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8 results on '"HIV-1/drug effects/genetics"'

1. Heritability of the HIV-1 reservoir size and decay under long-term suppressive ART

Author

Laura N Walti, Susana Posada Céspedes, Enos Bernasconi, Pietro Vernazza, Chenjie Wan, Matthieu Perreau, Huldrych F. Günthard, François Blanquart, Nadine Bachmann, Sabine Yerly, Teja Turk, Jacques Fellay, Volker Roth, Thomas Klimkait, Manuel Battegay, Jasmina Bogojeska, Niko Beerenwinkel, Venelin Mitov, Karin J. Metzner, Kathrin Neumann, Matthias Cavassini, Jürg Böni, Alexandra Calmy, Roger D. Kouyos, University hospital of Zurich [Zurich], Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Zurich, Kouyos, Roger D, Kaiser, Laurent, Swiss HIV Cohort Study, Anagnostopoulos, A., Battegay, M., Bernasconi, E., Böni, J., Braun, D.L., Bucher, H.C., Calmy, A., Cavassini, M., Ciuffi, A., Dollenmaier, G., Egger, M., Elzi, L., Fehr, J., Fellay, J., Furrer, H., Fux, C.A., Günthard, H.F., Haerry, D., Hasse, B., Hirsch, H.H., Hoffmann, M., Hösli, I., Huber, M., Kahlert, C., Kaiser, L., Keiser, O., Klimkait, T., Kouyos, R.D., Kovari, H., Ledergerber, B., Martinetti, G., de Tejada, B.M., Marzolini, C., Metzner, K.J., Müller, N., Nicca, D., Paioni, P., Pantaleo, G., Perreau, M., Rauch, A., Rudin, C., Scherrer, A.U., Schmid, P., Speck, R., Stöckle, M., Tarr, P., Trkola, A., Vernazza, P., Wandeler, G., Weber, R., and Yerly, S.

Subjects
10028 Institute of Medical Virology, CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Viral/genetics, Time Factors, Statistical methods, Human immunodeficiency virus (HIV), General Physics and Astronomy, HIV Infections, medicine.disease_cause, Genome, 10234 Clinic for Infectious Diseases, Cohort Studies, Viral, lcsh:Science, ddc:616, Multidisciplinary, virus diseases, HIV-1/drug effects/genetics, Viral Load, 3100 General Physics and Astronomy, 3. Good health, Phylogenetics, Anti-Retroviral Agents, Cohort, Anti-Retroviral Agents/pharmacology, Female, Adult, Science, 030106 microbiology, 610 Medicine & health, 1600 General Chemistry, Genome, Viral, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, CD4-Positive T-Lymphocytes/virology, DNA, Viral/genetics, HIV Infections/virology, HIV-1/drug effects, HIV-1/genetics, Humans, 1300 General Biochemistry, Genetics and Molecular Biology, medicine, ddc:613, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], DNA, General Chemistry, Heritability, Term (time), 030104 developmental biology, Evolutionary biology, DNA, Viral, HIV-1, lcsh:Q
Abstract

The HIV-1 reservoir is the major hurdle to curing HIV-1. However, the impact of the viral genome on the HIV-1 reservoir, i.e. its heritability, remains unknown. We investigate the heritability of the HIV-1 reservoir size and its long-term decay by analyzing the distribution of those traits on viral phylogenies from both partial-pol and viral near full-length genome sequences. We use a unique nationwide cohort of 610 well-characterized HIV-1 subtype-B infected individuals on suppressive ART for a median of 5.4 years. We find that a moderate but significant fraction of the HIV-1 reservoir size 1.5 years after the initiation of ART is explained by genetic factors. At the same time, we find more tentative evidence for the heritability of the long-term HIV-1 reservoir decay. Our findings indicate that viral genetic factors contribute to the HIV-1 reservoir size and hence the infecting HIV-1 strain may affect individual patients’ hurdle towards a cure., The HIV reservoir is a major hurdle for a cure of HIV, but the factors determining its size and dynamics remain unclear. Here the authors show in a large cohort of 610 HIV-1 infected individuals, who are on suppressive ART for a median of 5.4 years, that viral genetic factors contribute substantially to the HIV-1 reservoir size.

Published
2020
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2. Role of Gag mutations in PI resistance in the Swiss HIV cohort study: bystanders or contributors?

Author

Jens Verheyen, F Schöni-Affolter, Daniel Hoffmann, Vincent Aubert, Thomas Klimkait, Sabine Yerly, Jürg Böni, K Kletenkov, Daniel Struck, and University of Zurich

Subjects
10028 Institute of Medical Virology, 0301 basic medicine, Viral/genetics, medicine.medical_treatment, Medizin, Drug Resistance, HIV Infections, Drug resistance, ddc:616.07, medicine.disease_cause, gag Gene Products, Human Immunodeficiency Virus, Viral/blood, 2726 Microbiology (medical), Cohort Studies, HIV Protease, Genotype, Prevalence, 2736 Pharmacology (medical), HIV Protease Inhibitor, Pharmacology (medical), Treatment Failure, Gag, Mutation, Gag Gene Products, HIV-1/drug effects/genetics, Genes, gag, Phenotype, 3004 Pharmacology, Infectious Diseases, RNA, Viral, Biologie, Sequence Analysis, Switzerland, Microbiology (medical), swiss hiv cohort study, Mutation, Missense, Mutagenesis (molecular biology technique), Human Immunodeficiency Virus/genetics, 610 Medicine & health, 03 medical and health sciences, Drug Resistance, Viral, medicine, HIV Protease Inhibitors/pharmacology/therapeutic use, HIV Infections/blood/drug therapy/virology, Humans, Genotyping, Pharmacology, Protease, business.industry, HIV Protease/genetics, 2725 Infectious Diseases, HIV Protease Inhibitors, Sequence Analysis, DNA, DNA, Virology, 030104 developmental biology, Genes, HIV-1, 570 Life sciences, biology, RNA, mutation, Missense, business
Abstract

Background: HIV Gag mutations have been reported to confer PI drug resistance. However, clinical implications are still controversial and most current genotyping algorithms consider solely the protease gene for assessing PI resistance. Objectives: Our goal was to describe for HIV infections in Switzerland the potential role of the C-terminus of Gag (NC–p6) in PI resistance. We aimed to characterize resistance-relevant mutational patterns in Gag and protease and their possible interactions. Methods: Resistance information on plasma samples from 2004–12 was collected for patients treated by two diagnostic centres of the Swiss HIV Cohort Study. Sequence information on protease and the C-terminal Gag region was paired with the corresponding patient treatment history. The prevalence of Gag and protease mutations was analysed for PI treatment-experienced patients versus PI treatment-naive patients. In addition, we modelled multiple paths of an assumed ordered accumulation of genetic changes using random tree mixture models. Results: More than half of all PI treatment-experienced patients in our sample set carried HIV variants with at least one of the known Gag mutations, and 17.9% (66/369) carried at least one Gag mutation for which a phenotypic proof of PI resistance by in vitro mutagenesis has been reported. We were able to identify several novel Gag mutations that are associated with PI exposure and therapy failure. Conclusions: Our analysis confirmed the association of Gag mutations, well known and new, with PI exposure. This could have clinical implications, since the level of potential PI drug resistance might be underestimated.

Published
2017

3. Immunological recovery and antiretroviral therapy in HIV-1 infection

Author

Gilbert R. Kaufmann, Manuel Battegay, Reto Nüesch, and Bernard Hirschel

Subjects
CD4-Positive T-Lymphocytes, Tuberculosis, medicine.medical_treatment, HIV Infections, HIV Infections/ drug therapy/ immunology, Acquired immunodeficiency syndrome (AIDS), Immunopathology, medicine, Humans, CD4-Positive T-Lymphocytes/ immunology, RNA, Viral/blood, Sida, ddc:616, Chemotherapy, biology, business.industry, Anti-Retroviral Agents/ therapeutic use, Recovery of Function, HIV-1/drug effects/genetics, Viral Load, medicine.disease, biology.organism_classification, CD4 Lymphocyte Count, Infectious Diseases, Anti-Retroviral Agents, Lentivirus, Immunology, HIV-1, RNA, Viral, Viral disease, business, Viral load
Abstract

Potent antiretroviral therapy has dramatically improved the prognosis of patients infected with HIV-1. Primary and secondary prophylaxis against Pneumocystis carinii, Mycobacterium avium, cytomegalovirus, and other pathogens can be discontinued safely once CD4 cell counts have increased beyond pathogen-specific thresholds. Approximately one-third of individuals receiving antiretroviral therapy will not reach CD4 cell counts above 500 cells per muL after 5 years despite continuous suppression of plasma HIV-1 RNA. Whether this failure represents a risk factor for the long-term incidence of opportunistic diseases--eg, tuberculosis or malignancies--remains uncertain. We describe the time course of CD4 cell concentrations in patients whose plasma HIV-1 RNA is durably suppressed by antiretroviral therapy, in patients with incomplete suppression of plasma HIV-1 RNA, and during treatment interruptions. In addition, immune reconstitution disease, an inflammatory syndrome associated with immunological recovery occurring days to weeks after the start of antiretroviral therapy, is briefly described.

Published
2006
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4. Prevalence of HIV-1 drug resistance in treated patients with viral load >50 copies/mL in 2009: a French nationwide study

Author

Assoumou, Lambert, Descamps, Diane, Yerly, Sabine, dos Santos, Georges, Marcelin, Anne-Geneviève, Delaugerre, Constance, Morand-Joubert, Laurence, Ruffault, Annick, Izopet, Jacques, Plantier, Jean-Christophe, Pakianather, Sophie, Montes, Brigitte, Chaix, Marie-Laure, Wirden, Marc, Costagliola, Dominique, Masquelier, Bernard, Michelet, Christian, 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 ), 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 ), Núcleo de Bioinformática Estrutural ( NBI ), Embrapa Informática Agropecuária, Service de virologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service de microbiologie [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Service de bactériologie-virologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Unité de Rétrovirologie, Hôpital Pontchaillou, Laboratoire de virologie [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Département de microbiologie : Bactério, Virologie, Parasito, Hygiène, Laboratoire de Virologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Epidémiologie Clinique et Traitement de l'Infection à VIH, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR113-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Microbiologie cellulaire et moléculaire et pathogénicité ( MCMP ), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique ( CNRS ), Service de virologie et d'immunologie biologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Geneva University Hospital (HUG), Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Virologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Faculté de Médecine Purpan, Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, Université Paris Descartes - Paris 5 (UPD5), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ANRS AC11 Resistance Group, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de Virologie [Purpan], CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Département de microbiologie : Bactério, Virologie, Parasito, Hygiène-Hôpital Charles Nicolle [Rouen]-CHU Rouen, 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 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), Núcleo de Bioinformática Estrutural (NBI), Service de virologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Département de microbiologie : Bactério, Virologie, Parasito, Hygiène, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Microbiologie Fondamentale et Pathogénicité (MFP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Virologie, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Département de microbiologie : Bactério, Virologie, Parasito, Hygiène-Hôpital Charles Nicolle [Rouen]-CHU Rouen, Université Paris Descartes - Paris 5 ( UPD5 ), Institut de recherche, 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 ) -Université des Antilles ( UA ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
Male, Prevalence, Integrase inhibitor, HIV Infections, Drug resistance, France/epidemiology, 0302 clinical medicine, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, Antiretroviral Therapy, Highly Active, Pharmacology (medical), 030212 general & internal medicine, Treatment Failure, ComputingMilieux_MISCELLANEOUS, ddc:616, 0303 health sciences, virological failure, Data Collection, Proteolytic enzymes, HIV Infections/epidemiology/virology, HIV-1/drug effects/genetics, Middle Aged, Viral Load, 3. Good health, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, RNA, Viral, Female, epidemiology, France, Viral load, Microbiology (medical), Genotype, Anti-HIV Agents, antiretroviral therapy, Biology, 03 medical and health sciences, multidrug resistance, Drug Resistance, Viral, Humans, Amino Acid Sequence, RNA, Viral/blood, Genotyping, Aged, Pharmacology, 030306 microbiology, plasma HIV RNA, Virology, Health Surveys, Reverse transcriptase, Multiple drug resistance, Anti-HIV Agents/therapeutic use, HIV-1, HIV-1 drug resistance
Abstract

International audience; BACKGROUND: Surveillance of HIV-1 drug resistance in treated patients with plasma viral load (VL) >50 copies/mL. METHODS: The protease and reverse transcriptase (RT) genes were systematically sequenced in samples from 756 patients with VL >50 copies/mL in 2009. The genotyping results were interpreted for each antiretroviral drug (ARV) by using the ANRS algorithm v21. Weighted analyses were used to derive representative estimates of percentages of patients. Prevalence rates were compared with those obtained in 2004 among patients with VL >1000 copies/mL. RESULTS: Sequences were obtained for 506 patients. Sequencing was successful in 45%, 80% and 96% of samples with VL of 51-500, 501-1000 and >1000 copies/mL, respectively. Resistance or possible resistance to at least one ARV was observed in 59% of samples. Overall, 0.9% of samples contained viruses resistant to all drugs belonging to at least three drug classes. All resistance prevalence rates were significantly lower in 2009 than in 2004. CONCLUSION: In France, where 86% of patients were receiving combination antiretroviral therapy in 2009, only 15.0% of patients had a VL >50 copies/mL, suggesting that only 8.9% of treated patients could potentially transmit resistant viruses. Only 0.08% of patients harboured viruses fully resistant to at least three antiretroviral drug classes. Further studies are needed to determine whether resistance continues to decline over time.

Published
2013
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5. Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals

Author

Rubin, Lubomirov, Mona, Arab-Alameddine, Margalida, Rotger, Aurélie, Fayet-Mello, Raquel, Martinez, Monia, Guidi, Julia, di Iulio, Matthias, Cavassini, Huldrych F, Günthard, Hansjakob, Furrer, Catia, Marzolini, Enos, Bernasconi, Alexandra, Calmy, Thierry, Buclin, Laurent A, Decosterd, Chantal, Csajka, Amalio, Telenti, S, Yerly, and University of Zurich

Subjects
Male, Etravirine, HIV Infections, Pyridazines/pharmacokinetics/pharmacology, Pharmacology, 10234 Clinic for Infectious Diseases, Switzerland/epidemiology, Models, Cytochrome P-450 CYP3A, Tissue Distribution, Prospective Studies, General Pharmacology, Toxicology and Pharmaceutics, Genetics (clinical), ddc:616, education.field_of_study, ddc:615, HIV Protease Inhibitors/pharmacokinetics/pharmacology, HIV-1/drug effects/genetics, Middle Aged, Statistical, Prognosis, Pyridazines, Aryl Hydrocarbon Hydroxylases/genetics, Cytochrome P-450 CYP3A/genetics, Molecular Medicine, Population study, Female, Aryl Hydrocarbon Hydroxylases, Single Nucleotide/genetics, Switzerland, medicine.drug, Adult, 2716 Genetics (clinical), Adolescent, Population, 610 Medicine & health, CYP2C19, HIV Infections/drug therapy/epidemiology/genetics, Biology, Polymorphism, Single Nucleotide, digestive system, Young Adult, 1311 Genetics, Nitriles, Genetics, medicine, 1312 Molecular Biology, Humans, Polymorphism, CYP3A5, education, Molecular Biology, Darunavir, Aged, Models, Statistical, HIV Protease Inhibitors, Cytochrome P-450 CYP2C19, Pyrimidines, Pharmacogenetics, 1313 Molecular Medicine, HIV-1, Ritonavir
Abstract

OBJECTIVES: Etravirine (ETV) is metabolized by cytochrome P450 (CYP) 3A, 2C9, and 2C19. Metabolites are glucuronidated by uridine diphosphate glucuronosyltransferases (UGT). To identify the potential impact of genetic and non-genetic factors involved in ETV metabolism, we carried out a two-step pharmacogenetics-based population pharmacokinetic study in HIV-1 infected individuals. MATERIALS AND METHODS: The study population included 144 individuals contributing 289 ETV plasma concentrations and four individuals contributing 23 ETV plasma concentrations collected in a rich sampling design. Genetic variants [n=125 single-nucleotide polymorphisms (SNPs)] in 34 genes with a predicted role in ETV metabolism were selected. A first step population pharmacokinetic model included non-genetic and known genetic factors (seven SNPs in CYP2C, one SNP in CYP3A5) as covariates. Post-hoc individual ETV clearance (CL) was used in a second (discovery) step, in which the effect of the remaining 98 SNPs in CYP3A, P450 cytochrome oxidoreductase (POR), nuclear receptor genes, and UGTs was investigated. RESULTS: A one-compartment model with zero-order absorption best characterized ETV pharmacokinetics. The average ETV CL was 41 (l/h) (CV 51.1%), the volume of distribution was 1325 l, and the mean absorption time was 1.2 h. The administration of darunavir/ritonavir or tenofovir was the only non-genetic covariate influencing ETV CL significantly, resulting in a 40% [95% confidence interval (CI): 13-69%] and a 42% (95% CI: 17-68%) increase in ETV CL, respectively. Carriers of rs4244285 (CYP2C19*2) had 23% (8-38%) lower ETV CL. Co-administered antiretroviral agents and genetic factors explained 16% of the variance in ETV concentrations. None of the SNPs in the discovery step influenced ETV CL. CONCLUSION: ETV concentrations are highly variable, and co-administered antiretroviral agents and genetic factors explained only a modest part of the interindividual variability in ETV elimination. Opposing effects of interacting drugs effectively abrogate genetic influences on ETV CL, and vice-versa.

Published
2013

6. Viral resuppression and detection of drug resistance following interruption of a suppressive non-nucleoside reverse transcriptase inhibitor-based regimen

Author

Federico Pulido, Janak Koirala, Carlos Brites, Jens Lundgren, Pablo Okhuysen, DAVID DALMAU, Clifford Leen, Matti Ristola, Lorenzo Magenta, Lars Østergaard, Sean Emery, Angèle Gayet-Ageron, Michael Kozal, André Cabié, Nicholas Andrew Medland, and Philippa Easterbrook

Subjects
Adult, Male, medicine.medical_specialty, Immunology, HIV Infections, Drug resistance, Drug Administration Schedule, Nucleoside Reverse Transcriptase Inhibitor, Drug Resistance, Viral/genetics/ immunology, Clinical Protocols, immune system diseases, Internal medicine, Drug Resistance, Viral, medicine, Immunology and Allergy, Humans, HIV Infections/ drug therapy/genetics/immunology, ddc:616, Reverse-transcriptase inhibitor, business.industry, virus diseases, Reverse Transcriptase Inhibitors/ administration & dosage/immunology, Odds ratio, HIV-1/drug effects/genetics, Middle Aged, Viral Load, Virology, Confidence interval, HIV Reverse Transcriptase, Discontinuation, CD4 Lymphocyte Count, Regimen, Infectious Diseases, Treatment Outcome, Practice Guidelines as Topic, HIV-1, Reverse Transcriptase Inhibitors, Female, business, Viral load, HIV Reverse Transcriptase/genetics, medicine.drug
Abstract

Udgivelsesdato: 2008-Nov-12 BACKGROUND: Interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance. Limited data exist to guide clinical practice on the best interruption strategy to use. METHODS: Patients in the drug-conservation arm of the Strategies for Management of Antiretroviral Therapy (SMART) trial who interrupted a fully suppressive NNRTI-regimen were evaluated. From 2003, SMART recommended interruption of an NNRTI by a staggered interruption, in which the NNRTI was stopped before the NRTIs, or by replacing the NNRTI with another drug before interruption. Simultaneous interruption of all antiretrovirals was discouraged. Resuppression rates 4-8 months after reinitiating NNRTI-therapy were assessed, as was the detection of drug-resistance mutations within 2 months of the treatment interruption in a subset (N = 141). RESULTS: Overall, 601/688 (87.4%) patients who restarted an NNRTI achieved viral resuppression. The adjusted odds ratio (95% confidence interval) for achieving resuppression was 1.94 (1.02-3.69) for patients with a staggered interruption and 3.64 (1.37-9.64) for those with a switched interruption compared with patients with a simultaneous interruption. At least one NNRTI-mutation was detected in the virus of 16.4% patients with simultaneous interruption, 12.5% patients with staggered interruption and 4.2% patients with switched interruption. Fewer patients with detectable mutations (i.e. 69.2%) achieved HIV-RNA of 400 copies/ml or less compared with those in whom no mutations were detected (i.e. 86.7%; P = 0.05). CONCLUSION: In patients who interrupt a suppressive NNRTI-regimen, the choice of interruption strategy may influence resuppression rates when restarting a similar regimen. NNRTI drug-resistance mutations were observed in a relatively high proportion of patients. These data provide additional support for a staggered or switched interruption strategy for NNRTI drugs.

Published
2008
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7. Delavirdine in combination with zidovudine in treatment of human immunodeficiency virus type 1-infected patients: evaluation of efficacy and emergence of viral resistance in a randomized, comparative phase III trial. The M/3331/0013B Study Group

Author

Joly, V., Moroni, M., Concia, Ercole, Lazzarin, A., Hirschel, Bernard, Jost, J., Chiodo, F., Bentwich, Z., Love, W. C., Hawkins, D. A., Wilkins, E. G., Gatell, A. J., Vetter, N., Greenwald, C., Freimuth, W. W., and de Cian, W.

Subjects
ddc:616, HIV Infections/ drug therapy, Anti-HIV Agents/ therapeutic use, Zidovudine/therapeutic use, virus diseases, Drug Resistance, Microbial, Delavirdine/ therapeutic use, biochemical phenomena, metabolism, and nutrition, HIV-1/drug effects/genetics, Treatment Outcome, Double-Blind Method, Humans, Drug Therapy, Combination, HIV Reverse Transcriptase/genetics
Abstract

We compared the activity of delavirdine (DLV) plus zidovudine (AZT) (n = 300) with that of AZT (n = 297) against human immunodeficiency virus type 1 in a randomized, double-blind, placebo-controlled trial. DLV exerted a transient antiviral effect, and mutations for resistance to DLV were found in more than 90% of subjects at week 12. The K103N mutation, which confers nonnucleoside reverse transcriptase inhibitor cross-resistance, was found in 85% of the patients.

Published
2000

8. Long-Lasting Protection of Activity of Nucleoside Reverse Transcriptase Inhibitors and Protease Inhibitors (PIs) by Boosted PI Containing Regimens

Author

Scherrer, Alexandra U., Böni, Jürg, Yerly, Sabine, Klimkait, Thomas, Aubert, Vincent, Furrer, Hansjakob, Calmy, Alexandra, Cavassini, Matthias, Elzi, Luigia, Vernazza, Pietro L., Bernasconi, Enos, Ledergerber, Bruno, Günthard, Huldrych F., Swiss HIV Cohort Study (SHCS), University of Zurich, and the Swiss HIV Cohort Study (SHCS)

Subjects
10028 Institute of Medical Virology, Male, Oncology, Time Factors, Non-Clinical Medicine, Epidemiology, lcsh:Medicine, HIV Infections, Drug resistance, Pharmacology, Nucleoside Reverse Transcriptase Inhibitor, 10234 Clinic for Infectious Diseases, Cohort Studies, 0302 clinical medicine, Risk Factors, immune system diseases, Antiretroviral Therapy, Highly Active, Treatment Failure, 030212 general & internal medicine, lcsh:Science, ddc:616, 0303 health sciences, Multidisciplinary, Reverse-transcriptase inhibitor, medicine.diagnostic_test, virus diseases, HIV diagnosis and management, HIV-1/drug effects/genetics, Middle Aged, Viral Load, Protease Inhibitors/administration & dosage/therapeutic use, 3. Good health, AIDS, HIV epidemiology, Medicine, Infectious diseases, Reverse Transcriptase Inhibitors, Female, Viral load, Research Article, medicine.drug, Adult, Cart, medicine.medical_specialty, Infectious Disease Control, Genotype, Clinical Research Design, Anti-HIV Agents, Sexually Transmitted Diseases, 610 Medicine & health, Viral diseases, 1100 General Agricultural and Biological Sciences, macromolecular substances, Infectious Disease Epidemiology, 03 medical and health sciences, Pharmacotherapy, 1300 General Biochemistry, Genetics and Molecular Biology, Internal medicine, Drug Resistance, Viral, medicine, Humans, Protease Inhibitors, HIV Infections/drug therapy/virology, Anti-HIV Agents/administration & dosage/therapeutic use, Reverse Transcriptase Inhibitors/administration & dosage/therapeutic use, 030304 developmental biology, 1000 Multidisciplinary, Health Care Policy, business.industry, lcsh:R, HIV, Health Risk Analysis, Odds ratio, Drug Resistance, Viral/genetics, nervous system, Therapeutic drug monitoring, Mutation, HIV-1, 570 Life sciences, biology, lcsh:Q, business
Abstract

BACKGROUND: The accumulation of mutations after long-lasting exposure to a failing combination antiretroviral therapy (cART) is problematic and severely reduces the options for further successful treatments. METHODS: We studied patients from the Swiss HIV Cohort Study who failed cART with nucleoside reverse transcriptase inhibitors (NRTIs) and either a ritonavir-boosted PI (PI/r) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). The loss of genotypic activity 6 months after virological failure was analyzed with Stanford algorithm. Risk factors associated with early emergence of drug resistance mutations (6 months after failure: 8.8% vs. 38.2% (p = 0.009), 7.1% vs. 46.9% (p6 months after failure compared to 41.2%, 49.0% and 63.0% of those who have lost NNRTI activity (all p

Published
2012
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