6533b861fe1ef96bd12c43b7
RESEARCH PRODUCT
Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens
Carlo MagniBarbara MenzaghiValeria CentoFrancesca Ceccherini-silbersteinGiustino ParrutiAntonio Di BiagioVelia Chiara Di MaioSergio BabudieriAntonella D'arminio MonforteLoredana SarmatiLaura GianserraPaolo CasalinoTiziana QuirinoElena DanieliJeremie GuedjDante RomagnoliIlaria LenciSergio BernardiniLaura Ambra NicoliniElisa BiliottiMatteo BolisM. MelisMaddalena CerroneMassimo PuotiValeria MicheliCarlo Federico PernoVincenza CalvarusoThi Huyen Tram NguyenEnnio PolilliGiuliano RizzardiniMassimo SicilianoMassimo AndreoniMario AngelicoFrancesco Paolo AntonucciDomenico Di CarloCaterina PasquazziAntonio CraxìDaniele Di PaoloElisabetta TetiGloria TalianiRoberta Alfierisubject
Genetics and Molecular Biology (all)SimeprevirMaleHepacivirusHepacivirusPharmacologyBiochemistryStiffness0302 clinical medicineAnimal CellsMedicineAmino Acidslcsh:ScienceAlanineOrganic CompoundsLiver Diseases3. Good healthCirrhosisPhysical SciencesAdministrationInterferon030211 gastroenterology & hepatologyDrug Therapy CombinationCellular TypesOligopeptidesHumanOralMaterials ScienceGastroenterology and HepatologyMicrobiologyAntiviral Agents03 medical and health sciencesDrug TherapyHumansAgedKineticPharmacologyHepaciviruBiochemistry Genetics and Molecular Biology (all)Mathematical Modelinglcsh:RChemical CompoundsBiology and Life SciencesProteinsmedicine.diseasedigestive system diseasesAdministration Oral; Aged; Alanine Transaminase; Antiviral Agents; Drug Therapy Combination; Female; Hepacivirus; Hepatitis C; Humans; Interferons; Kinetics; Male; Middle Aged; Oligopeptides; RNA Viral; Ribavirin; Simeprevir; Sofosbuvir; Treatment Outcome; Viral Nonstructural Proteins; Biochemistry Genetics and Molecular Biology (all); Agricultural and Biological Sciences (all)030104 developmental biologyAgricultural and Biological Sciences (all)chemistryAliphatic Amino Acidslcsh:Q0301 basic medicineSofosbuvirlcsh:MedicineAdministration OralMedicine (all); Biochemistry Genetics and Molecular Biology (all); Agricultural and Biological Sciences (all)Viral Nonstructural ProteinsTelaprevirchemistry.chemical_compoundSimeprevirMedicine and Health SciencesViralMultidisciplinarybiologyAntimicrobialsMedicine (all)Simulation and ModelingDrugsAlanine TransaminaseHepatitis CMiddle AgedAntiviralsHepatitis CChemistryTreatment OutcomeLiverCombinationOligopeptideRNA ViralFemaleAnatomymedicine.drugResearch ArticleSettore MED/17 - Malattie InfettiveGeneral Science & TechnologyMaterial PropertiesResearch and Analysis MethodsMicrobial ControlVirologyRibavirinMechanical PropertiesNS5AAntiviral Agentbusiness.industryRibavirinHCV DAA ALTViral Nonstructural ProteinOrganic ChemistryCell Biologybiology.organism_classificationKineticsAlanine transaminaseAdministration Oral; Aged; Alanine Transaminase; Antiviral Agents; Drug Therapy Combination; Female; Hepacivirus; Hepatitis C; Humans; Interferons; Kinetics; Male; Middle Aged; Oligopeptides; RNA Viral; Ribavirin; Simeprevir; Sofosbuvir; Treatment Outcome; Viral Nonstructural Proteinsbiology.proteinHepatocytesRNAInterferonsSofosbuvirbusinessdescription
Background Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. Study design Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. Results HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted δ and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted λ, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. Conclusions Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of “cell-cure” by DAAs, leading to a fast improvement of liver homeostasis.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-01-31 |