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The influence of hepatitis B virus genotype on clinical course and outcome of chronic infection

dc.contributor.advisorDelić, Dragan
dc.contributor.otherLazarević, Ivana
dc.creatorMilošević, Ivana
dc.date.accessioned2016-01-05T12:07:13Z
dc.date.available2016-01-05T12:07:13Z
dc.date.available2020-07-03T08:54:41Z
dc.date.issued2014-06-13
dc.identifier.urihttps://nardus.mpn.gov.rs/handle/123456789/2480
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=1918
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:9642/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=46730767
dc.description.abstractCilj: Genetička varijabilnost heptitis B virusa (HBV) posledica je visokog stepena repikacije ovog virusa i nemogućnosti ispravljanja slučajno nastalih grešaka tokom ovog procesa. Pored toga, terapija nukleozidnim/nukleotidnim analozima (NA) neminovno vodi u selekciju rezistentnih sojeva. HBsAg serotipovi HBV otkriveni su na osnovu reaktivnosti HBsAg sa poznatim panelima antitela. Na osnovu razlike u nukelotidnim sekvencama duž genoma definisani su genotipovi odn. subgenotipovi. Glavni cilj istraživanja bio je da se analizira uticaj genotipova, subgenotipova i HBsAg subtipova na težinu kliničke slike, patohistološki nalaz u tkivu jetre i progresiju u cirozu jetre i hepatocelularni karcinom. Metodologija: U studiju je uključeno 162 terapijski nevina bolesnika (126 muškara i 36 žena), sa potvrđenom dijagnozom hroničnog hepatitisa B (HHB). HHB je povrđen na osnovu biohemijskih, seroloških i virusoloških parametara infekcije, kao i patohistološkog pregleda tkiva jetre. U cilju praćenja prirodnog toka HHB, kod bolesnika su određivani aktivnost alaninaminotrasferaze (ALT), protrombinsko vreme (PV) i koncentracija serumskih albumina, svakih šest meseci, pre uvođenja antivirusne terapije i tokom terapije lamivudinom. Pored toga ispitanicima su određivani i HBeAg, antiHBe, antiHBc, HBV DNK PCR, genotip, subgenotip i HBsAg subtip. Terapija lamivudinom je sprovedena kod bolesnika koji su ispunili kriterijume Evropskog udruženja za izučavanje jetre. Povoljan ishod terapije podrazumevao je supresiju virusne DNK i normalizaciju aktivnosti ALT. Pojava rezistencije HBV na lamivudin definisana je kroz virusološki i biohemijski proboj, odnosno kao izostanak supresije virusne replikacije. . Rezultati: Kod 14,2% ispitanika bio je prisutan genotip A, a kod ostalih genotip D. Svi bolesnici sa genotipom A, imali su subgenotip A2 i HBsAg subtip adw2. Kod bolesnika sa genotipom D, potvrđena su tri subgenotipa: D1 kod 14 (8,6%) bolesnika, D2 kod 47 (29%) bolesnika i najzastupljeniji D3 kod 78 (48,1%) bolesnika. Kod 158 (97,5%) ispitanika određeni su HBsAg subtipovi: adw2 (14,5%), ayw2 (50%), ayw3 (34,2%), ayw4 (1,3%). Prisustvo HBeAg+ serologije bilo je značajno više kod infekcije genotipom A nego D (60,8% vs. 30,9%; p=0,02). Stepen viremije (HBV DNK IU/l) nije se razlikovao u zavisnosti od genotipoa, subgenotipa i HBsAg subtipa. Stepen viremije bio je različit u zavisnosti od HBeAg/antiHBe statusa: kod bolesnika sa HBeAg+/antiHBe−, HBeAg−/antiHB+ i HBeAg−/antiHBe− serološkim nalazima, vrednosti HBV DNK bila je 4,24, 2,67 i 2,69 log10IU/l (p=0,01). Srednje vreme do progresije u cirozu iznosilo je 23,2±3,4 godina za genotip A i 15,1±8,4 godina genotip D (P = 0.02). Uspeh terapije lamivudinom nije zavio od genotipa, subgenotipa, HBsAg subtipa i stepena preterapije viremije. Kod bolesnika sa manje uznapredovalom bolešću (bez fibroze odn. sa lakom fibrozom), verovatnoća da se razvije rezistencija na lamivudin bila je značajno manja nego kod bolesnika sa teškom fibrozom fibrozom (48,9% vs. 76,1%; p=0,03). Zaključak: Aktivnost ALT i koncentarcija serumskih albumina nisu se razlikovali u zavisnosti od genotipa, subgenotipa i HBsAg subtipa. Bolesnici sa genotipom D imali su bržu progresiju u cirozu jetre od bolesnika sa genotipom A. HBeAg pozitivnost je bila češća kod bolesnika inficiranih genotipom A, subgenotipom A2 i adw2 subtipom. Teška fibroza i ciroza jetre bili su negativni prediktivni faktori za uspešnost lečenja lamivudinom.sr
dc.description.abstractPurpose: Genetic variability of hepatitis B virus (HBV) is a consequence of the high degree of viral replication and its inability to correct accidental errors arising during this process. In addition, therapy with nucleoside/nucleotide analogues (NA) leads to the selection of resistant strains. HBsAg serotypes are detected on the basis of HBsAg reactivity with known antibody panels. HBV genotypes and subgenotypes are defined based on differences in nucleotide sequences along the genome. The main objective of this study was to analyze the effect of genotype, subgenotypes and HBsAg subtypes on the clinical course, histopathologic changes in liver and the progression to liver cirrhosis and hepatocellular carcinoma. Methodology: This study included 162 treatment naive patients (126 men and 36 women) with a confirmed diagnosis of chronic hepatitis B (CHB). The diagnosis of CHB was established according to clinical presentation, biochemical and virological markers of infection, along with pathohistology findings at aspiration liver biopsy. In order to assess the natural history of chronic HBV infection, along with treatment response, serum bilirubin, ALT, prothrombin time and albumin levels were measured at the time of diagnosis, and every six months, before the introduction of antiviral therapy with lamivudine, and at same intervals thereafter in both subgroups of treated and untreated patients. Different serological markers, such as HBsAg/Ab, HBeAg/Ab and HBcAb, as well as HBV DNA level, genotypes, subgenotypes and HBsAg subtypes also were evaluated. Lamivudine therapy was introduced in patients who met the criteria of the European Association for the Study of Liver. Suppression of viral DNA along with ALT normalization was considered a favorable response to antiviral therapy. Emergence of HBV resistance to lamivudine was considered most probable in those patients who experienced virological and biochemical breakthrough, and/or in those who never reached viral suppression. Results: 14.2% of patients had genotype A, while other had genotype D. Patients with genotype A, had subgenotype A2 and HBsAg subtype adw2. Patients with genotype D, had three subgenotypes: D1 (8,6% of patients), D2 (29%) and the most common D3 (48,1%). Different HBsAg subtypes were found: adw2 (14,5%), ayw2 (50%), ayw3 (34,2 %) and ayw4 (1,3%). The prevalence of HBeAg+ serology of 60.8% among patients infected with genotype A was significantly higher then 30.9% recorded among those with genotype D (P = 0.02). The viral loads (HBV DNA IU/l) did not differ depending on genotypes, subgenotypes and HBsAg subtypes. The patients with HBeAg +/HBeAb-, HBeAg-/HBeAb+ and both HBeAg and HBeAb negative serologic patterns had differnet viral loads: 4.24, 2.67 and 2.69 log10IU/L (p = 0.01). Mean time to liver cirrhosis was 23.2±3.4 years and 15.1±8.4 years, for genotypes A and D, respectively (P= 0.02). Genotypes, subgenotypes and HBsAg subtypes, as well as pretreatment viral loads did not influence the lamivudine treatment outcome. The probability of lamivudine resistance was significantly lower in patient with less advanced disease (with no/mild fibrosis) than in patients with severe fibrosis ( 48,9 % vs. 76,1%, p=0,03). Conclusion: Genotypes, subgenotypes and HBsAg subtypes did not influence the serum ALT activity and albumin concentration. Patients with genotype D had faster progression to liver cirrhosis than in patients with genotype A. HBeAg positivity was more common in patients infected with genotype A, subgenotype A2 and adw2 subtype. Severe fibrosis and cirrhosis were negative predictive factors for lamivudine treatment outcome.en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Медицински факултетsr
dc.rightsopenAccessen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceУниверзитет у Београдуsr
dc.subjectHBVsr
dc.subjectHBVen
dc.subjectgenotipsr
dc.subjectsubgenotipsr
dc.subjectHBsAg subtipsr
dc.subjectprognozasr
dc.subjectgenotypeen
dc.subjectsubgenotypeen
dc.subjectHBsAg sutypeen
dc.subjectprognosisen
dc.titleUticaj genotipa virusa hepatitisa B na klinički tok i ishod hronične infekcijesr
dc.titleThe influence of hepatitis B virus genotype on clinical course and outcome of chronic infectionen
dc.typedoctoralThesisen
dc.rights.licenseBY-NC-ND
dcterms.abstractДелић, Драган; Лазаревић, Ивана; Милошевић, Ивана; Утицај генотипа вируса хепатитиса Б на клинички ток и исход хроничне инфекције; Утицај генотипа вируса хепатитиса Б на клинички ток и исход хроничне инфекције;
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/11265/Disertacija.pdf
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/11265/Disertacija.pdf
dc.identifier.rcubhttps://hdl.handle.net/21.15107/rcub_nardus_2480


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