Course Of Chronic Hepatitis B Virus Infection Research Articles

Hepatitis B virus genetic multiplicity and the associated HBV lamivudine resistance mutations in HBV/HIV co-infection in Western Kenya: A review article.

Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) co-infections are common as the two viruses use same routes of transmission. Studies show that HIV infection modifies the natural course of chronic HBV infection, leading to more severe and progressive liver disease, and a higher incidence of cirrhosis, liver cancer and mortality. Therefore, determining HBV status and genotypes among HIV co-infected patients would improve their therapeutic management. This article reviewed the HBV genetic multiplicity and the associated HBV Lamivudine resistance mutations in HBV/HIV co-infection in western Kenya. Comprehensive literature searches and analysis were performed in peer-reviewed journals in the National council for biotechnology information (NCBI), PubMed, and Web of science using key words of HIV, Hepatitis B genotypes, HBV/HIV co-infection and Lamivudine resistance. HBV genotype A is predominant. D and E are also present in Kenya and neighboring countries in the region. HBV polymerase rtV173L, rtL180M, and rtM204V major substitutional mutations were identified. Currently, TDF+3TC+DTG are recommended for treatment of HBV/HIV co-infection. Evidence shows that HBV/HIV co-infection places a heavy burden to the society. Along with ART regimen, HBV genotype is a major factor determining the course of disease and treatment outcome. Treating HIV in HBV/HIV co-infection with antiretroviral agents may result in a very high prevalence of HBV 3TC-resistance mutations. Therefore, improved screening for HBV and extended follow-up of HBV/HIV co-infected individuals is needed to better understand the impact of different ART regimens on clinical outcomes.

Hepatitis B Virus Infection in Pregnancy: Immunological Response, Natural Course and Pregnancy Outcomes.

This review aimed to provide an update on the impact of pregnancy on the natural course of hepatitis B virus (HBV) infection and also on the impact of HBV infection on adverse pregnancy outcomes, including mother-to-child transmission (MTCT). For the literature review, original research articles, review articles, and guidelines were narratively reviewed and comprehensively validated. The databases of PubMed, EMBASE, and CINAHL were carefully searched for articles in English on topics related to HBV infection, pregnancy, and vertical transmission from 1960 to May 2021. Immunological changes during pregnancy such as suppression of Th1 response and induction of Th2 immunity lead to an impaired immune reaction to HBV and stimulate viral activity along with the reduction of CD8 T cells to escape immune detection. The impact of pregnancy on the natural course of chronic HBV infection seems to be minimal, while pregnancy can increase morbidity and mortality in the case of advanced HBV hepatitis or cirrhosis. Importantly, hepatitis flare or alanine aminotransferase (ALT) flare can occur during pregnancy and is more common during the postpartum period due to the interaction between HBV and the immune response. Interestingly, the impact of HBV infection on adverse pregnancy outcomes is more serious than ever thought. Updated evidence indicates that pregnancies with chronic HBV infection increase the risk of preterm birth and gestational diabetes, especially in cases of positive hepatitis e antigen (HBeAg).

Hepatitis B virus X gene mutants emerge during antiviral therapy and increase cccDNA levels to compensate for replication suppression.

Hepatitis B virus (HBV) X gene (HBx) mutants can develop during the natural course of chronic HBV infection. However, little is known about whether the emergence of HBx mutants during long-term antiviral therapy is an adaptation of HBV to antiviral stress. This study was to identify HBx mutants that emerged in patients experiencing Lamivudine resistance or suboptimal treatment. Forty-six Lamivudine-resistant patients and 46 patients with suboptimal treatment responses to Entecavir were enrolled in this study. HBx mutants were identified by sequence analysis and their roles in the HBV replication cycle were characterized. We show that deletion/truncation/insertion mutations were only detected in the Lamivudine resistance group, while synonymous mutations were found in both groups. Follow-up analyses revealed that five patients in the Lamivudine group developed hepatocellular carcinoma, while patients in the Entecavir group did not. These mutants were characterized by a significant decrease in transactivation of the pre-S1 promoter, and varying effects on transactivation of the X promoter. Co-transfection of HBx-mutant plasmid and HBV replication-competent clone into HepG2 cells resulted in increased nuclear-to-cytoplamic HBV core antigen, HBV-DNA ratios, and nuclear covalently closed circular DNA (cccDNA). Antiviral drug sensitivity assays revealed that these mutants exhibited a compensatory effect to counteract antiviral drug suppression, resulting in elevated secretory HBV-DNA levels. Our study demonstrates that HBx mutants can emerge during Lamivudine or Entecavir therapy. These mutants exhibit altered transactivation of the HBV pre-S1 and X promoters, leading to increased cccDNA levels to compensate for replication suppression.

HEPATITIS B VIRUS AND RHEUMATIC DISEASES

Hepatitis B virus (HBV) is often found and associated with immune-mediated inflammatory rheumatic diseases (IMIRDs), necessitating the modification of both antiviral and antirheumatic therapies. The review provides basic information about the structure of HBV, the course of chronic HBV infection, and the prevention of HBV reactivation in patients with IMIRDs who receive immunosuppressive therapy.

Serum HBV RNA quantification: useful for monitoring natural history of chronic hepatitis B infection

BackgroundAs an alternative biomarker of intrahepatic covalently closed circular DNA (cccDNA) transcriptional activity, hepatitis B virus (HBV) RNA may evolve during long-lasting virus-host interactions during chronic hepatitis B viral infection. The distribution pattern of serum HBV RNA levels in the natural course of chronic HBV infection remains unclear. The aim of this study was to evaluate the levels of HBV RNA during the natural course of CHB and the role in distinguishing the natural history of HBV infection.MethodsA total of 291 treatment-naïve chronic HBV carriers were enrolled. Based on the clinical, biochemical, serological, and histological data as well as HBV DNA levels, patients were classified into the following four categories: the immune-tolerant phase (IT,n = 35), HBeAg-positive immune-active phase (EPIA,n = 121), inactive chronic hepatitis B(ICH,n = 77) and HBeAg-negative immune reactive hepatitis (ENH,n = 58). The parameters and distribution patterns of serum HBV RNA were evaluated in relation to viral replication status, immune phase, disease category and Child-Pugh class. The relationships between serum HBV RNA and other serum hepatitis B viral markers were also analyzed.ResultsSerum HBV RNA levels were significantly lower in the HBeAg-negative patients compared to those in the HBeAg-positive patients, with the lowest levels seen in inactive carriers. In HBeAg-negative patients, serum HBV RNA levels increased if there is reactivation to active hepatitis and showed obvious superiority for the combination of serum HBV DNA (cutoff>3.39 Log copies/mL) and HBsAg (cutoff>2.74 Log IU/mL) in discriminating between ‘HBeAg-negative immune reactive’ phase and inactive chronic hepatitis B phases of HBeAg-negative chronic HBV infection. Serum HBV RNA levels were positively correlated with serum HBV DNA and HBsAg levels in all chronic HBV-infected patients. A stratified analysis revealed that a correlation between serum HBV RNA and HBV DNA or HBsAg was present in HBeAg-positive patients; however, in HBeAg-negative patients, serum HBV RNA was positively correlated with HBV DNA only.ConclusionDuring the natural course of chronic HBV infection, serum HBV RNA levels vary. Serum HBV RNA can act as a biomarker to predict the natural history of disease in chronic hepatitis B patients. In treatment-naïve HBeAg-negative chronic HBV-infected individuals, serum HBV RNA shows superiority in differentiating the ‘HBeAg-negative reactive’ phase.

An Assessment of Upper Limits of Normal for ALT and the Impact on Evaluating Natural Course of Chronic Hepatitis B Virus Infection in Chinese Children.

The current upper limits of normal (ULN) for serum alanine aminotransferase (ALT) are increasingly challenged. We aimed to re-evaluate the ULN for ALT and assess the potential impact on the classification of natural course of chronic hepatitis B virus (HBV) infection in children. Laboratory data obtained from three hospitals in China were retrospectively analysed. In total, 2054 children with chronic HBV infection and 8149 healthy children at age ≤18 years were included in the study. Age-specific and gender-specific ULNs for ALT, at averages of 30 U/L for boys and 24 U/L for girls, were calculated from the data of healthy children. Using the revised ULNs vs. the current ULNs (40-50 U/L), 31-60% vs. 9-17% of the 2054 HBV-infected children had an abnormal result as seen in their ALT baseline analysis, and the highest abnormality rate was seen in the infants. Data of 516 HBV-infected children were applied for the classification of clinical phase, 28.8% vs. 19.8% of the children were classified into the phases of hepatitis B e antigen (HBeAg-)positive/negative hepatitis. During a median follow-up of 62 months, 39 of 153 children underwent HBeAg seroconversion, whereas 3 of them had persistently "normal" ALT, according to the current ULN. The revision of ULN for ALT in children substantially impacts the classification of the natural course of chronic HBV infection. Mild ALT fluctuation is common during the stage childhood, suggesting a need to rethink the current conceptions of immune tolerance and natural course of chronic HBV infection in the children.

Hepatitis B virus infection.

Hepatitis B virus (HBV) is a hepatotropic virus that can establish a persistent and chronic infection in humans through immune anergy. Currently, 3.5% of the global population is chronically infected with HBV, although the incidence of HBV infections is decreasing owing to vaccination and, to a lesser extent, the use of antiviral therapy to reduce the viral load of chronically infected individuals. The course of chronic HBV infection typically comprises different clinical phases, each of which potentially lasts for decades. Well-defined and verified serum and liver biopsy diagnostic markers enable the assessment of disease severity, viral replication status, patient risk stratification and treatment decisions. Current therapy includes antiviral agents that directly act on viral replication and immunomodulators, such as interferon therapy. Antiviral agents for HBV include reverse transcriptase inhibitors, which are nucleoside or nucleotide analogues that can profoundly suppress HBV replication but require long-term maintenance therapy. Novel compounds are being actively investigated to achieve the goal of HBV surface antigen seroclearance (functional cure), a serological state that is associated with a higher remission rate (thus, no viral rebound) after treatment cessation and a lower rate of cirrhosis and hepatocellular carcinoma. This Primer addresses several aspects of HBV infection, including epidemiology, immune pathophysiology, diagnosis, prevention and management.

The Impact of Hepatitis B Vaccine Failure on Long-term Natural Course of Chronic Hepatitis B Virus Infection in Hepatitis B e Antigen-Seropositive Children.

Vaccine failure with chronic hepatitis B virus (HBV) infection still develops in children after universal hepatitis B immunization. This study aimed to investigate the natural course of chronic HBV infection in children with vaccine failure and compare it with that of nonvaccinated children. Three hundred fifty-six hepatitis B e antigen (HBeAg)-seropositive, hepatitis B surface antigen (HBsAg) carrier children, who were followed for at least 1 year without antiviral therapy, were enrolled. These comprised 105 vaccine failure subjects who received 3 doses of HBV vaccine in infancy and 251 nonvaccinated subjects. The clinical, serologic, and virologic features were compared between the 2 groups. The cumulative HBeAg seroconversion rate was significantly lower in the vaccine failure group than in the nonvaccinated group (30.5% vs 77.7%, P < .0001). Genotype C HBV infection was more frequent in the vaccine failure group (33.7% vs 13.4%, P < .0001), and the maternal HBsAg-positive rate was higher (97.1% vs 66.4%, P < .0001). In a multivariate analysis, vaccine failure, genotype C infection, and maternal HBsAg positivity were significantly associated with delayed HBeAg seroconversion. HBeAg-seropositive vaccine failure HBV-carrier children were associated with delayed HBeAg seroconversion during long-term follow-up, and more HBV genotype C infection and maternal HBsAg seropositivity.

Circulating soluble programmed death-1 levels may differentiate immune-tolerant phase from other phases and hepatocellular carcinoma from other clinical diseases in chronic hepatitis B virus infection.

Programmed death-1 (PD-1) is involved in the immune dysfunction of hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study analyzed the association of circulating soluble PD-1 (sPD-1) levels with the phases and clinical diseases in chronic HBV infection. Serum sPD-1 levels were determined by enzyme linked immunosorbent assay in patients with different phases and liver diseases of chronic HBV infection. The sPD-1 levels in patients with chronic HBV infection were significantly elevated compared with HBV infection resolvers or healthy controls. According to phases, sPD-1 level in immune-tolerant phase (IT) was significantly lower than in other phases. Multivariate analysis showed that sPD-1 was an independent factor associated with IT. Area under the receiver operating characteristic (ROC) curves (AUC) showed that sPD-1 was significantly discriminative of IT from other phases with a cut-off of 1.535 ng/mL (AUC, 0.984; P<0.001). According to clinical diseases, sPD-1 level in HBV-related HCC was significantly higher than in other clinical diseases. Multivariate analysis showed that sPD-1 was an independent factor associated with HCC. The sPD-1 was significantly discriminative of HCC from other clinical diseases with a cut-off of 6.058 ng/mL (AUC, 0.962; P<0.001). The sPD-1 levels were significantly associated with HCC patients’ overall survival. HCC resection resulted in remarkable reduction in sPD-1 levels. These results demonstrate the involvement of sPD-1 in the disease course of chronic HBV infection and indicate the potential to apply sPD-1 as a biomarker for differentiating IT from other phases and HCC from other disease conditions in chronic HBV infection.

Baseline characteristics of HIV & hepatitis B virus (HIV/HBV) co-infected patients from Kolkata, India.

Background & objectives:Hepatitis B virus (HBV) and HIV co-infection has variable prevalence worldwide. In comparison to HBV mono-infection, the course of chronic HBV infection is accelerated in HIV/HBV co-infected patients. The present study was carried out to analyse the baseline characteristics (clinical, biochemical, serological and virological) of treatment naïve HIV/HBV co-infected and HIV mono-infected patients.Methods:Between July 2011 and January 2013, a total number of 1331 HIV-seropositive treatment naïve individuals, enrolled in the ART Centre of Calcutta School of Tropical Medicine, Kolkata, India, were screened for hepatitis B surface antigen (HBsAg). A total of 1253 HIV mono-infected and 78 HIV/HBV co-infected patients were characterized. The co-infected patients were evaluated for HBeAg and anti-HBe antibody by ELISA. HIV RNA was quantified for all co-infected patients. HBV DNA was detected and quantified by real time-PCR amplification followed by HBV genotype determination.Results:HIV/HBV co-infected patients had proportionately more advanced HIV disease (WHO clinical stage 3 and 4) than HIV mono-infected individuals (37.1 vs. 19.9%). The co-infected patients had significantly higher serum bilirubin, alanine aminotransferase (ALT), alkaline phosphatase and ALT/platelet ratio index (APRI). CD4 count was non-significantly lower in co-infected patients. Majority (61.5%) were HBeAg positive with higher HIV RNA (P<0.05), HBV DNA (P<0.001) and APRI (P<0.05) compared to those who were HBeAg negative. HBV/D was the predominant genotype (73.2%) and D2 (43.7%) was the commonest subgenotype.Interpretation & conclusions:HIV/HBV co-infected patients had significantly higher serum bilirubin, ALT, alkaline phosphatase and lower platelet count. HBeAg positive co-infected patients had higher HIV RNA and HBV DNA compared to HBeAg negative co-infected patients. Prior to initiation of antiretroviral treatment (ART) all patients should be screened for HBsAg to initiate appropriate ART regimen.

Natural history of chronic hepatitis B virus infection from infancy to adult life - the mechanism of inflammation triggering and long-term impacts.

Chronic hepatitis B virus (HBV) infection in endemic areas usually starts since infancy and early childhood and persists lifelong. The clinical course varies among different chronic infected subjects. Majority of chronic HBV infected children present with immune-tolerant status initially, experience the immune clearance phase with various degree of liver injury during or beyond puberty, and then enter the inactive phase after hepatitis B e antigen (HBeAg) seroconversion. Part of them may have HBV DNA titers elevation with hepatitis flare after HBeAg seroconversion, the so call HBeAg-negative hepatitis flare. Liver cirrhosis, and even hepatocellular carcinoma may develop afterward.The complex course of chronic HBV infection is associated with the age/route of viral acquisition, host factors such as immune and endocrine factors, viral factors, and host-viral interactions. The adrenarche and puberty onset modulate the start of immune clearance and the severity of liver inflammation in chronic HBV infected children. The genotype and phenotype of human cytokines, innate immunity, and human leukocyte antigens are also associated with the onset of immune clearance of HBV and severity of inflammation. Immune escape HBV mutant strains, emerged during the immune clearance phase under host immune surveillance, may cause different impacts on viral biosynthesis, host immune responses, and clinical course.Early events in childhood during chronic HBV infection may serve as important predictors for the later outcome in adulthood. Understanding the mechanisms triggering liver inflammation and their long-term impacts may enhance the development of better and earlier therapeutic strategies for patients with chronic HBV infection.

MicroRNA-4717 differentially interacts with its polymorphic target in the PD1 3' untranslated region: A mechanism for regulating PD-1 expression and function in HBV-associated liver diseases.

Programmed cell death-1 (PD-1) is involved in hepatitis B virus (HBV) infection, the leading cause of hepatocellular carcinoma (HCC) worldwide. Single-nucleotide polymorphism, rs10204525, located in the PD1 3' untranslated regions (UTR), is associated with chronic HBV infection. MicroRNAs (miRNAs) regulate gene expression via specific binding to the target 3'UTR of mRNA. In this study, three miRNAs were predicted to putatively interact with PD1 rs10204525 polymorphic site of allele G. One of them, miRNA-4717, was demonstrated to allele-specifically affect luciferase activity in a dose-dependent manner in cells transfected with vectors containing different rs10204525 alleles. In lymphocytes from chronic HBV patients withrs10204525 genotype GG, miR-4717 mimics significantly decreased PD-1 expression and increased (TNF)-α and interferon (IFN)-γ production. miR-4717 inhibitor significantly increased PD-1 expression and decreased TNF-α and IFN-γ production although not significantly. In lymphocytes from chronic HBV patients with rs10204525 genotype AA, no similar effects were observed. miR-4717 levels in peripheral lymphocytes from patients with HBV-related chronic hepatitis, cirrhosis and HCC were significantly decreased. In conclusion, miR-4717 may allele-specifically regulate PD-1 expression through interaction with the 3' UTR of PD1 mRNA, leading to the alteration of immune regulation and affecting the susceptibility and disease course of chronic HBV infection.

Correlation Between Hepatitis B G1896A Precore Mutations and HBeAg in Chronic HBV Patients.

Background:Hepatitis B virus (HBV) infection is an important health concern worldwide, with critical outcomes. Hepatitis B e antigen (HBeAg) negative chronic hepatitis B is frequently caused by a mutation (G1896A) in the hepatitis B virus (HBV) precore (PC) reading frame, which creates a stop codon, causing premature termination of the HBe protein.Objectives:This study aimed to investigate the G1896A PC mutation and its effect on HBeAg detection in chronic HBV patients.Patients and Methods:In this study, 120 chronic HBV patients neither vaccinated or who had benefited from immunoglobulin therapy, were recruited. The HBV-DNA was extracted from plasma and polymerase chain reaction (PCR) was performed. Positive PCR products were subjected to automated sequencing. The HBV serological markers [hepatitis B s antigen (HBsAg), HBeAg] were tested.Results:One hundred out of 120 (83.3%) patients were HBeAg negative and 100% were HBsAg positive. The comparison of nucleotide sequences with the reference sequence (Accession number: AB033559) in HBeAg negative patients showed that there was a high rate of mutations in G1896A (93.18%).Conclusions:This study indicates that the rate of G1896A mutation at the PC region among HBeAg negative patients, in the Golestan province of Iran, was similar to the average rate encountered in other parts of Iran. The PC stop codon mutation was detected in 93.18% of HBeAg negative patients. Further studies with larger sample sizes are required to elucidate the exact role of these mutations in the clinical course of chronic HBV infection.

Current and future directions for treating hepatitis B virus infection.

Hepatitis B virus (HBV) persistently infects approximately 350 million people, and approximately 600000 liver-related deaths are observed per year worldwide. HBV infection is also one of the major risk factors for hepatocellular carcinoma (HCC). The persistence of serum hepatitis B e antigen (HBeAg) and high level of serum HBV DNA are thought to reflect a high HBV replication status in hepatocytes, causing cirrhosis, HCC and liver-related deaths. It has been reported that antiviral therapy, such as peginterferon and nucleos(t)ide analogues (NUCs), could suppress liver-related death by inhibiting the HBV DNA levels and inducing seroconversion from HBeAg to antibody to HBe antigen. Currently, peginterferon is widely used, but there are also several disadvantages in the use of peginterferon, such as various adverse events, the administration route and duration. It is difficult to predict the effects of treatment and interferon is contraindicated for the patients with advanced fibrosis of the liver and cirrhosis. With respect to NUCs, entecavir and tenofovir disoproxil fumarate are current the first-choice drugs. NUCs can be administered orally, and their anti-viral effects are stronger than that of peginterferon. However, because cessation of NUC administration leads to high levels of viral replication and causes severe hepatitis, they must be administered for a long time. On the other hand, the use of both interferon and NUCs cannot eliminate covalently closed circular DNA of HBV. In this review, we evaluate the natural course of chronic HBV infection and then provide an outline of these representative drugs, such as peginterferon, entecavir and tenofovir disoproxil fumarate.

PD-1 mRNA expression is associated with clinical and viral profile and PD1 3′-untranslated region polymorphism in patients with chronic HBV infection

Programmed cell death-1 (PD-1) is involved in hepatitis B virus (HBV) infection and single-nucleotide polymorphism (SNP) rs10204525 in the 3′-untranslated region (3′ UTR) of PD1 gene was shown to be associated with the disease course of HBV infection. This study examined the associations of PD-1 mRNA expression with the clinical and viral profiles and the genotypes of rs10204525 in HBV infection. PD-1 mRNA levels in peripheral blood nuclear cells were determined by real-time quantitative reverse transcription polymerase chain reaction (PCR). PD1 rs10204525 was genotyped by bidirectional PCR amplification of specific alleles. The results showed that patients with chronic HBV infection had significantly elevated PD-1 mRNA levels than healthy controls. Patients with chronic hepatitis and hepatocellular carcinoma had significantly higher PD-1 mRNA levels than healthy controls. HBeAg (+) patients had significantly higher PD-1 mRNA levels than HBeAg (−) patients (P<0.001). PD-1 mRNA levels were sequentially increased with the elevation of HBV DNA levels. In HBV patients, but not in healthy controls, PD-1 mRNA levels were sequentially decreased from rs10204525 genotypes AA, AG to GG and the levels in genotype AA were significantly higher than in genotype GG (P=0.039). These findings suggest that increased PD-1 expression may affect the disease course of chronic HBV infection by facilitating HBV viral replication, and this may at least partially relate to PD1 3′ UTR polymorphism.

New perspective on the natural course of chronic HBV infection.

Chronic hepatitis B virus (HBV) infection is a significant threat to public health and an enormous burden on society. Mechanisms responsible for chronic HBV infection remain poorly understood. A better understanding of the natural course of chronic HBV infection may shed new light on the mechanisms underlying this disease and help in designing new antiviral strategies. Natural course of chronic HBV infection is conventionally viewed as an uninterrupted process that is usually marked by HBV e antigen (HBeAg) seroconversion or characterized by different phases associated with assumed host responses to HBV infection. However, none of these descriptions captures or highlights the core events that determine the natural course of chronic HBV infection. In this review, we briefly present the current knowledge on this subject and explain the significance and implication of events that occur during infection. A pre-core mutant becomes predominant in the viral population following elimination of the wild-type virus in duck hepatitis B virus-chronically infected animals. The coupled events in which first there is viral clearance that clears wild-type virus and then there is the reinfection of wild-type virus cleared livers with mutant virus are highly relevant to understanding of the natural course of chronic HBV infection under both treated and untreated conditions. In our new perspective, a general natural course of chronic HBV infection comprises cycles of viral clearance and reinfection, and such cycles prolong the chronic HBV infection course. Reviewing published data on the natural course of chronic HBV infection can reduce the possibility of missing important points in the initial data interpretation.

Advances in some common chronic liver diseases. Preface.

Chronic liver diseases (CLDs) are a diversified group of primary hepatic pathophysiological injury caused by various infectious, genetic and metabolic, hepatotoxic, autoimmune, and other underlying etiologies. If diagnosis and treatment are delayed, most CLDs could progress to cirrhosis that can be further associated with development of hepatocellular carcinoma (HCC). Significant medical advances have been made in diagnosing and treating CLDs. We are very pleased to present this special issue of Frontiers of Medicine that covers some important topics in clinical hepatology. It is estimated approximately 450 million people are infected by hepatitis B virus (HBV) worldwide. Chronic HBV infection can result in chronic hepatitis B (CHB), cirrhosis and HCC. CHB is one of the most common CLDs in China. Implementation of hepatitis B vaccination and availability of effective treatment for CHB have significantly reduced the prevalence of HBV infection, and effective treatment has also resulted in significantly improved outcomes of this disease. In this issue of the Journal, Drs. Zhang, Hu and Duan’s paper entitled “New perspective on the natural course of chronic HBV infection” has re-reviewed current research updates on HBV pathogenesis and proposed their opinion on pathogenesis of the persistence of chronic HBV infection, that shed light on further improving our current HBV treatment. In Dr. Hou and his colleagues’ paper, they have provided a thorough update on “Chronic hepatitis B virus infection: epidemiology, prevention, and treatment in China.” The paper by Drs. Skupsky and Hu entitled “Current hepatitis B treatment guidelines and future research directions” systemically reviewed current main guidelines and recommendations on HBV treatment, and future research direction. It is known that, even the application of both hepatitis B vaccination and hepatitis B immunoglobulin (HBIG) may not entirely prevent perinatal HBV transmission. Drs. Park and Pan’s paper entitled “Current recommendations of managing HBV infection in preconception or pregnancy” provides a very detailed update and recommendations on this important issue. Hepatitis C is a global public health problem. It is estimated that approximately 170–180million people are infected with the hepatitis C virus (HCV) globally. Morbidity and mortality from hepatitis C is primarily due to cirrhosis related complications such as variceal bleeding, ascites, hepatic encephalopathy and HCC. Clearly, HCV and its associated complications result in significant medical and economic burdens. The therapy for hepatitis C has made significant progress in the past 2 decades. In the mid-1990s, pegylated interferon and ribavirin combination therapy reached the 50% rate of sustained virological response (SVR). With the advance in our understanding of the hepatitis C replicative cycle and molecular biology, numerous oral direct-acting antiviral drugs (DAAs) targeting specific hepatitis C viral proteins were developed. In 2011, the first generation HCV protease inhibitors, telaprevir and boceprevir, were approved by the FDA in the United States. In December 2013, two other DAAs, namely sofosbuvir and simeprevir, became available. They have excellent antiviral potency and improved side-effect profiles. Extensive studies keep going on for even better and safer HCV treatment options. Dr. Pockros’s paper entitled “Advances in newly developing therapy for chronic hepatitis C virus infection” provides a very timely and systemic review in this field that will prepare us to move on to a new era of HCV treatment. It should be noted that American Association for the Study of Liver Diseases (AASLD), together with Infectious Diseases Society of America (IDSA) and International Antiviral Society-USA (IAS-USA), recently released a joint-society comprehensive updated recommendations on management of chronic hepatitis C. HCC can be developed from many CLDs, especially cirrhosis. Significant advances have been made in managing PREFACE

Relationship between cytokine gene polymorphisms and chronic hepatitis B virus infection.

Hepatitis B virus (HBV) infection is still a public health problem worldwide, being endemic in some parts of the world. It can lead to serious liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular cancer. The differences in host immune response can be one of the reasons for the various clinical presentations of HBV infection. Polymorphisms of genes encoding the proinflammatory and antiinflammatory cytokines, which are responsible for regulation of the immune response, can affect the clinical presentation of the infection. Particularly, the polymorphisms of the genes encoding cytokines such as interleukin (IL)-1, IL-6, IL-8, IL-10, IL-18, IL-28B, interferon-γ, tumor necrosis factor-α, tumor growth factor-β1, and regulatory molecules like vitamin D receptor and chemokine receptor 5 can be responsible for different clinical presentations of HBV infections. The genomic information about cytokines and other mediators can be important for determining high-risk people for developing chronic hepatitis or hepatocellular cancer and may be used to plan treatment and preventive approaches for these people. In this review, the current knowledge in the literature on the association between cytokine/regulatory molecule gene polymorphisms and clinical course of chronic HBV infection is summarized, and the clinical implementations and future prospects regarding this knowledge are discussed.

Hepatitis B surface antigen seroclearance in patients with chronic hepatitis B infection: A clinical study

To investigate the clinical characteristics of hepatitis B surface antigen (HBsAg) seroclearance in patients with chronic hepatitis B virus (HBV) infection. Patients with chronic HBV infection who achieved sustained virological response (SVR) within 6 years of ceasing formal antiviral treatment were assessed for HBsAg seroclearance (defined as loss of serum HBsAg on repeated testing for a period of >6 months), using enzyme immunoassays. Phase of HBV infection and liver function (serum alanine aminotransferase [ALT] and aspartate aminotransferase [AST] levels) and HBV DNA levels were also assessed. In total, 272 patients with chronic HBV and SVR were included; HBsAg seroclearance was achieved in 42 patients and not achieved in 230 patients. Serum HBsAg and ALT levels, ratios of HBsAg to HBV DNA and ratios of AST to ALT were significantly different between patients achieving, and not achieving, HBsAg seroclearance. The area under the receiver operating characteristic (ROC) curve of HBsAg levels for predicting the likelihood of HBsAg seroclearance was 0.85; the cut-off value was 203.86 IU/ml. These data demonstrate that HBsAg seroclearance was independently associated with host immunity, serum HBsAg level, serum ALT level, serum HBsAg to HBV DNA ratio and timing of drug therapy within the course of chronic HBV infection.

Immune characteristics of different immune phases in natural course of chronic HBV infection.

The hepatitis B virus (HBV) infection course is divided into 4 immune phases which were mainly characterized by clinical markers. We investigated the immune markers, especially inhibitory receptors, cytokine and chemokine expressions among the immune phases especially between immune tolerance (IT) phase and immune control (IC) phase. Blood and serum samples of 64 patients and serum samples of 22 healthy controls were obtained. We used flow cytometric methods for measurements of PD-1, PD-L1 and flow fluorescence immunoassay for the serum cytokines and chemokines concentrations. IL-27 was measured by ELISA and the receptor IL-27R was detected too. The proportions of PD1 positive cells in CD4+, CD4+CD45RO+, and CD8+ T-cell subsets in IC phase were greater than in IC phase. The frequencies of PD1 expressions in CD8+pentamer+ and CD8+CD45RA-pentamer+ T cells were higher in IC phase than in IT and ICC phases. The serum concentration of IL-27 in IT group was higher than in IC, ICC and HC groups. Concentrations of cytokines TNF-α and IL-10 and chemokines RANTES, IL-8 and IP-10 were higher in HBV infected patients. The reduction of percentages of PD-1 positive cells may contribute to estimate entering the IC phase and decide the opportune moment to start antivirus therapy.