Chronic hepatitis C: predictors of treatment response in Estonian patients
Date
2014-10-28
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Abstract
C-hepatiidi viirusest (HCV) põhjustatud krooniline hepatiit on suur tervishoiuprobleem, sest haigestunud võib olla ligikaudu 2.3% maailma rahvastikust. Eestis on C-hepatiidi viirusega nakatunud hinnanguliselt vähemalt 1% rahvastikust. C-hepatiidi viirus kuulub Flaviviridae sugukonda ja Hepacivirus’e perekonda. Sellel viirusel on seitse genotüüpi ja üle 60 alltüübi. Eestis on enam levinud 1b genotüüp, millele järgneb 3a genotüüp.
Alfa-peginterferoon ja ribaviriin on aastaid olnud kroonilise C-hepatiidi standardravi. Viirusvastase ravi eesmärk on C hepatiidi viiruse kadumine verest ehk C-hepatiidi viiruse RNA (HCV RNA) puudumine veres. Viirusvastase ravi tõhususe kriteerium on püsiv viirusvastus – HCV RNA on negatiivne 24 nädalat pärast ravi. Viirusvastase ravi tõhusust mõjutavad mitu patsiendist olenevat ja ka mitu C-hepatiidi viirusest tulenevat tegurit. HCV genoomi muutlikkus võib samuti mõjutada viirusvastase ravi tõhusust.
Käesoleva uurimistöö eesmärk oli uurida varem viirusvastast ravi mittesaanud (nn ravinaiivsetel) kroonilise C-hepatiidiga patsientidel peremeesorganismist ja C hepatiidi viirusest tulenevaid tegureid, sealhulgas HCV NS5A valgu muutlikkust, et prognoosida alfa-peginterferooni ning ribaviriiniga ravimise tõhusust.
Uurimistöö näitas et viiruse genotüüp ja vanus alla 40 aasta olid viirusvastase
ravi tõhususe olulised prognoosivad tegurid. Kroonilise C hepatiidi 1b genotüübiga
patsiendid allusid ravile halvemini kui 3a genotüübiga patsiendid. Vanus alla 40 aasta,
maksafibroosi puudumine või kerge kuni mõõdukas fibroos, aktiivse maksapõletiku
puudumine või kerge aktiivsus, referentsväärtuses trombotsüütide arv ja
gammaglutamüüli transferaasi väärtus ning viirusekoguse vähenemine 4. ja 12.
ravinädalal olid kroonilise C-hepatiidi 1b genotüübiga ravinaiivsetel patsientidel
ravivastuse kindlad kriteeriumid.
Aminohapete polümorfismi uuringus puudus seos nii HCV terve NS5A valgu kui ka
NS5A valgu eri piirkondade mutatsioonide arvu ning ravivastuse (püsiv viirusvastus,
non-response või relapse) vahel. Leiti korrelatsioon ravivastuse (püsiv viirusvastus, non-
response või relapse) ja NS5A valgu varem mittekirjeldatud spetsiifiliste aminohapete
asenduste vahel. Fülogeneetilisel analüüsil selgus 11 uut aminohapete asendust terves
NS5A valgus, millele tuginedes võib prognoosida ravi tõhusust Eesti kroonilise C-
hepatiidi 1b genotüübiga ravinaiivsetel patsientidel.
The hepatitis C virus (HCV) with an estimated prevalence of about 2.35% worldwide is the leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma. In Estonia up to 1% or even more out of 1.34 million inhabitants are infected with HCV. The HCV has been classified into 7 major genotypes and a number of subtypes. In Estonia the most predominant HCV subtypes are 1b and 3a. Therapy with peginterferon alfa-2a/2b (PegIFN) plus ribavirin (RBV) has been recognized as the current standard of care for chronic hepatitis C. The aim of antiviral therapy is the eradication of HCV infection in order to prevent the complications of HCV-related liver diseases. The endpoint of therapy is a sustained virological response (SVR). Different pre- and on-treatment host and viral factors, as well as treatment-related factors influence treatment outcome in HCV-infected patients. The main objective of the study was to assess the efficacy of PegIFN/RBV therapy in Estonian treatment-naïve patients with CHC in relation to different host and viral factors, including the polymorphisms within the entire NS5A region of HCV genome. Study showed that the efficacy of PegIFN/RBV therapy was strongly predetermined by the HCV genotype and younger age of the studied patients. The SVR rate for patients infected with HCV genotype 1b was significantly lower compared with SVR rate for patients infected with HCV genotype 3a. Age below 40 years, absence of or mild and moderate liver fibrosis, absence of severe inflammatory activity, normal platelet count and normal GGT level with pronounced changes in viral kinetics at weeks 4 and 12 were valuable predictors of treatment response. Study of amino acid polymorphisms failed to demonstrate association between number of mutations within the either entire NS5A protein of HCV or its different known functional regions, and different types of response (SVR, non-response or relapse) to PegIFN/RBV therapy. Correlation between treatment response (SVR, non-response or relapse) and specific amino acid substitutions at different previously not described positions within the NS5A protein was identified. Phylogenetic analysis revealed 11 novel aa substitutions in the full-length NS5A protein, which can be used as tags to predict treatment response in Estonian patients with the chronic hepatitis C 1b genotype.
The hepatitis C virus (HCV) with an estimated prevalence of about 2.35% worldwide is the leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma. In Estonia up to 1% or even more out of 1.34 million inhabitants are infected with HCV. The HCV has been classified into 7 major genotypes and a number of subtypes. In Estonia the most predominant HCV subtypes are 1b and 3a. Therapy with peginterferon alfa-2a/2b (PegIFN) plus ribavirin (RBV) has been recognized as the current standard of care for chronic hepatitis C. The aim of antiviral therapy is the eradication of HCV infection in order to prevent the complications of HCV-related liver diseases. The endpoint of therapy is a sustained virological response (SVR). Different pre- and on-treatment host and viral factors, as well as treatment-related factors influence treatment outcome in HCV-infected patients. The main objective of the study was to assess the efficacy of PegIFN/RBV therapy in Estonian treatment-naïve patients with CHC in relation to different host and viral factors, including the polymorphisms within the entire NS5A region of HCV genome. Study showed that the efficacy of PegIFN/RBV therapy was strongly predetermined by the HCV genotype and younger age of the studied patients. The SVR rate for patients infected with HCV genotype 1b was significantly lower compared with SVR rate for patients infected with HCV genotype 3a. Age below 40 years, absence of or mild and moderate liver fibrosis, absence of severe inflammatory activity, normal platelet count and normal GGT level with pronounced changes in viral kinetics at weeks 4 and 12 were valuable predictors of treatment response. Study of amino acid polymorphisms failed to demonstrate association between number of mutations within the either entire NS5A protein of HCV or its different known functional regions, and different types of response (SVR, non-response or relapse) to PegIFN/RBV therapy. Correlation between treatment response (SVR, non-response or relapse) and specific amino acid substitutions at different previously not described positions within the NS5A protein was identified. Phylogenetic analysis revealed 11 novel aa substitutions in the full-length NS5A protein, which can be used as tags to predict treatment response in Estonian patients with the chronic hepatitis C 1b genotype.
Description
Väitekirja elektrooniline versioon ei sisalda publikatsioone.
Keywords
krooniline hepatiit, genotüüp, viirusevastased ravimid, ravitulemused, prognoosid, Eesti, chronic hepatitis, genotype, antiviral agents, results of treatment, predictions, Estonia