Frequency and clinical significance of core promoter and precore region mutations in Tunisian patients infected chronically with hepatitis B

Abstract

Genetic variability of hepatitis B virus (HBV) in the C gene and its association with the different stages of chronic liver disease has been studied inadequately with controversial results. The objectives of the current study were to determine the frequency of core promoter and precore mutations in chronic hepatitis B in Tunisia and to evaluate their impact on viral replication and disease progression. Sequencing was performed in upstream regulatory sequence (URS), pre-core (PreC) and basal core promoter (BCP) regions for 123 chronic infected patients by HBV genotype D at different status of disease. Mutations were detected in 98.4% of cases, affecting URS, BCP and Pre-C in 95.1%, 95.9% and 87.8% respectively. Multi-mutations increased significantly from asymptomatic carrier to advanced liver disease status. G1896A (74.8%), G1764A/T/C (71.5%), G1899A (54.4%) and T1678C (52%) were the most common. Special attention should be paid to A1703T, T1678C/G-A1703T, and A1652G-A1679G mutations probably specific of Tunisians sequences; they were observed in 40.6%, 41.5% and 30.1% respectively. A1679G/C, T1753C/G/A, A1762T/G and A1762T-G1764A were more prevalent in older patients. High DNA levels were associated with G1899A or G1764T/C-C1766G-C1799G and advanced liver disease with mutations at positions 1762, 1764 and/or 1899 alone or in double or triple mutations. It was also shown that substitutions at nucleotides 1762, 1764 and 1899 have an impact on the disease progression. It is the first report for specific mutations in the URS region for genotype D. It should be completed by studying eventual correlation with clinical progression and the response to treatment.

Evaluation of PCR-RFLP in the Pre-S Region as Molecular Method for Hepatitis B Virus Genotyping

“…These atypical profiles were observed especially after a long evolution of the disease, since they were significantly associated with advanced age and PLD rather than groups of CAH and IC. These findings support previous reports about chronic HBV infection, which was characterized, in its ultimate stages, by an accumulation of mutations under host immune pressure (34, 42-46). Finally, atypical profiles could be explained by inability of the method used in this study to distinguish between eight sub-genotypes described for Genotype D (31) or to detect genotypes G and H (16).…”

“…The multiplicity of patterns for the same genotype with variability in their geographical distribution should be taken into consideration especially in countries where only one genotype predominantly circulates; it plays, probably, an important role in disease progression and response to antiviral therapy. Accordingly, ongoing studies are primarily interested in molecular aspects of genotype D sub-genotypes and mutations in different regions of the genome rather than comparison between different genotypes to understand the evolution of chronic hepatitis B (34). …”

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

“…Therefore, it is not surprising that T1753V is more frequently linked to HBV genotype C than genotype B (19.2% vs 1.9%; P = 0.013) [15] . G1899A combined with the BCP double mutation is the single risk factor indicating HCC risk in Thailand and Tunisia, but the linkages between mutations are less clear in South Korea [33,37,45,48] . Our data indicate that while G1896A increases steadily with time, the accumulation of A1846T begins to increase during the quadruple phase of mutations.…”

Characterization of Basal Core Promoter/Precore Gene Mutations in Chronically Infected Patients with Hepatitis B Virus Genotype D in Mersin Province, Turkey

“…1858 pozisyonunda T-A baz eşleşmesi nedeniyle pregenomik kapsidasyon sinyalinin sekonder yapı stabilitesini artırdığı için, PC G1896A varyantı, Akdeniz ülkelerinde predominant olan D genotipi ile enfekte hastalar arasında en yaygın bulunmaktadır 8,30,32 . Bu durum viral replikasyonun devamını ve böylece immün temizlenmeden kaçmada avantaj sağladığı için viral persistansa yardımcı olmaktadır 8,32 . Japonya ve Güneydoğu Asya'da en çok görünen genotip B ve C'de, PC nt.…”