Variability in the Precore and Core Promoter Regions of HBV Strains in Morocco: Characterization and Impact on Liver Disease Progression

Bouchra Kitab,Rajaa Afifi,Christian Trepo,Isabelle Chemin,Abdellah Essaid El Feydi,Soumaya Benjelloun,Fabien Zoulim,Sayeh Ezzikouri,Mustapha Benazzouz,Hanane Salih Alj,Wafaa Essamri

doi:10.1371/journal.pone.0042891

Bouchra Kitab, Rajaa Afifi + Show 9 more

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https://doi.org/10.1371/journal.pone.0042891

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Abstract

BackgroundHepatitis B virus (HBV) is one of the most common human pathogens that cause aggressive hepatitis and advanced liver disease (AdLD), including liver cirrhosis and Hepatocellular Carcinoma. The persistence of active HBV replication and liver damage after the loss of hepatitis B e antigen (HBeAg) has been frequently associated with mutations in the pre-core (pre-C) and core promoter (CP) regions of HBV genome that abolish or reduce HBeAg expression. The purpose of this study was to assess the prevalence of pre-C and CP mutations and their impact on the subsequent course of liver disease in Morocco.Methods/Principal FindingsA cohort of 186 patients with HBeAg-negative chronic HBV infection was studied (81 inactive carriers, 69 with active chronic hepatitis, 36 with AdLD). Pre-C and CP mutations were analyzed by PCR-direct sequencing method. The pre-C stop codon G1896A mutation was the most frequent (83.9%) and was associated with a lower risk of AdLD development (OR, 0.4; 95% CI, 0.15–1.04; p = 0.04). HBV-DNA levels in patients with G1896A were not significantly different from the other patients carrying wild-type strains (p = 0.84). CP mutations C1653T, T1753V, A1762T/G1764A, and C1766T/T1768A were associated with higher HBV-DNA level and increased liver disease severity. Multiple logistic regression analysis showed that older age (≥40 years), male sex, high viral load (>4.3 log10 IU/mL) and CP mutations C1653T, T1753V, A1762T/G1764A, and C1766T/T1768A were independent risk factors for AdLD development. Combination of these mutations was significantly associated with AdLD (OR, 7.52; 95% CI, 4.8–8; p<0.0001).ConclusionsThis study shows for the first time the association of HBV viral load and CP mutations with the severity of liver disease in Moroccan HBV chronic carriers. The examination of CP mutations alone or in combination could be helpful for prediction of the clinical outcome.

Highlights

Hepatitis B virus (HBV) infection is a major public health problem, with approximately 360 million chronic carriers worldwide
This study shows for the first time the association of HBV viral load and core promoter (CP) mutations with the severity of liver disease in Moroccan HBV chronic carriers
These patients are at increased risk of developing advanced liver disease (AdLD), including liver cirrhosis (LC) and hepatocellular carcinoma (HCC), accounting for 0.5 to 1.2 million deaths annually [1,2]

Summary

Introduction

Hepatitis B virus (HBV) infection is a major public health problem, with approximately 360 million chronic carriers worldwide These patients are at increased risk of developing advanced liver disease (AdLD), including liver cirrhosis (LC) and hepatocellular carcinoma (HCC), accounting for 0.5 to 1.2 million deaths annually [1,2]. The majority of patients remain for life time in an inactive carrier state, other HBeAg-negative subjects retain or redevelop active HBV replication associated with progressive liver damage [11] This form of disease is referred as HBeAg-negative CHB (e-CHB) and is mostly associated with mutations in the precore (pre-C, nucleotides (nts) 1814–1900) and core promoter (CP, nts 1613–1849) regions of HBV genome [12].

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