muthanakhalil
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2 months ago Hepatitis B virus (HBV) is a partially double-stranded DNA virus with four overlapping open reading frames (ORFs) encoding surface proteins, polymerase, capsid proteins, and X protein. HBV exhibits a higher mutation rate compared to other DNA viruses due to its replication mechanism involving an RNA intermediate and a reverse transcriptase lacking proofreading capability (1). Nine genotypes (A-I) have been identified, with genotype D predominant in Mediterranean regions, Northern Africa, India, and the Middle East, while genotypes B and C are prevalent in East Asia (1, 2). Mutations in specific genomic regions, particularly the precore (PC) and basal core promoter (BCP), are associated with HBV-mediated liver disease progression. These mutations can inhibit or downregulate hepatitis B e antigen (HBeAg) production, leading to HBeAg-negative chronic HBV infection (3). Notably, the G1896A mutation in the precore region and the A1762T/G1764A double mutation in the BCP have been implicated in HBeAg loss and increased hepatocellular carcinoma (HCC) risk, respectively (2, 3). The core/capsid protein (HBcAg) and HBeAg, encoded by the precore/core ORF, play crucial roles in viral replication and immune response. Mutations in this region can affect protein expression, structure, and antigenicity, potentially enabling immune escape and persistent infection. HBeAg-negative patients typically exhibit reduced response to conventional interferon therapy compared to HBeAg-positive cases (3, 4). Understanding the prevalence and distribution of mutations in the surface, BCP, and PC genes is essential for accurate diagnosis, management of immune escape mutants, and global HBV elimination efforts. These mutations significantly impact clinical management, treatment response prediction, HCC risk assessment, disease progression monitoring, and personalized treatment strategies (4-5).
The core or capsid protein (HBcAg) and HBeAg are encoded on the precore/core ORF, and variations in this region can impact protein structure, expression, encapsidation, and antigenicity, potentially influencing disease progression (3). HBeAg-negative chronic patients respond less to conventional interferon therapy than HBeAg-positive cases (8). The HBeAg phenotype is caused by substitutions, particularly a stop codon W28* in the precursor sequence, which abolishes HBeAg expression (9). Studies on precore variations and molecular mechanisms have confirmed the role of HBeAg-negative status in HCC development (9,10).
Certain mutations in HBcAg, a protein of 183 residues, are important for disease progression (3,10). HBcAg is an immunogenic protein that triggers a strong immune response by cytotoxic T lymphocytes (8). These mutations enable the virus to evade host immune responses and establish a persistent infection (8,10). Numerous HBcAg substitutions are associated with immune escape and more severe liver disease (10).
During long-term HBV infection, the immune system and nucleotide substitutions shape viral populations, leading to the emergence of variants with mutations (2). Several mutations in the surface (S), BCP, and PC genes of HBV have been linked to inaccurate diagnosis and the development of immune escape mutants (IEMs), which can result in chronic infection (1). Understanding the prevalence and spread of these mutations is essential for global HBV elimination efforts (1).
HBV's variable genome comprises ten genotypes and sub-genotypes with 4-8% intra-genotypic divergence (1). HBV core/pre-core mutations play a vital role in chronic HBV infection, impacting disease progression, treatment response, and HCC risk. Understanding these mutations is crucial for personalized treatment and patient management (2,5). Identifying mutations in the precore and core promoter regions is essential for tailoring personalized treatment plans, predicting treatment response, monitoring disease progression, and reducing HCC risk (3b).
HBV core/pre-core mutations impact clinical management, treatment response prediction, HCC risk stratification, viral transmission dynamics, and guiding research and development of new antiviral therapies (11).Identification of core/pre-core mutations is crucial for: Clinical management: Guiding decisions on monitoring frequency and treatment initiation. Treatment response prediction: Informing the selection of appropriate antiviral therapies. HCC risk stratification: Enabling closer monitoring and early intervention in high-risk patients. Disease progression monitoring: Assessing the potential for severe liver disease and treatment efficacy. Epidemiological studies: Tracing transmission routes and understanding infection dynamics. In conclusion, comprehensive analysis of HBV core/pre-core mutations is vital for optimizing patient outcomes, enhancing treatment efficacy, and informing public health strategies. This knowledge also contributes to the development of novel antiviral therapies and guides research efforts in combating chronic HBV infection. Determining the genotype-specific frequencies of precore and core promoter mutations among HBeAg-negative chronic hepatitis B patients in Iraq, and correlating these mutations with disease progression and treatment outcomes, is complicated by the genetic diversity of HBV, regional variations in HBV genotypes, and the influence of these mutations on clinical management. There is a scarcity of comprehensive data on the genotype-specific prevalence of precore and core promoter mutations in HBeAg-negative chronic hepatitis B patients in Iraq. This study aims to fill this knowledge gap by conducting a thorough investigation of these mutations in the Iraqi population. The correlation between precore and core promoter mutations and disease progression and treatment outcomes in HBeAg-negative chronic hepatitis B patients is not well-understood. This study seeks to elucidate the relationship between these mutations and the clinical course of the disease, as well as their influence on treatment efficacy. The genetic diversity and complexity of HBV, with its multiple genotypes and sub-genotypes, make it challenging to study the genotype-specific prevalence and impact of precore and core promoter mutations. This study will employ advanced molecular techniques to accurately identify and characterize these mutations in the Iraqi population. Understanding the genotype-specific frequencies and impact of precore and core promoter mutations in HBeAg-negative chronic hepatitis B patients can have significant clinical implications for personalized treatment strategies. This study aims to provide valuable insights that can guide treatment decisions and improve patient outcomes in the Iraqi population. Overall, the challenge lies in addressing the gaps in knowledge regarding the genotype-specific prevalence and impact of precore and core promoter mutations in HBeAg-negative chronic hepatitis B patients in Iraq, and in elucidating their clinical implications for personalized treatment strategies. This study addresses the lack of data on genotype-specific prevalence of precore and core promoter mutations in HBeAg-negative chronic hepatitis B patients in Iraq. It aims to investigate the correlation between these mutations and disease progression, treatment outcomes, and the genetic diversity of HBV in the Iraqi population. The study seeks to provide valuable insights for personalized treatment strategies and improve patient outcomes in this context.
1-To determine the distribution of HBV genotypes among HBeAg-negative chronic hepatitis B patients in Iraq. 2-Genotyping of HBV in precore and core promoter mutations in HBeAg-negative chronic hepatitis B patients 2-To identify and quantify the prevalence of precore and core promoter mutations in HBeAg-negative chronic hepatitis B patients in Iraq. 3-To determine the prevalence of prevalence of precore mutation (such as G1898A, G1901A, G1910A, and G1915A mutations) and its association with severe liver diseases. 4-To analyze the genotype-specific frequencies of precore and core promoter mutations in the study population. 5-To investigate the correlation between specific precore and core promoter mutations and markers of disease progression (e.g., viral load, liver enzyme levels, fibrosis stage). 6-To assess the relationship between precore and core promoter mutations and treatment outcomes in patients receiving antiviral therapy. 7-To compare the prevalence and patterns of mutations found in the Iraqi population with those reported in other geographic regions or ethnic groups. 8-To evaluate potential associations between patient demographics (age, gender, region) and the presence of specific mutations or genotypes. 9-To explore the impact of different mutation patterns on the clinical course of HBeAg-negative chronic hepatitis B in the Iraqi population. Objective 1-To identify the distribution of HBV genotypes among HBeAg-negative chronic hepatitis B patients in Iraq. 2-To quantify the prevalence of precore (such as G1898A, G1901A, G1910A, and G1915A mutations) mutation) and core promoter mutations in the study population and its association with severe liver diseases. 3-To analyze the frequency of these mutations across different HBV genotypes found in the Iraqi population.
5-To assess the correlation between specific precore and core promoter mutations and indicators of disease progression, such as viral load, liver enzyme levels, and fibrosis stage. 6-To evaluate the impact of these mutations on treatment outcomes in patients receiving antiviral therapy.