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Pharmacologie clinique et pharmacogénétique de la prise en charge complexe des sujets infectés par HIV ou co-infectés par HIV et HCV

English title Clinical Pharmacology and Pharmacogenetics In the Complex Care of HIV and HIV/HCV co-infected Individuals
Applicant Decosterd Laurent Arthur
Number 141234
Funding scheme Project funding (special)
Research institution Division de Pharmacologie clinique Département de Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Clinical Pharmacology
Start/End 01.04.2012 - 31.03.2015
Approved amount 448'118.00
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Keywords (10)

clinical pharmacokinetics; metabolite profiling; antiretrovirals; pharmacogenetics; liquid chromatography tandem mass spectrometry; drug-drug interactions; personalized medicine; HCV protease inhibitors; large nested project; Swiss HIV Cohort Study

Lay Summary (English)

Lead
Lay summary

Antiretroviral drug (ARV) therapy has dramatically improved the prognosis of HIV infection converting it from a deadly disease into a chronic manageable condition. Nevertheless, despite the impressive therapeutic benefit of ARVs, the currently available molecules suppress, but do not eliminate the infection. This is due to the persistence of minimal residual viral replication or of viral latency, such that relapse is an inevitable consequence of therapy interruption, and thus long-term therapy is necessary. Unfortunately, treatment intolerance is observed in approximately one third of HIV-infected patients receiving first line ARVs, leading to treatment modification or interruption. Coordinated research projects integrating basic and applied pharmacogenetic, pharmacokinetic and pharmacodynamic aspects of HIV therapeutics remain therefore a high priority because of the prevalence of toxicity, the life-long nature of treatment, and the complexity inherent to multidrug therapy. Genetic and non-genetic factors influence drug exposure, toxicity and clinical response to therapy. The important interindividual pharmacokinetic variability observed for antiretroviral agents is not only explained by pharmacogenetic predisposition affecting drug’s transport and metabolism, but also by patho-physiological conditions and by environmental influences, including co-administered drugs.

The present research project aims at studying the complex gene-drug-environmental interplay relevant to antiviral treatment in HIV-infected patients. Specifically, co-infection with the Hepatitis C Virus (HCV) is common in HIV-infected individuals and chronic hepatitis C is a leading cause of morbidity and death in HIV/HCV coinfected patients. Therefore, eradication of HCV through therapeutic interventions is of particular importance in this population. HIV/HCV co-infected patients will be increasingly treated by the novel HCV protease inhibitors (HCV-PI) that allow cure rates never encountered so far in HCV genotype-1 infected patients. However, these new molecules have a high potential of drug interactions, notably with ARVs, and the influence of patients’ pharmacogenetic background on the intensity of these drug interactions remains to be investigated.

The exploitation of the Swiss HIV Cohort Study (SHCS) Pharmacology database from the National Therapeutic Drug Monitoring Service focusing on new ARVs and anti-HCV drugs will be reinforced by prospective clinical studies realized within the framework of the SHCS, integrating the clinical pharmacokinetics/dynamics and (pharmaco)genetics analysis of first-line antiretroviral regimen in treatment-naïve HIV patients, and of the novel HCV-PI-based therapy in HIV/HCV co-infected patients.

The project aims at responding to clinically relevant therapeutic issues such as the importance of new pharmacogenetics and pharmacokinetics tools for improving the long-term tolerability and response to antiviral treatment, and should open the way to personalized prescription of antiviral drugs. The ultimate goal is the selection of first-line regimens according to patients’ genetic background, and the careful drug dosage adjustment through population pharmacokinetics-based therapeutic drug monitoring.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Population pharmacokinetics of dolutegravir: influence of drug–drug interactions in a real-life setting
Barcelo Catalina, Aouri Manel, Courlet Perrine, Guidi Monia, Braun Dominique L, Günthard Huldrych F, Piso Rein J, Cavassini Matthias, Buclin Thierry, Decosterd Laurent A, Csajka Chantal, 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, et al. (2019), Population pharmacokinetics of dolutegravir: influence of drug–drug interactions in a real-life setting, in Journal of Antimicrobial Chemotherapy, 74(9), 2690-2697.
Protease Inhibitors to Treat Hepatitis C in the Swiss HIV Cohort Study: High Efficacy but Low Treatment Uptake
Schaerer V et al. (2015), Protease Inhibitors to Treat Hepatitis C in the Swiss HIV Cohort Study: High Efficacy but Low Treatment Uptake, in HIV medicine, hiv.12269.
Sofosbuvir and ribavirin before liver re-transplantation for graft failure due to recurrent hepatitis C: a case report.
Vionnet J et al (2015), Sofosbuvir and ribavirin before liver re-transplantation for graft failure due to recurrent hepatitis C: a case report., in BMC Gastroenterology 15 , 15, 38.
Vitamin D time profile based on the contribution of non-genetic and genetic factors in HIV-infected individuals of European ancestry.
Guidi M et al (2015), Vitamin D time profile based on the contribution of non-genetic and genetic factors in HIV-infected individuals of European ancestry., in Antiviral Therapy, 20, 261-269.
Population Pharmacokinetic Modeling and evaluation of different dosage regimens for of Darunavir and Ritonavir in HIV-Infected Individuals.
Arab-Alameddine M et al (2014), Population Pharmacokinetic Modeling and evaluation of different dosage regimens for of Darunavir and Ritonavir in HIV-Infected Individuals., in J Antimicrob Chemother , 69, 2489-2498.
A Multiplex LC MS/MS Assay for the Simultaneous Therapeutic Drug Monitoring of Ribavirin, Boceprevir and Telaprevir.
Aouri Manel et al (2013), A Multiplex LC MS/MS Assay for the Simultaneous Therapeutic Drug Monitoring of Ribavirin, Boceprevir and Telaprevir., in Antimicrob Agents Chemother , 57, 3147-3158.
A validated assay by liquid chromatography –tandem mass spectrometry for the simultaneous quantification of elvitegravir and rilpivirine in HIV patients.
Aouri M et al (2013), A validated assay by liquid chromatography –tandem mass spectrometry for the simultaneous quantification of elvitegravir and rilpivirine in HIV patients., in J. Mass Spectrom , 48, 616-625.
Efavirenz intoxication due to a new CYP2B6 constellation
Anagnostopoulos A et al. (2013), Efavirenz intoxication due to a new CYP2B6 constellation, in Antivir Ther, 18, 739-743.
Free and total plasma levels of lopinavir during pregnancy, at delivery and in post-partum: implication for dosage adjustments in pregnant women
Fayet-Mello A et al (2013), Free and total plasma levels of lopinavir during pregnancy, at delivery and in post-partum: implication for dosage adjustments in pregnant women, in Antiviral Therapy, 18 , 171-182.
Higher CNS Penetration-Effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid
Cusini A et al (2013), Higher CNS Penetration-Effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid, in JAIDS, 62,, 28 -35.
Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals.
Lubomirov R et al (2013), Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals., in Pharmacogen Genom , 23, 9-18.
Determinants of Sustained Viral Suppression in HIV-Infected Patients with Self-Reported Poor Adherence to Antiretroviral Therapy.
Glass TR (2012), Determinants of Sustained Viral Suppression in HIV-Infected Patients with Self-Reported Poor Adherence to Antiretroviral Therapy., in PLosOne, 7 , e29186.
Dosage optimization of treatments using population pharmacokinetic modeling and simulation.
Guidi Monia et al (2012), Dosage optimization of treatments using population pharmacokinetic modeling and simulation., in Chimia, 66, 291-295.
Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia.
Aouri Manel et al (2012), Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia., in AIDS, 26, 776-778.
Population Pharmacokinetic Analysis, Pharmacogenetics and Effects of Raltegravir In HIV positive and Healthy Individuals
Arab-Alameddine Monia (2012), Population Pharmacokinetic Analysis, Pharmacogenetics and Effects of Raltegravir In HIV positive and Healthy Individuals, in Antimicrob Agents Chemother , 56, 2959-2966.
A lead-in with silibinin prior to triple-therapy translates into favorable treatment outcomes in difficult-to-treat HIV/hepatitis C coinfected patients
Braun D et al, A lead-in with silibinin prior to triple-therapy translates into favorable treatment outcomes in difficult-to-treat HIV/hepatitis C coinfected patients, in PLosOne.

Collaboration

Group / person Country
Types of collaboration
Dr Mylène Docquier, Genomics Platform, CMU Geneva Switzerland (Europe)
- Research Infrastructure
Swiss HIV Cohort Study Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Industry/business/other use-inspired collaboration
Prof Huldrych Günthard, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof Chin Eap, Laboratory of Biochemistry and Psychopharmacology, University Hospital Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Plateform of Chromatography/ Mass spectrometry of the CHUV University Hospital Switzerland (Europe)
- Research Infrastructure
Prof Darius Moradpour CHUV Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
130699 24 hours in the life of HIV-1 01.04.2010 Project funding
124943 Pharmacocinétique de population, pharmacogénétique, et profils métaboliques de la thérapie anti-HIV 01.04.2009 Project funding (special)
121314 Demande de soutien pour l'acquisition d'un instrument de chromatographie à ultra performance couplé à un détecteur de masse triple quadripôles en tandem (UPLC-MS/MS) pour la recherche biomédicale 01.08.2008 R'EQUIP
116862 Impact of HIV and antiretroviral therapy on Hepatitis C virus (HCV) evolution and on HCV-specific cellular immunity 01.06.2007 Project funding (special)
132863 Host evolutionary genomics of HIV-1 and other retroviruses 01.11.2010 Project funding
113127 Genotyping and transcriptome analyses; illumina platform 01.10.2006 R'EQUIP
124943 Pharmacocinétique de population, pharmacogénétique, et profils métaboliques de la thérapie anti-HIV 01.04.2009 Project funding (special)
146143 Understanding and Predicting the Hepatitis C Epidemic in HIV-infected Patients 01.05.2013 Project funding (special)
148522 Swiss HIV Cohort Study (SHCS) 01.01.2014 Cohort Studies Large
165956 Modélisation, Simulation et Validation clinique des Interactions Médicamenteuses dans la Swiss HIV Cohort Study 01.09.2016 Project funding (special)

Abstract

Coordinated research projects integrating basic and applied pharmacogenetic, pharmacokinetic and pharmacodynamic aspects of HIV therapeutics remain a high priority because of the prevalence of toxicity, the life-long nature of treatment, and the complexity inherent to multidrug therapy. Genetic and non-genetic factors influence drug exposure, toxicity and clinical response to therapy. Pharmacogenetics has a profound impact on our current understanding of the variability observed in drug exposure (pharmacokinetics), clinical response and toxicity (pharmacodynamics). However, the important interindividual pharmacokinetic variability observed for antiretroviral agents is not only explained by pharmacogenetic predisposition affecting drug’s transport and metabolism, but also by pathophysiological conditions and by environmental influences, including co-administered drugs.Over the last funding period we have:1.Stengthened our technical methodologies (mass spectrometry facility for antiretroviral drugs and metabolites profiles analysis, massive and facilitated access to integrated pharmacology and genetics databases, population pharmacokinetics expertise (NONMEM) and pharmacogenetics plateforms for high throughput genotyping and genome analysis). 2.Completed coordinated research projects integrating basic and applied pharmacogenetic, pharmacokinetics and pharmacodynamic aspects of HIV therapy.The present proposal aims at pursuing and expanding our research program on complex gene-drug-environmental interplay relevant to antiviral treatment in HIV-infected patients. Specifically, coinfection with the Hepatitis C Virus (HCV) is common in HIV-infected individuals; these patients will be increasingly treated by the latest generation of HCV protease inhibitors (HCV-PI). These new molecules have a high potential of drug interactions.The successful exploitation of the Swiss HIV Cohort Study (SHCS) Pharmacology database from the National Therapeutic Drug Monitoring Service focusing on new antiretroviral drugs will be reinforced by prospective clinical studies realized within the framework of the SHCS, integrating the clinical pharmacokinetics/dynamics and (pharmaco)genetics analysis of first-line antiretroviral regimen in treatment-naïve HIV patients, and of the novel HCV-PI-based therapy in HIV/HCV co-infected patients. Thus, the current proposal addresses the:1.Development of population pharmacokinetic /pharmacogenetics models for the newest antiretroviral and antiviral drugs2.Clinically relevant issues of drug interactions between antiretroviral agents and new HCV-PIs 3.Translation into clinical trials aiming at validating the usefulness of optimized pharmacokinetic and pharmacogenetic tools for personalized drug prescription. The project aims at responding to clinically relevant therapeutic issues such as the importance of new pharmacogenetics and pharmacokinetics tools for improving the long-term tolerability and response to antiviral treatment, and should open the way to personalized prescription of antiviral drugs. The ultimate goal is the selection of first-line regimens according to patients’ genetic background, and the careful dosage adjustment through population pharmacokinetics-based therapeutic drug monitoring.
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