Different Stages Of Hepatitis Research Articles

The effect of intrahepatic cholestasis in pregnancy combined with different stages of hepatitis B virus infection on pregnancy outcomes: a retrospective study.

To investigate the impact of intrahepatic cholestasis of pregnancy (ICP) with hepatitis B virus (HBV) infection on pregnancy outcomes. We selected 512 pregnant women, collected the data including maternal demographics, main adverse pregnancy outcomes and maternal HBV infected markers HBeAg and HBV-DNA loads status, then have a comparative analysis. There were 319 solitary ICP patients without HBV infection (Group I) and 193 ICP patients with HBV infection. Of the latter, there were 118 cases with abnormal liver function(Group II) and 80 cases with normal liver function(Group III). All HBV-infected pregnant women with ICP were divided into hepatitis Be antigen (HBeAg)-positive group (102 cases) and HBeAg-negative group (91 cases), according to the level of the serum HBeAg status; and into high viral load group (92 cases), moderate viral load group (46 cases) and low viral load group (55 cases) according to the maternal HBV-DNA level. Group II had a higher level of serum total bile acids, transaminase, bilirubin as well as a higher percentage of premature delivery, neonatal intensive care unit (NICU) admission and meconium-stained amniotic fluid (MSAF) compared with the other two groups(P < 0.05), but there were no significant differences in the above indicators between the Group I and Group III. Among the HBV-infected patients with ICP, HBeAg-positive group had a higher level of serum transaminase, bilirubin and bile acid as well as earlier gestational weeks of delivery, lower birth weight of new-borns and a higher rate of NICU admission than HBeAg-negative group (P < 0.05). Those with a high viral load (HBV-DNA > 106IU/ml) had a higher level of transaminase, bilirubin, and bile acid as well as shorter gestational weeks of delivery, lower birth weight of new-borns and a higher rate of NICU admission compared with those with a low or moderate viral load (P < 0.05). HBV-infected pregnant women with ICP combined with abnormal liver function have more severe liver damage, a higher percentage of preterm birth and NICU admission. HBeAg-positive status and a high HBV-DNA load will increase the severity of conditions in HBV-infected pregnant women with ICP. HBV-infected patients with ICP who have abnormal liver function, HBeAg-positive or a high viral load should be treated more actively.

Serum Expression Level of MicroRNA-122 and its Significance in different Stages of Hepatitis B Virus Infection.

This study aims to determine the serum expression level of miRNA-122 and its significance in the different stages of Hepatitis B virus infection. The study subjects were recruited and grouped for Hepatitis B associated with Chronic Hepatitis B infection, hepatic sclerosis, hepatocellular carcinoma, and healthy controls were also considered. Venous blood was collected from the participants including the controls and routine blood tests and quantification of miRNA-122 were done and analyzed in each case of hepatitis B infection and compared with that of healthy controls. The miRNA-122 was determined, which came to be highest in patients with Chronic Hepatitis B while patients with hepatic sclerosis and patients with hepatocellular carcinoma showed a subsequent number of copies. The number of copies of miRNA-122 in the CHB, hepatic sclerosis, and HCC group was significantly higher than in the healthy control. The quantification of miRNA-122 and subsequently plotting the ROC curve has shown that miRNA-122 can be considered as a biomarker of hepatitis B for screening and diagnosis purposes.

Diversity and composition of gut microbiota in healthy individuals and patients at different stages of hepatitis B virus-related liver disease

BackgroundHepatitis B virus (HBV) causes chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma. The evolution of human gut microbiota during the progression of HBV-related liver diseases remains unclear. Therefore, we prospectively enrolled patients with HBV-related liver diseases and healthy individuals. Through 16S ribosomal RNA amplicon sequencing, we characterized the gut microbiota of the participants and predicted the functions of microbial communities.ResultsWe analyzed the gut microbiota of 56 healthy controls and 106 patients with HBV-related liver disease [14 with resolved HBV infection, 58 with CHB, and 34 with advanced liver disease (15 with liver cirrhosis and 19 with hepatocellular carcinoma)]. Patients with HBV-related liver disease exhibited a higher degree of bacterial richness (all P < 0.05) than did healthy controls. Beta diversity analyses revealed a distinct clustering pattern between healthy controls and patients with HBV-related liver disease (all P < 0.05). The composition of bacteria (from the phylum level to the genus level) varied across the stages of liver disease. Linear discriminant analysis effect size revealed multiple taxa that differ significantly in abundance between healthy controls and patients with HBV-related liver disease; however, fewer differences were observed among patients with resolved HBV infection, those with CHB, and those with advanced liver disease. The ratio of Firmicutes to Bacteroidetes was increased in all three patient groups compared with the ratio in healthy controls (all P < 0.001). The analysis of the sequencing data by using PICRUSt2 revealed the changes in microbial functions with disease progression.ConclusionsThe diversity and composition of gut microbiota appear to vary significantly between healthy controls and patients at different stages of HBV-related liver disease. The understanding of gut microbiota may provide novel therapeutic options in these patients.

The role of non-coding RNAs in the diagnosis of different stages (HCC, CHB, OBI) of hepatitis B infection.

Despite the availability of an effective hepatitis B virus (HBV) vaccine and universal immunization schedules, HBV has remained a health problem in various stages such as occult hepatitis B infection (OBI), chronic hepatitis B (CHB), and hepatocellular carcinoma (HCC), which is considered one of the possible phases during chronic HBV infection. OBI is defined as the persistence of HBV genomes in hepatocytes of patients with a negative HBV surface antigen (HBsAg) test and detectable or undetectable HBV DNA in the blood. OBI is occasionally associated with infection caused by mutant viruses that produce a modified HBsAg that is undetected by diagnostic procedures or with replication-defective variations. Many aspects of HBV (OBI more than any other stage) including prevalence, pathobiology, and clinical implications has remained controversial. According to a growing body of research, non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been linked to the development and progression of a number of illnesses, including viral infectious disorders. Despite a shortage of knowledge regarding the expression and biological activities of lncRNAs and miRNAs in HBV infection, Hepatitis B remains a major global public health concern. This review summarizes the role of lncRNAs in the diagnosis and treatment of different stages of hepatitis B infection.

Patients with COVID-19 and HBV Coinfection are at Risk of Poor Prognosis.

IntroductionThis study aimed to determine whether there is a difference in the risk of death/critical illness between different stages of hepatitis B virus (HBV) (resolved hepatitis B, HBeAg (−) chronic hepatitis B [CHB]/infection, HBeAg (+) CHB/infection, and HBV reactivation) coinfected with coronavirus disease 2019 (COVID-19); and if there is a difference, whether it is due to abnormal liver function and to what extent.MethodsThis cohort study included all COVID-19 inpatients of a single-center tertiary care academic hospital in Wuhan, Hubei, China, between February 4, 2020, and follow-up to April 14, 2020. A total of 2899 patients with COVID-19 were included as participants in this study, and they were divided into five groups based on hepatitis B infection status. Follow-up was conducted for mortality and ICU admission during hospitalization.ResultsThe median follow-up time was 39 days (IQR, 30–50), with 66 deaths and 126 ICU admissions. After adjustment, compared with patients without CHB, the hazard ratio (HR) for ICU admission was 1.86 (95% CI: 1.05–3.31) for patients with HBeAg (+) CHB/infection. The HR for death was 3.19 (95% CI: 1.62–6.25) for patients with HBeAg (+) CHB/infection. The results for the mediating effect indicated that the total effect of HBeAg (+) CHB/infection on death/ICU stay was partially mediated by abnormal liver function, which accounted for 79.60% and 73.53%, respectively.ConclusionPatients with COVID-19 coinfected with HBV at the HBeAg (+) CHB/infection stage have an increased risk of poor prognosis, and abnormal liver function partially mediates this increased risk of poor prognosis caused by the coinfection.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00638-4.

Artificial intelligence for hepatitis evaluation.

Recently, increasing attention has been paid to the application of artificial intelligence (AI) to the diagnosis of diverse hepatic diseases, which comprises traditional machine learning and deep learning. Recent studies have shown the possible value of AI based data mining in predicting the incidence of hepatitis, classifying the different stages of hepatitis, diagnosing or screening for hepatitis, forecasting the progression of hepatitis, and predicting response to antiviral drugs in chronic hepatitis C patients. More importantly, AI based on radiology has been proven to be useful in predicting hepatitis and liver fibrosis as well as grading hepatocellular carcinoma (HCC) and differentiating it from benign liver tumors. It can predict the risk of vascular invasion of HCC, the risk of hepatic encephalopathy secondary to hepatitis B related cirrhosis, and the risk of liver failure after hepatectomy in HCC patients. In this review, we summarize the application of AI in hepatitis, and identify the challenges and future perspectives.

Application of serum N -glycan profiling diagnostic model in evaluation of liver fibrosis in patients with hepatitis C

Objective: To study the changes of serum N-glycan abundance in patients with liver fibrosis at different stages of hepatitis C, and to establish and evaluate the diagnostic model for clinical application value. Methods: Data of 169 hepatitis C virus-infected cases with liver fibrosis were enrolled. Nine kinds of serum N-glycans were detected and analyzed using DNA sequencer-assisted fluorophore-assisted capillary electrophoresis technology. A binary logistics regression method was used to establish a diagnostic model based on the changes in the relative content of N-glycans in each stage of liver fibrosis. Receiver operating characteristic curve was used to evaluate and compare the diagnostic efficacy with other liver fibrosis diagnostic models. Results: N-glycan diagnostic model (B and C) had highest AUROC= 0.776, 0.827 for distinguishing fibrosis S1~S2 to S3~S4 and S1~S3 to S4 than GlycoFibroTest (AUROC = 0.760, 0.807), GlycoCirrhoTest (AUROC = 0.722, 0.787), aspartate aminotransferase to platelet ratio index (AUROC = 0.755, 0.751), FIB-4 index (AUROC = 0.730, 0.774), and S-index (AUROC = 0.707, 0.744). However, the diagnostic efficacy of model A (AUROC = 0.752) for distinguishing fibrosis S1 with S2~S4 had lower diagnostic potency than that of the aspartate aminotransferase to platelet ratio index (AUROC = 0.807). Diagnostic efficiency was improved when the N-glycan profiling and the aspartate aminotransferase to platelet ratio index were combined to diagnose liver fibrosis in each stage, and the area under the receiver operating characteristic curve was 0.839, 0.825, and 0.837, respectively. Conclusion: The serum N-glycan profiling diagnostic model has potential clinical application value in the diagnosis of liver fibrosis in patients with hepatitis C.

Evaluating serum levels of miR-181a and miR-let7a in HCV infected Iranian patients compared with healthy individuals

IntroductionHepatitis C virus (HCV) is a single-stranded RNA virus which causes acute liver disorder that could develop cirrhosis and hepatocellular carcinoma of the HCV life cycle, and their different expression. Currently, the prevalence of hepatitis C disorder among the general population of Iran is estimated to be 0.3%. MiR-let7a and miR-181a have effects on multiple steps of the HCV life cycle and their differential expression levels have been observed in different stages of hepatitis C infection. At the current study, we investigated the serum levels of miR-let7a and miR-181a in HCV-infected individuals compared to the healthy ones. Materials and methods97 serum samples of hepatitis C-infected patients (case group) and 97 serum samples of healthy individuals (control group) were used for total RNA extraction, cDNA synthesis, real-time polymerase chain reaction (PCR) performance, and final evaluation of serum levels of miR-let7a and miR-181a in the case group, compared with the healthy ones. ResultsLevels of miR-let7a in serum samples of the case group compared with the healthy group showed a considerable decrease with a P value <0.001, while there was no significant difference in the serum levels of miR-181a between these two groups (P value = 0.064). ConclusionsThe serum levels of miR-let7a in the case group had a decrease compared with the control group, and the serum levels of miR-181a in these two groups did not differ significantly. Accordingly, further studies on the possible role of miR-let7a levels in different stages of HCV infection are necessary.

Potential role of\xa0intestinal microflora\xa0in disease progression among patients with different stages of Hepatitis B

BackgroundIncreasing evidence demonstrate that the gut microbiota is involved in the pathogenesis of liver diseases, and faecal microbiota transplantation is considered to be a promising new treatment option. However, there are no reports on the intestinal flora of asymptomatic HBV carriers using next-generation sequencing. This study intends to investigate the potential role of the intestinal microflora in predicting the progression of Hepatitis B patients in different non-cancerous stages.ResultsA total of 266 patients with different stages of Hepatitis B and 31 healthy controls were included in this study. Some of the subjects (217 cases) underwent 16S rRNA gene sequencing. Compared with the control group (CK), the α diversity of patients in Group A (HBV carrier) slightly increased, while that of patients in the other three groups decreased. Each group of patients, especially those in Group C (cirrhosis) and Group D (acute-on-chronic liver failure), could be separated from the CK using weighted UniFrac PCoA and ANOSIM. LEfSe revealed that 40 taxa belonging to three phyla had an LDA larger than 4. In addition to the comparison between Group B (chronic Hepatitis B) and Group C, the specific flora and potential taxonomic function were also identified. Different microbial communities were found to be highly correlated with clinical indicators and the Child-Pugh scores. Changes in the microbial community were highly related to the alternations of host metabolism, which in turn, was related to the development of Hepatitis B. Our analysis identified a total of 47 strains with potential biomarker functions at all levels except for the phylum level.ConclusionsFaecal microbiota transplantation of some potential beneficial bacteria can change with the occurrence of disease, and HBV carriers might be the most suitable donors.

Serum Hepcidin Level in Different Stages of Hepatitis C Induced Chronic Liver Disease

Patients with chronic hepatitis C (CHC) often have increased liver iron, a condition associated with more rapid progression to cirrhosis. Hepcidin decrease is a possible pathophysiological mechanism of iron overload in these patients.

Changes of procoagulant and anticoagulant functions in different stages of hepatitis B virus-associated liver disease

Changes of procoagulant and anticoagulant functions in different stages of hepatitis B virus-associated liver disease

Gut microbiota dysbiosis in patients with hepatitis B virus-induced chronic liver disease covering chronic hepatitis, liver cirrhosis and hepatocellular carcinoma.

The information regarding the effect of hepatitis B virus (HBV) infection on gut microbiota and the relationship between gut microbiota dysbiosis and hepatitis B virus-induced chronic liver disease (HBVCLD) is limited. In this study, we aimed at characterizing the gut microbiota composition in the three different stages of hepatitis B virus-induced chronic liver disease patients and healthy individuals. Faecal samples and clinical data were collected from HBVCLD patients and healthy individuals. The 16S rDNA gene amplification products were sequenced. Bioinformatic analysis including alpha diversity and PICRUSt was performed. A total of 19 phyla, 43 classes, 72 orders, 126 families and 225 genera were detected. The beta-diversity showed a separate clustering of healthy controls and HBVCLD patients covering chronic hepatitis (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC); and gut microbiota of healthy controls was more consistent, whereas those of CHB, LC and HCC varied substantially. The abundance of Firmicutes was lower, and Bacteroidetes was higher in patients with CHB, LC and HCC than in healthy controls. Predicted metagenomics of microbial communities showed an increase in glycan biosynthesis and metabolism-related genes and lipid metabolism-related genes in HBVCLD than in healthy individuals. Our study suggested that HBVCLD is associated with gut dysbiosis, with characteristics including, a gain in potential bacteria and a loss in potential beneficial bacteria or genes. Further study of CHB, LC and HCC based on microbiota may provide a novel insight into the pathogenesis of HBVCLD as well as a novel treatment strategy.

Enhanced sentinel surveillance for hepatitis B infection in 200 counties in China, 2013-2016.

Hepatitis B infection is a major public health challenge in China. Clinicians report hepatitis B cases to the National Notifiable Disease Reporting System. A 2007 study found that only 35% of hepatitis B cases that had been reported as acute infections met a rigorous case definition of acute hepatitis B, implying overreporting of new-onset infections. To increase the accuracy of reported acute hepatitis B infections, in 2013, we initiated enhanced hepatitis B surveillance in 200 sentinel counties. We compared incidences and proportions of different stages of hepatitis B infection before and after implementation of enhanced surveillance. We checked the accuracy of reported data and re-diagnosed hepatitis B cases reported as acute infection according to the enhanced diagnostic criteria and calculated positive predictive value(PPV) of acute hepatitis B reports. Compared to previous surveillance, with enhanced surveillance, the incidence of reported acute hepatitis B infection decreased by 53.7% and the proportion of unclassified hepatitis B infection was reduced by 79.4%. From 2013 to 2016, the PPV of acute hepatitis B increased (55.8% to 71.0%); PPV rates in western and rural areas were lower than in other areas. We recommend enhancing hepatitis B surveillance nationwide using these new standards, and raising western and rural areas clinicians’ diagnostic and reporting capacity, and ensuring sufficient resources for IgM anti-HBc testing.

Automated Diagnosis of Hepatitis B Using Multilayer Mamdani Fuzzy Inference System.

In this research, a new multilayered mamdani fuzzy inference system (Ml-MFIS) is proposed to diagnose hepatitis B. The proposed automated diagnosis of hepatitis B using multilayer mamdani fuzzy inference system (ADHB-ML-MFIS) expert system can classify the different stages of hepatitis B such as no hepatitis, acute HBV, or chronic HBV. The expert system has two input variables at layer I and seven input variables at layer II. At layer I, input variables are ALT and AST that detect the output condition of the liver to be normal or to have hepatitis or infection and/or other problems. The further input variables at layer II are HBsAg, anti-HBsAg, anti-HBcAg, anti-HBcAg-IgM, HBeAg, anti-HBeAg, and HBV-DNA that determine the output condition of hepatitis such as no hepatitis, acute hepatitis, or chronic hepatitis and other reasons that arise due to enzyme vaccination or due to previous hepatitis infection. This paper presents an analysis of the results accurately using the proposed ADHB-ML-MFIS expert system to model the complex hepatitis B processes with the medical expert opinion that is collected from the Pathology Department of Shalamar Hospital, Lahore, Pakistan. The overall accuracy of the proposed ADHB-ML-MFIS expert system is 92.2%.

Serum alkaline phosphatase levels as a simple and useful test in screening for significant fibrosis in treatment-naive patients with hepatitis B e-antigen negative chronic hepatitis B.

BackgroundStaging of liver fibrosis is critical in guiding the treatment of chronic hepatitis B (CHB) virus. Many efforts have been made toward the research of noninvasive techniques, mostly focusing on hepatitis B e-antigen (HBeAg)-positive [HBeAg(+)] CHB patients, whereas HBeAg(+) and HBeA-negative [HBeAg(−)] represent different stages of hepatitis B virus infection. Thus, in this study, we aimed to search for routinely available clinical noninvasive liver fibrosis markers and separately analysed the markers in HBeAg(+) and HBeAg(−) CHB patients.MethodsPatients with CHB who were treatment naive and who underwent a liver biopsy at our hospital from 1 January 2016 to 31 April 2017 were enrolled. Liver histology was scored using the Scheuer classification system. The area under the receiver operator curve was used to determine the diagnostic accuracy.ResultsA total of 191 patients, including 104 HBeAg(+) and 87 HBeAg(−) treatment-naive CHB patients, were enrolled in this study. Serum alkaline phosphatase (ALP) levels increased gradually in all patients and separately in HBeAg(−) CHB patients, but not in HBeAg(+) CHB patients. ALP was an independent factors predicting significant fibrosis (S≥2) in all of the patients and separately in HBeAg(−) patients, with area under the receiver operator curves of 0.651 and 0.717, respectively. Further, the optimal cut-off value of ALP (>69.5 IU/l) for distinguishing HBeAg(−) CHB patients with significant fibrosis was determined (S≥2).ConclusionSerum ALP levels can identify significant fibrosis (S≥2) in treatment-naive HBeAg(−) CHB patients and could potentially reduce the need for liver biopsies and help to guide the clinical treatment of CHB.

The Clinical Impact of Serum Testosterone Levels in Egyptian Patients with Different Stages of Hepatitis C Virus

The Clinical Impact of Serum Testosterone Levels in Egyptian Patients with Different Stages of Hepatitis C Virus

Soluble MICB protein levels and platelet counts during hepatitis B virus infection and response to hepatocellular carcinoma treatment.

BackgroundThe human major histocompatibility complex class I polypeptide-related sequence B (MICB) is a protein that modulates the NK and T cell activation through the NKG2D receptor and is related to several diseases including cancer.MethodsThe study investigated the prognostic role of soluble MICB (sMICB) protein in the progression of HBV-related liver diseases and to HBV-related HCC treatment. The sMICB serum levels were measured in 266 chronic HBV-infected Vietnamese patients and in healthy controls, and correlated with clinical and laboratory parameters and with therapeutic interventions for HBV-related HCC.ResultsSignificant differences in both clinical and laboratory parameters were observed among the patient groups with different stages of hepatitis. The platelet counts were significantly decreased with disease progression (P < 0.001). The sMICB serum levels were significantly increased in HBV patients compared to healthy controls (P < 0.0001). Among the patients with different stages of hepatitis, asymptomatic individuals (ASYM) revealed higher sMICB serum levels while liver cirrhosis (LC) patients revealed lower sMICB serum levels (P < 0.0001) compared to other patient groups. Notably, the sMICB serum levels were decreased in treated HCC patient group compared to not-treated HCC patient group (P = 0.05). Additionally, the sMICB levels were significantly correlated with platelet counts in ASYM and HCC patients (r = −0.37, P = 0.009; and r = 0.22, P = 0.025, respectively).ConclusionsOur results demonstrate a potential role of sMICB serum levels and platelet counts during immune response to the HBV infection, liver disease progression and response to the HCC treatment.

Genome-wide methylation profiling of the different stages of hepatitis B virus-related hepatocellular carcinoma development in plasma cell-free DNA reveals potential biomarkers for early detection and high-risk monitoring of hepatocellular carcinoma.

BackgroundAn important model of hepatocellular carcinoma (HCC) that has been described in southeast Asia includes the transition from chronic hepatitis B infection (CHB) to liver cirrhosis (LC) and, finally, to HCC. The genome-wide methylation profiling of plasma cell-free DNA (cfDNA) has not previously been used to assess HCC development. Using MethylCap-seq, we analyzed the genome-wide cfDNA methylation profiles by separately pooling healthy control (HC), CHB, LC and HCC samples and independently validating the library data for the tissue DNA and cfDNA by MSP, qMSP and Multiplex-BSP-seq.ResultsThe dynamic features of cfDNA methylation coincided with the natural course of HCC development. Data mining revealed the presence of 240, 272 and 286 differentially methylated genes (DMGs) corresponding to the early, middle and late stages of HCC progression, respectively. The validation of the DNA and cfDNA results in independent tissues identified three DMGs, including ZNF300, SLC22A20 and SHISA7, with the potential for distinguishing between CHB and LC as well as between LC and HCC. The area under the curve (AUC) ranged from 0.65 to 0.80, and the odds ratio (OR) values ranged from 5.18 to 14.2.ConclusionsOur data revealed highly dynamic cfDNA methylation profiles in support of HBV-related HCC development. We have identified a panel of DMGs that are predictive for the early, middle and late stages of HCC development, and these are potential markers for the early detection of HCC as well as the screening of high-risk populations.Electronic supplementary materialThe online version of this article (doi:10.1186/1868-7083-6-30) contains supplementary material, which is available to authorized users.

Chitotriosidase Activity in Different Stages of Hepatitis C. It may a Possible Tumor Marker for Hepatocellular Carcinoma

Chitotriosidase is synthesized and secreted especially in activated macrophages. The aim of this study was to evaluate chitotriosidase activity in patients with various stages of hepatitis C. The study included a total of 90 patients. The patients were divided into four groups. Group 1 included 54 patients with chronic active hepatitis, Group 2 included 20 patients with recovered HCV, Group 3 included 6 patients with HCV induced hepatocellular carcinoma, and Group 4 included 10 patients with HCV cirrhosis. Chitotriosidase activity was measured with spectrophotometry (SigmaAldrich ®). The mean chitotriosidase activity of the four groups was 0,927u/L (0.804u/L in Group 1, 0.521u/L in Group 2, 3.211u/L in Group 3 and 1.030u/L in Group 4). Chitotriosidase activity was significantly higher in Group 3. ROC analysis, used to evaluate chitotriosidase activity for the diagnosis of hepatocellular carcinoma, showed that chitotriosidase activity of 0,935 was below the curve (CI: 95%; 0,862 - 0,976), which was statistically significant (p= 0,0001). The cut-off value was >1,098 with a sensitivity of 100% and a specifity of 81%. Chitotriosidase activity can be a marker with a high sensitivity and specifity for the diagnosis of hepatocellular carcinoma.

Positive selection signals of hepatitis B virus and their association with disease stages and viral genotypes

The hepatitis B virus (HBV) is a global health problem that causes different types of liver diseases. The high mutation rate of HBV, which results from a lack of proofreading activity of the viral polymerase, leads to the actively adaptive evolution of mutant strains under various selection pressures. This study focuses on the positive selection signals in the whole HBV genome and the association of these selection signals with the disease stages and/or viral genotypes. A total of 486 complete HBV genomes from HBV-infected individuals of different illness categories (i.e., acute, chronic, and severe hepatitis) were analyzed. To obtain a panoramic view of the selection signals, codon-based maximum likelihood analysis, three-dimensional (3D) mapping, and allele frequency comparison were conducted on genotypes B and C HBV from subjects with different stages of hepatitis. A total of 95 selected codons were resolved, and a significantly higher number of positive selection signatures were found in the chronic and severe hepatitis groups compared with the acute groups. Many of the selected codons were associated with either a unique disease stage or a specific genotype. The conservation analysis of the selection signals in the viral core protein (HBcAg) illustrated the occurrence of selected codons in the highly diversified regions. The allele-frequency-based analysis identified eight additional nucleotide substitutions, and the frequencies of these mutations were found to increase with disease progression. Moreover, we found that three substitutions, including A1762T, G1764A, and A2739C, were nearly fixed. The mapping of all of the selected codons and nucleotide substitutions to the functional domains of the viral proteins suggested that more than 60% of the mutations were subject to selection forces from host immune surveillance, antiviral therapy, and replication fitness.