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

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.

HLA-DPPolymorphisms Affect the Outcomes of Chronic Hepatitis B Virus Infections, Possibly through Interacting with Viral Mutations

“…The C1653T, T1674C/G, G1719T, A1727T, C1730G, and C1799G mutations were located in the core promoter region (nt 1591 to nt 1882) (45), resulting in amino acid substitutions at H94Y, S101P, V116L, K118N, D119E, and S142C, respectively, in the C-terminal region of HBx. The C1653T mutation also changes the box-␣ binding site for the transcription factor C/EBP, which enhances the activity of the core promoter and viral replication (46). The C1673T mutation does not cause an amino acid substitution but binds to transcription factors such as C/EBP (47), resulting in possible alterations in viral activities.…”

“…The G1896A mutation introduces a stop codon, W28Stop, in the pre-C region, which impairs HBeAg expression (46). The HBV mutations in the core promoter region fall in HLA-A2-restricted epitopes, while A31T and T49A mutations in the pre-S2 region fall in the restricted epitopes of HLA-A2/A3 and HLA-DR1/DR2 as well as HLA-A2 and HLA-DR1, respectively (49).…”

Different precore/core mutations of hepatitis B interact with, limit, or favor liver fibrosis severity

“…CHB is a dynamic process that results in a balance between the host immune response and HBV replication. During the HBeAg seroconversion phase, the pressure by the host immune system selects a number of genetic variants in the basal core promoter (BCP) and precore (PC) regions . The major missense or nonsense mutations in the PC region are found in codons 1, 2, 28, and 29.…”

Clinical utility of complex mutations in the core promoter and proximal precore regions of the hepatitis B virus genome

“…The respective odds ratios for HCC were 5.4286 (95%CI: .353-21.7821). The combination of C1766T and T1768A appears to enhance the carcinogenic effects of the X protein, but these mutations are rarely identified in South Korea [33,50] . Multivariate analyses of variables in relation to HCC indicate that mutation number is the only significantly independent viral factor [33] .…”