Uticaj genotipa virusa hepatitisa B na klinički tok i ishod hronične infekcije
The influence of hepatitis B virus genotype on clinical course and outcome of chronic infection
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Cilj: 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 pri...rodnog 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.
Purpose: 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 p...athohistology 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.