treatment Outcome, Darunavir, media_common, Sulfonamides, MESH: Middle Aged, MESH: Drug Resistance, Viral, Medicine (all), Standard treatment, MESH: HIV Infections, General Medicine, Middle Aged, Pyrrolidinones, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, Drug Therapy, Combination, Female, MESH: Cholesterol, HDL, MESH: Organophosphonates, MESH: Cholesterol, LDL, medicine.drug, Adult, medicine.medical_specialty, MESH: Adenine, Anti-HIV Agents, Organophosphonates, MESH: Pyrrolidinones, Raltegravir Potassium, Internal medicine, Drug Resistance, Viral, medicine, Humans, media_common.cataloged_instance, European union, Tenofovir, MESH: Kaplan-Meier Estimate, MESH: Humans, Ritonavir, business.industry, Adenine, MESH: Deoxycytidine, Cholesterol, HDL, MESH: Adult, Cholesterol, LDL, Raltegravir, MESH: Male, CD4 Lymphocyte Count, MESH: Drug Therapy, Combination, Regimen, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, HIV-1, MESH: Ritonavir, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female
Abstract

Summary Background Standard first-line antiretroviral therapy for HIV-1 infection includes two nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs), but these drugs have limitations. We assessed the 96 week efficacy and safety of an NtRTI-sparing regimen. Methods Between August, 2010, and September, 2011, we enrolled treatment-naive adults into this randomised, open-label, non-inferiority trial in treatment-naive adults in 15 European countries. The composite primary outcome was change to randomised treatment before week 32 because of insufficient virological response, no virological response by week 32, HIV-1 RNA concentration 50 copies per mL or higher at any time after week 32; death from any cause; any new or recurrent AIDS event; or any serious non-AIDS event. Patients were randomised in a 1:1 ratio to receive oral treatment with 400 mg raltegravir twice daily plus 800 mg darunavir and 100 mg ritonavir once daily (NtRTI-sparing regimen) or tenofovir–emtricitabine in a 245 mg and 200 mg fixed-dose combination once daily, plus 800 mg darunavir and 100 mg ritonavir once daily (standard regimen). This trial was registered with ClinicalTrials.gov, number NCT01066962. Findings Of 805 patients enrolled, 401 received the NtRTI-sparing regimen and 404 the standard regimen, with median follow-up of 123 weeks (IQR 112–133). Treatment failure was seen in 77 (19%) in the NtRTI-sparing group and 61 (15%) in the standard group. Kaplan-Meier estimated proportions of treatment failure by week 96 were 17·8% and 13·8%, respectively (difference 4·0%, 95% CI −0·8 to 8·8). The frequency of serious or treatment-modifying adverse events were similar (10·2 vs 8·3 per 100 person-years and 3·9 vs 4·2 per 100 person-years, respectively). Interpretation Our NtRTI-sparing regimen was non-inferior to standard treatment and represents a treatment option for patients with CD4 cell counts higher than 200 cells per μL. Funding European Union Sixth Framework Programme, Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck Laboratories.

Published
2014

3. Intensification of Antiretroviral Therapy through Addition of Enfuvirtide in Naive HIV-1-Infected Patients with Severe Immunosuppression Does Not Improve Immunological Response: Results of a Randomized Multicenter Trial (ANRS 130 Apollo)

Author

Charlotte Charpentier, Véronique Joly, Carine Grondin, Sophie Tabuteau, Yazdan Yazdanpanah, François Raffi, André Cabié, Catherine Fagard, Patrick Yeni, Geneviève Chêne, Nathalie Colin de Verdiere, Diane Descamps, Service de maladies infectieuses et tropicales, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie, 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), Modélisation, Aide à la Décision, et Coût-Efficacité en Maladies Infectieuses (ATIP-Avenir Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Maladies Infectieuses et Tropicales, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Maladies infectieuses et tropicales, Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles et de la Guyane (UAG), ANRS (French National Agency for Research on AIDS and Viral Hepatitis), ANRS 130 Apollo Trial Group, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], 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], Le Corre, Morgane, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Université Bordeaux Segalen - Bordeaux 2

Subjects
CD4-Positive T-Lymphocytes, Cyclopropanes, Male, Enfuvirtide, MESH: CD4 Lymphocyte Count, MESH: HIV Envelope Protein gp41, HIV Infections, Deoxycytidine, MESH: Antiretroviral Therapy, Highly Active, Lopinavir, MESH: HIV-1, chemistry.chemical_compound, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, Emtricitabine, Pharmacology (medical), 030212 general & internal medicine, MESH: Anti-HIV Agents, MESH: Peptide Fragments, MESH: Treatment Outcome, 0303 health sciences, MESH: Lopinavir, MESH: CD4-Positive T-Lymphocytes, virus diseases, MESH: HIV Infections, Viral Load, HIV Envelope Protein gp41, 3. Good health, Drug Combinations, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Treatment Outcome, Infectious Diseases, MESH: RNA, Viral, MESH: Benzoxazines, Alkynes, RNA, Viral, Female, medicine.symptom, MESH: Viral Load, MESH: Organophosphonates, Viral load, medicine.drug, Adult, medicine.medical_specialty, MESH: Adenine, MESH: Immune Tolerance, Efavirenz, Anti-HIV Agents, Organophosphonates, Antiviral Agents, Asymptomatic, 03 medical and health sciences, Multicenter trial, Internal medicine, Immune Tolerance, medicine, Humans, Tenofovir, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Drug Combinations, Pharmacology, MESH: Humans, Ritonavir, 030306 microbiology, business.industry, Adenine, MESH: Deoxycytidine, MESH: Adult, MESH: Male, Peptide Fragments, Benzoxazines, CD4 Lymphocyte Count, Surgery, chemistry, HIV-1, MESH: Ritonavir, business, MESH: Female
Abstract

We studied whether addition of enfuvirtide (ENF) to a background combination antiretroviral therapy (cART) would improve the CD4 cell count response at week 24 in naive patients with advanced HIV disease. ANRS 130 Apollo is a randomized study, conducted in naive HIV-1-infected patients, either asymptomatic with CD4 counts of 3 or stage B/C disease with CD4 counts of 3 . Patients received tenofovir-emtricitabine with lopinavir-ritonavir (LPV/r) or efavirenz and were randomized to receive ENF for 24 weeks (ENF arm) or not (control arm). The primary endpoint was the proportion of patients with CD4 counts of ≥200/mm 3 at week 24. A total of 195 patients were randomized: 73% had stage C disease, 78% were male, the mean age was 44 years, the median CD4 count was 30/mm 3 , and the median HIV-1 RNA load was 5.4 log 10 copies/ml. Eighty-one percent of patients received LPV/r. One patient was lost to follow-up, and eight discontinued the study (four in each arm). The proportions of patients with CD4 counts of ≥200/mm 3 at week 24 were 34% and 38% in the ENF and control arms, respectively ( P = 0.53). The proportions of patients with HIV-1 RNA loads of P < 0.02), and the proportion reached 79% in both arms at week 48. Twenty (20%) and 12 patients (13%) in the ENF and control arms, respectively, experienced at least one AIDS event during follow-up ( P = 0.17). Although inducing a more rapid virological response, addition of ENF to a standard cART does not improve the immunological outcome in naive HIV-infected patients with severe immunosuppression.

Published
2013

4. Differential effect of HIV protease inhibitors on adipogenesis

Author

Cécile Vernochet, Stéphane Azoulay, Danièle Duval, Roger Guedj, Gérard Ailhaud, Christian Dani, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Laboratoire de Chimie des Molécules Bioactives et des Arômes (LCMBA), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

Subjects
MESH: Cell Differentiation, MESH: 3T3 Cells, viruses, MESH: Nelfinavir, Immunology, MESH: Saquinavir, MESH: Sulfonamides, MESH: Pyrimidinones, Enzyme-Linked Immunosorbent Assay, Indinavir, Mice, Inbred Strains, Pyrimidinones, MESH: Mice, Inbred Strains, Lopinavir, Cell Line, Mice, immune system diseases, Adipocytes, Animals, Immunology and Allergy, MESH: Animals, Furans, MESH: Mice, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Saquinavir, MESH: Adipocytes, MESH: HIV Protease Inhibitors, Sulfonamides, Nelfinavir, Ritonavir, MESH: Carbamates, MESH: Indinavir, virus diseases, MESH: Enzyme-Linked Immunosorbent Assay, Cell Differentiation, 3T3 Cells, HIV Protease Inhibitors, biochemical phenomena, metabolism, and nutrition, MESH: Cell Line, Infectious Diseases, MESH: Ritonavir, Carbamates
Abstract

International audience; OBJECTIVES: Lipodystrophy is a major side effect of HIV protease inhibitor (PI) antiretroviral therapy. It has been shown that protease inhibitors interfere in vitro with adipocyte differentiation. However, there is no evidence that PIs accumulate into preadipocytes and adipocytes and that intra-cellular accumulation is sufficient to alter differentiation. We assessed the effect of six different PIs on the differentiation of cells from four clonal lines. We also studied the capacity of ritonavir to accumulate both into drug-sensitive and drug-resistant cultured adipocytes. METHODS: Adipocyte differentiation of mouse 3T3-F442A, 3T3-L1 and Ob1771 cells as well as embryonic stem cells were investigated at pharmacological concentrations of indinavir, saquinavir, ritonavir, amprenavir, nelfinavir and lopinavir. We used a sensitive ELISA to determine intracellular concentration of ritonavir from 3T3-L1 and Ob1771 preadipocytes. RESULTS: Nelfinavir and lopinavir inhibited adipocyte differentiation whereas amprenavir was ineffective. Indinavir, saquinavir and ritonavir inhibited differentiation of 3T3-L1 and 3T3-F442A cells but did not alter differentiation of either Ob1771 or embryonic stem cells. We showed that ritonavir accumulated in preadipocytes and fully differentiated 3T3-L1 adipocytes as a function of its extracellular concentration. Although Ob1771 cells were resistant and 3T3-L1 cells were sensitive to ritonavir, the drug accumulated to similar levels in both cases. CONCLUSIONS: Protease inhibitors inhibit adipocyte differentiation depending on the cell model used. We showed for the first time that ritonavir accumulates into preadipocytes and adipocytes, suggesting a direct effect on intracellular targets. However, intracellular accumulation was clearly not sufficient as Ob1771 cells remained resistant to the inhibitory effect of ritonavir.

Published
2003

5. Effect of adherence as measured by MEMS, ritonavir boosting, and CYP3A5 genotype on atazanavir pharmacokinetics in treatment-naive HIV-infected patients

Author

Aurélie Barrail-Tran, Bernard Vrijens, Radojka M. Savic, F Mentré, Nembot G, Céline Verstuyft, Xavière Panhard, Diane Descamps, Xavier Duval, Cécile Goujard, Anne-Marie Taburet, Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques (U738 / UMR_S738), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Bioengineering and Therapeutic Sciences, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Service de pharmacie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Faculté de Pharmacie, Université Paris-Sud - Paris 11 (UP11), Laboratoire de Virologie, 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), Service de génétique moléculaire, pharmacogénétique et hormonologie, AARDEX Group, Service de médecine interne et maladies infectieuses, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, the ANRS 134 - COPHAR 3 study group, Comets, Emmanuelle, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), University of California [San Francisco] (UCSF), University of California-University of California, and Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Male, Pyridines, MESH: Drug Interactions, HIV Infections, Pharmacology, Deoxycytidine, 030226 pharmacology & pharmacy, MESH: Genotype, 0302 clinical medicine, immune system diseases, Cytochrome P-450 CYP3A, Emtricitabine, Drug Interactions, Pharmacology (medical), Population pharmacokinetics, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Aged, MESH: Cytochrome P-450 CYP3A, 0303 health sciences, MESH: Middle Aged, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], virus diseases, MESH: HIV Infections, Middle Aged, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, MESH: Nonlinear Dynamics, MESH: Young Adult, MESH: Oligopeptides, Drug Therapy, Combination, Female, Oligopeptides, MESH: Organophosphonates, medicine.drug, Adult, MESH: Adenine, Genotype, Atazanavir Sulfate, Organophosphonates, MESH: Pharmacogenetics, Models, Biological, Article, Medication Adherence, Atazanavir, Young Adult, 03 medical and health sciences, Pharmacotherapy, Pharmacokinetics, medicine, Humans, Dosing, Tenofovir, Alleles, Aged, MESH: HIV Protease Inhibitors, Ritonavir, MESH: Humans, 030306 microbiology, business.industry, Adenine, MESH: Alleles, MESH: Pyridines, MESH: Deoxycytidine, MESH: Models, Biological, MESH: Adult, HIV Protease Inhibitors, MESH: Medication Adherence, MESH: Male, MESH: Drug Therapy, Combination, Nonlinear Dynamics, Adherence, Pharmacogenetics, MESH: Ritonavir, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, human activities, MESH: Female
Abstract

International audience; We investigated population pharmacokinetics and pharmacogenetics of ritonavir-boosted atazanavir (ATV), using drug intake times exactly recorded by the Medication Event Monitoring System. The ANRS 134-COPHAR 3 trial was conducted in 35 HIV-infected treatment-naive patients. ATV (300 mg), ritonavir (100 mg), and tenofovir (300 mg) + emtricitabine (200 mg), in bottles with MEMS caps, were taken once daily for 6 months. Six blood samples were collected at week 4 to measure drug concentrations, and trough levels were measured bimonthly. A model integrating ATV and ritonavir pharmacokinetics and pharmacogenetics used nonlinear mixed effects. Use of exact dosing data halved unexplained variability in ATV clearance. The ritonavir-ATV interaction model suggested that optimal boosting effect is achievable at lower ritonavir exposures. Patients with at least one copy of the CYP3A5*1 allele exhibited 28% higher oral clearance. We provide evidence that variability in ATV pharmacokinetics is defined by adherence, CYP3A5 genotype, and ritonavir exposure.

Published
2012

6. Long-term efficacy and safety of raltegravir, etravirine, and darunavir/ritonavir in treatment-experienced patients: week 96 results from the ANRS 139 TRIO trial

Author

Fagard, Catherine, Colin, Céline, Charpentier, Charlotte, Rami, Agathe, Jacomet, Christine, Yeni, Patrick, Vittecoq, Daniel, Katlama, Christine, Molina, Jean-Michel, Descamps, Diane, Chêne, Geneviève, Yazdanpanah, Yazdan, Michelet, Christian, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie, 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), Impacts de la puissance antivirale des antirétroviraux et de la résistance virale sur les stratégies thérapeutiques des infections par les virus de l'immunodéficience humaine, Université Paris Diderot - Paris 7 (UPD7), Service des Maladies Infectieuses et Tropicales, AP-HP, Hôpital Paul Brousse, Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Maladies Infectieuses et Tropicales, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Modélisation, Aide à la Décision, et Coût-Efficacité en Maladies Infectieuses (ATIP-Avenir Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), French National Agency for Research on AIDS and Viral Hepatitis (ANRS), ANRS 139 TRIO Trial Group, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], 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
Male, Enfuvirtide, MESH: Sulfonamides, Etravirine, HIV Infections, Pharmacology, Raltegravir Potassium, 0302 clinical medicine, MESH: Drug Resistance, Multiple, Viral, Pharmacology (medical), 030212 general & internal medicine, Darunavir, 0303 health sciences, Sulfonamides, MESH: Middle Aged, biology, MESH: Follow-Up Studies, MESH: HIV Infections, Middle Aged, Pyrrolidinones, 3. Good health, Pyridazines, Infectious Diseases, MESH: RNA, Viral, Lentivirus, RNA, Viral, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, raltegravir, medicine.drug, Adult, medicine.medical_specialty, MESH: Pyrrolidinones, 03 medical and health sciences, Drug Resistance, Multiple, Viral, Internal medicine, MESH: Pyridazines, Nitriles, medicine, Humans, darunavir/ritonavir, etravirine, MESH: HIV Protease Inhibitors, Ritonavir, MESH: Humans, 030306 microbiology, business.industry, multidrug resistant, HIV, MESH: Adult, HIV Protease Inhibitors, Raltegravir, biology.organism_classification, MESH: Male, Regimen, Pyrimidines, MESH: Ritonavir, business, MESH: Female, Follow-Up Studies
Abstract

International audience; Among 103 patients with multidrug-resistant HIV who initiated raltegravir, etravirine, and darunavir/ritonavir-containing regimen in the ANRS 139 TRIO trial, 100 participated in extended follow-up and continued study treatment until week 96. Among them, 87 (87%) received an optimized background therapy including either nucleoside reverse transcriptase inhibitors or enfuvirtide, they were 78 (78%) at week 96. At week 96, 88% achieved durable virologic response (

Published
2012

7. Effectiveness and safety of saquinavir/ritonavir in HIV-infected pregnant women: INEMA cohort

Author

Véronique Reliquet, L. De Saint Martin, G. Le Moal, C. Brunet, E. Bui, N. Winer, Nicolas Venisse, François Raffi, P. Perfezou, T. Jovelin, Service de maladies infectieuses et tropicales [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Pharmacocinétique (POITIERS - Pharmacocinétique), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Gynécologie Obstétrique (NANTES - Gynéco Obstétrique), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Médecine Interne, Maladies Infectieuses et Tropicales [CHU Poitiers], Service de Pneumologie (CHIC - Pneumologie), CHIC Quimper, Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), and Service des maladies infectieuses et tropicales [CHU Nantes]

Subjects
Male, MESH: CD4 Lymphocyte Count, [SDV]Life Sciences [q-bio], HIV Infections, MESH: HIV-1, Cohort Studies, MESH: Pregnancy, 0302 clinical medicine, MESH: HIV-2, Pregnancy, Medicine, 030212 general & internal medicine, Prospective Studies, Pregnancy Complications, Infectious, 10. No inequality, MESH: Cohort Studies, Saquinavir, MESH: Treatment Outcome, 0303 health sciences, Vaginal delivery, Obstetrics, MESH: Infant, Newborn, Pregnancy Outcome, MESH: Zidovudine, MESH: HIV Infections, Viral Load, 3. Good health, MESH: Infectious Disease Transmission, Vertical, Infectious Diseases, Treatment Outcome, MESH: Young Adult, Cohort, Drug Therapy, Combination, Female, Chemical and Drug Induced Liver Injury, MESH: Viral Load, Viral load, Zidovudine, medicine.drug, Adult, MESH: Drug-Induced Liver Injury, medicine.medical_specialty, MESH: Saquinavir, 03 medical and health sciences, Young Adult, Humans, MESH: Pregnancy Complications, Infectious, Viremia, MESH: Viremia, Adverse effect, MESH: HIV Protease Inhibitors, MESH: Humans, Ritonavir, 030306 microbiology, business.industry, Infant, Newborn, MESH: Adult, HIV Protease Inhibitors, MESH: Pregnancy Outcome, medicine.disease, Delivery, Obstetric, MESH: Male, MESH: Prospective Studies, Infectious Disease Transmission, Vertical, Surgery, CD4 Lymphocyte Count, MESH: Drug Therapy, Combination, Regimen, HIV-2, HIV-1, MESH: Ritonavir, MESH: Delivery, Obstetric, business, MESH: Female
Abstract

International audience; OBJECTIVE: The authors had for aim to describe the effectiveness and the safety of a saquinavir/ritonavir (SQV/r) regimen, 1000/100mg twice daily, in HIV-infected pregnant patients. PATIENTS AND METHOD: We made a prospective and observational study of HIV positive female patients beginning or going on SQV/r antiretroviral treatment (ART) during pregnancy. RESULTS: Sixty-two patients were enrolled from July 2007 to June 2009 in 10 infectious diseases units in France. Thirty-six women (group 1) were ART naive on inclusion, 20 (group 2) had been previously treated and then switched to SQV/r, six (group 3) were treated with SQV/r before pregnancy. 58 patients delivered while on SQV/r regimen after a median pregnancy duration of 39 WA. Eighty percent had a viral load below 50 copies/mL and 93% below 400 copies/mL: respectively 77% and 93.5% in group 1, 83% and 89% in group 2, 83% and 100% in group 3. The median SQV minimum concentrations (C(min)) measured at the third trimester and at delivery were adequate, respectively 0.91 mg/L and 0.86 mg/L. Most women (52%) had a vaginal delivery; 12 (21%) had an elective caesarean section, for obstetrics factors in eight cases. None of the newborns were HIV-infected at 6 months of age (n = 59, one death at day 3). Only one severe adverse event occurred due to saquinavir (maternal grade 3 hepatotoxicity). CONCLUSION: SQV/r 1000/100mg twice daily seems to be effective and safe in HIV-infected pregnant women with adequate saquinavir C(min).

Published
2012

8. Effects of HIV protease inhibitors on progression of monocrotaline- and hypoxia-induced pulmonary hypertension in rats

Author

Aline Perrin, Serge Adnot, Elisabeth Marcos, Valérie Amsellem, Olivier Sitbon, Jean-Luc Dubois-Randé, Laurent Savale, Guillaume Gary-Bobo, Jérémy Brégeon, Dominique Rideau, Pierre Pacaud, Amal Houssaini, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de chirurgie thoracique et d'anatomopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Hôtel Dieu, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Service de pneumologie [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Guellaen, Georges

Subjects
Male, muscle, MESH: Sulfonamides, MESH: Anoxia, Blood Pressure, 030204 cardiovascular system & hematology, Pharmacology, MESH: Animals, Newborn, MESH: Antiretroviral Therapy, Highly Active, MESH: Monocrotaline, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, HIV Protease Inhibitor, MESH: Animals, Hypoxia, remodeling, Sulfonamides, 0303 health sciences, Monocrotaline, Nelfinavir, MESH: Blood Pressure, 3. Good health, AIDS, MESH: Cell Division, medicine.symptom, Cardiology and Cardiovascular Medicine, Cell Division, medicine.drug, smooth, MESH: Antiviral Agents, MESH: Hemodynamics, MESH: Rats, Hypertension, Pulmonary, MESH: Nelfinavir, MESH: Pulmonary Artery, Pulmonary Artery, Antiviral Agents, Article, Pulmonary heart disease, 03 medical and health sciences, Physiology (medical), [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, pulmonary heart disease, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Rats, Wistar, Furans, Protein kinase B, 030304 developmental biology, MESH: HIV Protease Inhibitors, Ritonavir, MESH: Hypertension, Pulmonary, MESH: Carbamates, business.industry, Hemodynamics, HIV Protease Inhibitors, MESH: Rats, Wistar, Hypoxia (medical), medicine.disease, Pulmonary hypertension, MESH: Male, Rats, Blood pressure, Animals, Newborn, Immunology, MESH: Ritonavir, Carbamates, business
Abstract

Background— Pulmonary hypertension (PH) is among the complications of HIV infection. Combination antiretroviral therapy may influence the progression of HIV-related PH. Because Akt signaling is a potential molecular target of HIV protease inhibitors (HPIs), we hypothesized that these drugs altered monocrotaline- and hypoxia-induced PH in rats by downregulating the Akt pathway, thereby inhibiting pulmonary artery smooth muscle cell proliferation. Methods and Results— Daily treatment with each of 3 first-generation HPIs (ritonavir 30 mg/kg, amprenavir 100 mg/kg, and nelfinavir 500 mg/kg) started 3 weeks after a subcutaneous monocrotaline injection (60 mg/kg) substantially diminished pulmonary artery pressure, right ventricular hypertrophy, number of muscularized pulmonary vessels, pulmonary arterial wall thickness, and proliferating pulmonary vascular Ki67-labeled cells without affecting vessel caspase 3 staining. HPI treatment partially prevented the development of hypoxia- and monocrotaline-induced PH. Monocrotaline-induced PH was associated with marked activation of Akt signaling in the lungs and proximal pulmonary arteries, with increases in phosphorylated Akt, phosphorylated glycogen-synthase-kinase-3β (GSK3), and phosphorylated endothelial nitric oxide synthase, all of which decreased markedly after treatment with each HPI. In contrast, PH-associated increases in phosphorylated extracellular signal-related kinase 1/2 and myosin light-chain phosphatase were unaltered by the HPIs. The 3 HPIs and the phosphatidylinositol 3-kinase inhibitor LY294002 inhibited platelet-derived growth factor–induced phosphorylation of Akt and GSK3 in cultured pulmonary artery smooth muscle cells and blocked cell proliferation; this last effect was abolished by the GSK3 inhibitor SB216763. Conclusion— These results support an effect of HPIs on pulmonary vascular remodeling mediated by inhibition of Akt phosphorylation and consequently of pulmonary artery smooth muscle cell proliferation.

Published
2010

9. The use of drug resistance algorithms and genotypic inhibitory quotient in prediction of lopinavir-ritonavir treatment response in human immunodeficiency virus type 1 protease inhibitor-experienced patients

Author

Pierre Tattevin, Annick Ruffault, Danièle Bentué-Ferrer, Christian Michelet, Anne Maillard, Olivier Tribut, Cédric Arvieux, Jean-Marc Chapplain, Unité de Rétrovirologie, Hôpital Pontchaillou, Service des maladies infectieuses et réanimation médicale [Rennes] = Infectious Disease and Intensive Care [Rennes], CHU Pontchaillou [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université de Rennes (UR)

Subjects
Male, Salvage therapy, Lopinavir/ritonavir, HIV Infections, Drug resistance, Lopinavir, Cohort Studies, MESH: Genotype, MESH: HIV-1, 0302 clinical medicine, 030212 general & internal medicine, MESH: Cohort Studies, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Drug Resistance, Viral, Genotypic inhibitory quotient, MESH: Lopinavir, MESH: HIV Infections, Middle Aged, Viral Load, 3. Good health, Infectious Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Viral disease, MESH: Viral Load, Viral load, Algorithm, Algorithms, medicine.drug, Adult, Genotype, MESH: Pyrimidinones, MESH: Algorithms, Pyrimidinones, Biology, Sensitivity and Specificity, 03 medical and health sciences, Virology, Drug Resistance, Viral, medicine, Humans, Aged, Retrospective Studies, MESH: HIV Protease Inhibitors, Ritonavir, MESH: Humans, Receiver operating characteristic, 030306 microbiology, Genotypic resistance interpretation's algorithms, MESH: Adult, MESH: Retrospective Studies, HIV Protease Inhibitors, MESH: Male, MESH: Sensitivity and Specificity, HIV-1, MESH: Ritonavir, MESH: Female
Abstract

International audience; BACKGROUND: Different approaches using genotypic, pharmacokinetic parameters or combination of both have been recently developed to monitor antiretroviral treatment in HIV-1-infected individuals. Their uses in clinical practice may improve the benefit of protease inhibitor-based salvage therapy while reducing treatment toxicity and emergence of viral resistance. OBJECTIVES: To assess the prediction of genotypic inhibitory quotient (GIQ) using different genotypic drug resistance interpretation's algorithms and lopinavir plasma concentration in PI-experienced patients treated by lopinavir/ritonavir (LPV/r). Genotypic susceptibility score (GSS) was also evaluated. STUDY DESIGN: Forty-seven HIV-1 PI-experienced, but LPV naïve patients were included in a retrospective cohort study. Plasma HIV-1 viral load (VL), CD4 cell count and LPV plasma concentrations were assessed at weeks (W) 12 and 24. Interpretation of baseline resistance genotype was achieved according to four different algorithms and GSS calculated using two expert systems. GIQ was defined as the ratio of LPV concentration to the number of LPV resistance mutations at day 0 (D0) and patients classified by units of GIQ. The end point of the study was the virological response expressed in HIV VL median decrease from D0 to W24. RESULTS: The overall median VL decrease from D0 to W24 was -2.42 log(10)copies/mL and 60% of patients had VL below 400 copies/mL. The LPV mutation score was predictive of response for all algorithms whereas plasma concentrations of LPV were not. Mean VL decrease was greater for higher GIQ classes and difference reached statistical significance at W24. When considering virological response at W24, GSS calculated with ANRS and Stanford system were good predictor scores as areas under the receiver operating characteristics (ROC) curves were 0.76 for both. CONCLUSION: GIQ was found to be a useful drug-monitoring tool which could be helpful in targeting LPV concentrations in order to achieve long-term undetectable viral load, particularly in genotypic resistant patients.

Published
2007

10. Resistance-Associated Loss of Viral Fitness in Human Immunodeficiency Virus Type 1: Phenotypic Analysis of Protease andgag Coevolution in Protease Inhibitor-Treated Patients

Author

Caroline Petit, François Clavel, Fabrizio Mammano, Oncologie virale, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported in part by the Agence Française de Recherches sur le Sida (ANRS). F.M. is the recipient of a fellowship from ANRS., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Drug Resistance, Microbial, medicine.medical_treatment, viruses, HIV Infections, MESH: Amino Acid Sequence, MESH: HIV-1, HIV Protease, HIV Protease Inhibitor, MESH: Anti-HIV Agents, Saquinavir, MESH: Evolution, Molecular, Cell Line, Transformed, 0303 health sciences, Drug Resistance, Microbial, MESH: HIV Infections, Phenotype, 3. Good health, MESH: Gene Products, gag, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, medicine.drug, Proteases, gag, Anti-HIV Agents, Immunology, Molecular Sequence Data, MESH: Saquinavir, Gene Products, gag, Viral Pathogenesis and Immunity, Biology, Cleavage (embryo), MESH: Phenotype, Microbiology, Evolution, Molecular, 03 medical and health sciences, MESH: HIV Protease, Virology, medicine, Humans, Gene Products, Amino Acid Sequence, MESH: Cell Line, Transformed, 030304 developmental biology, MESH: HIV Protease Inhibitors, Protease, Ritonavir, MESH: Humans, MESH: Molecular Sequence Data, 030306 microbiology, HIV Protease Inhibitors, NS2-3 protease, Insect Science, MESH: HeLa Cells, HIV-1, MESH: Ritonavir, HeLa Cells
Abstract

We have studied the phenotypic impact of adaptative Gag cleavage site mutations in patient-derived human immunodeficiency virus type 1 (HIV-1) variants having developed resistance to the protease inhibitor ritonavir or saquinavir. We found that Gag mutations occurred in a minority of resistant viruses, regardless of the duration of the treatment and of the protease mutation profile. Gag mutations exerted only a partial corrective effect on resistance-associated loss of viral fitness. Reconstructed viruses with resistant proteases displayed multiple Gag cleavage defects, and in spite of Gag adaptation, several of these defects remained, explaining the limited corrective effect of cleavage site mutations on fitness. Our data provide clear evidence of the interplay between resistance and fitness in HIV-1 evolution in patients treated with protease inhibitors.

Published
1998

11. Increased Risk of Renal Stones in Patients Treated With Atazanavir

Author

Matthieu Revest, Cédric Arvieux, Jean-Marc Chapplain, Pierre Tattevin, Christian Michelet, Maja Ratajczak-Enselme, Service des maladies infectieuses et réanimation médicale [Rennes] = Infectious Disease and Intensive Care [Rennes], 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 ), 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
Male, Microbiology (medical), medicine.medical_specialty, Anti-HIV Agents, Pyridines, Urology, HIV Infections, MESH: Antiretroviral Therapy, Highly Active, Kidney Calculi, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Interquartile range, Antiretroviral Therapy, Highly Active, MESH: Kidney Calculi, Humans, Medicine, In patient, 030212 general & internal medicine, MESH: Anti-HIV Agents, Risk factor, 10. No inequality, ComputingMilieux_MISCELLANEOUS, MESH: HIV Protease Inhibitors, 030304 developmental biology, 0303 health sciences, Ritonavir, MESH: Humans, business.industry, Incidence (epidemiology), MESH: Pyridines, Lopinavir, HIV Protease Inhibitors, MESH: HIV Infections, MESH: Male, 3. Good health, Surgery, Atazanavir, Infectious Diseases, Increased risk, MESH: Oligopeptides, MESH: Ritonavir, Female, business, Oligopeptides, MESH: Female, human activities, medicine.drug
Abstract

TO THE EDITOR—We read with much interest the recent study of Hamada et al on the incidence of renal stones among human immunodeficiency virus–infected patients on ritonavir-boosted atazanavir (ATV/r) [1]. Although their study was limited by its design (retrospective monocentric), the authors convincingly demonstrated that ATV/r use is a strong and independent risk factor for clinically significant renal stones. However, 3 limitations were not addressed in the discussion. First, given that >70% of patients in the “other protease inhibitors [PIs] group” were receiving ritonavir-boosted lopinavir (LPV/r), the authors’ conclusion that “the incidence of renal stones is substantially higher among patients in the ATV/r group, compared with patients in the other PIs group” only applies to the comparison of renal stones incidence between patients receiving ATV/r and those receiving LPV/r. For the other PIs, sample sizes do not allow such a conclusion. Second, the median observation period was 8 months longer for patients receiving ATV/r (31.0 months; interquartile range [IQR], 15.0–48.7), than for patients receiving other PIs (23.0 months; IQR, 10.3–42.4). Given that the median time from the commencement of antiretroviral treatment to the diagnosis of renal stones was 24.5 months (IQR, 14.7– 34.6), the longer observation period for patients receiving ATV/r probably overestimated the increased risk of renal stones in this group. Last, although the authors included only patients receiving ritonavir-boosted ATV in the “ATV group” (inclusion criteria), patients treated with unboosted PIs could be included in the “other PIs group”: By increasing drug exposure, ritonavir boosting is likely to increase the risk of drug-related renal stones, whatever the companion PI. Hence, allowing unboosted PI in one arm, and not in the other, may also result in an overestimation of the increased risk of renal stones associated with the use of ATV, as compared to other PIs. That being said, Hamada et al are to be commended for the clever design of their monocentric study: Although the magnitude of the effect of ATV on the risk of renal stones may have been somewhat overestimated, their conclusion is robust, and adds another brick in the wall, supporting previous reports that ATV is associated with an increased risk of clinically significant renal stones [2] and cholelithiasis [3]. Note

Published
2013

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