Natural History Of Chronic Hepatitis B Research Articles

Antagonism Between Gut Ruminococcus gnavus and Akkermansia muciniphila Modulates the Progression of Chronic Hepatitis B

A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s)triggering IA entry and HBe-SC in the natural history of CHB. To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n= 102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed. Ruminococcus gnavus was the most abundant species in CHB patients in the IT phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with alanine aminotransferase flares, HBeAg loss, and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients because R gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R gnavus to allow HBV elimination. R gnavus and A muciniphila play opposite roles in HBV infection. A muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.

Plasma interferon-gamma-inducible-protein 10 level as a predictive factor of spontaneous hepatitis B surface antigen seroclearance in chronic hepatitis B patients.

Spontaneous seroclearance of hepatitis B surface antigen (HBsAg) is a rare event that occurs in patients that are chronically infected with the hepatitis B virus. As the functional cure and ultimate treatment endpoint of chronic hepatitis B (CHB), HBsAg seroclearance is an important milestone in the natural history of CHB and serves great clinical value. This study aims to identify host and viral factors associated with HBsAg seroclearance. This is a retrospective study carried out in the Queen Mary Hospital, Hong Kong. By analyzing the plasma retrieved from the serum archive (collected during 2011-2021) of 100 CHB patients attending the hospital's liver clinic, the longitudinal cytokine profiles between the HBsAg-losers and the control groups were compared. Data revealed that plasma levels of IP-10 were significantly lower at 3-5years prior to HBsAg seroclearance compared with patients who remained HBsAg positive (P<0.05). Receiver operating characteristic curve analysis reveals that plasma IP-10 levels at multiple time points before HBsAg seroclearance return area under receivor-operating characteristic curve (AUC) greater than 0.7. Plasma IP-10 levels at 42.39pg/mL produced an AUC=0.723 with 74.0% sensitivity and 75.5% specificity to predict subsequent HBsAg seroclearance in the next 3-5years. Low plasma IP-10 identified 91.4% patients with quantitative HBsAg <100IU/mL who would subsequently develop HBsAg seroclearance, compared with 37% with higher plasma IP-10 levels (P<0.001). Low plasma levels of IP-10 are associated with subsequent HBsAg seroclearance, suggesting potential clinical utilities of measurement of IP-10 in predicting HBsAg seroclearance, especially among patients with low HBsAg.

Perception of disease, well-being and financial burden by patients with chronic hepatitis B: A self-reported assessment

Dear Editor, Chronic hepatitis B (CHB) infection affects approximately 248 million individuals in the world1 and 3.6% of the Singapore population.2 Given the natural history of CHB, regular surveillance with blood tests is necessary to ensure early detection of complications such as cirrhosis and hepatocellular carcinoma in patients. Our study aimed to evaluate patients’ perception

Treatment Algorithm for Managing Chronic Hepatitis B Virus Infection in the United States: 2021 Update

Chronic hepatitis B (CHB) infection remains the most frequent etiology of hepatocellular carcinoma globally as well as a major cause of cirrhosis. Despite vaccination, substantial numbers of persons have already been infected with hepatitis B virus and remain at risk of progressive liver disease. In 2004, a CHB management algorithm was developed by a panel of North American hepatologists, which was subsequently updated in 2006, 2008, and 2015. Since the most recent version, several developments have altered the management of CHB. Tenofovir alafenamide, with a more favorable safety profile than tenofovir disoproxil fumarate, has been introduced as an initial antiviral choice as well as an alternative for long-term therapy. Quantitation of hepatitis B surface antigen is becoming more widely available in clinical practice, with implications for monitoring response to treatment. Additionally, there has been a shift in howthe natural history of CHB is perceived, as newer evidence has challenged the concept that during the immunotolerant phase of infection disease progression is not a concern. Finally, recent analyses indicate that in the United States, the average age of patients with CHB has increased, implying that the presence of comorbidities, including metabolic liver disease, increasing use of biologics associated with aging will increasingly affect disease management. This updated algorithm is intended to serve as a guide to manage CHB while new antiviral strategies are developed. Recommendations have been based on evidence from the scientific literature, when possible, as well as clinical experience and consensus expert opinion. Points of continued debate and areas of research need are also described.

A perspective of the relationship of serum HBV DNA and HBsAg apportioned by the same hepatic parenchyma cell volume with inflammation in the natural history of chronic hepatitis B.

This study aimed to investigate the dynamic changes of serum HBV DNA and hepatitis B surface antigen (HBsAg) titers apportioned by the same hepatic parenchyma cell volume (HPCV) at different liver histological inflammation grades in the natural history of chronic hepatitis B (CHB). The serum HBV DNA and HBsAg titers were detected by real-time polymerase chain reaction and electrochemiluminescence, separately, in CHB patients without any treatment. The serum HBV DNA levels and HBsAg titers apportioned by the same HPCV were figured out based on sphere geometry theory. In addition, the differences of HBV DNA levels and HBsAg titers apportioned by the same HPCV in different liver inflammation grades were further assessed based on statistical analysis. There was no difference of serum HBV DNA levels or HBsAg titers before apportioned by the same HPCV in liver inflammation grades 1-4, but significant differences were observed after apportion in CHB patients (HBV DNA: P=0.101; HBsAg: P=0.211 & HBV DNA apportioned by HPCV: P<0.001; HBsAg apportioned by HPCV: P<0.001). No correlation was observed between HBV DNA levels and liver inflammation grades (r=0.083, P=0.186), or between HBsAg titers and liver inflammation grades (r=0.083, P=0.078). A significant correlation was observed between HBV DNA levels apportioned by HPCV and liver inflammation grades (r=0.249, P<0.001), and obvious correlation of HBsAg titers apportioned by HPCV and liver inflammation grades was also found in CHB patients (r=0.554, P<0.001). These results suggest that the levels of serum HBV DNA and HBsAg apportioned by the same HPCV are correlated with the severity of liver histological inflammation grade in the natural history of CHB.

Serum ERK1/2 proteins fluctuating with HBV infection report frequency of viral-specific CD8+ T cells and predict IFNα therapeutic effect in chronic hepatitis B patients

Chronic hepatitis B (CHB) is a life-threatening disease caused by HBV infection. Our previous work proved that activation of ERK1/2 and STAT3 signaling was involved in HBV tolerance. We herein investigated clinical significances of serum ERK1/2 and STAT3 proteins in CHB. Results showed that ERK1/2 and STAT3 were fluctuated with natural history of CHB. In addition, STAT3 was found to be positively correlated to the elevation of ALT, AST and GGT, while ERK1 was negatively correlated to decreases of TP and ALB. Also, there was a positive correlation between the anti-HBc antibody and ERK1, ERK2 or STAT3 in HBeAg-negative patients. Strikingly, serum ERK1 and ERK2 could reflect level of HBsAg-specific CD8+ T cells. A model composed with baseline ERK1 and ERK2 levels had a high accuracy to predict the effect of IFNα treatment. In conclusion, serum ERK1, ERK2 and STAT3 could serve as novel biomarkers in chronic HBV infections.

New perspectives on the hepatitis B virus life cycle in the human liver.

The central role of the transcriptional template of the hepatitis B virus (HBV), covalently closed circular DNA (cccDNA), has been difficult to study in patients with chronic hepatitis B (CHB) infection. In this issue of the JCI, Zhang and colleagues reveal a mosaic distribution of viral antigens and nucleic acids and a mismatch between HBV cccDNA, RNA, and expression of the hepatitis B surface antigen (HBsAg). These unusual patterns varied over the natural history of CHB, prompting the authors to propose a new three-stage model of the HBV life cycle at the single-cell level.

Antibody to hepatitis B core antigen levels in the natural history of chronic hepatitis B: a prospective observational study.

Previous studies have revealed antibody to hepatitis B core antigen (anti-HBc) levels as a predictor of treatment response in hepatitis B early antigen (HBeAg)-positive chronic hepatitis B (CHB) patients in both interferon and nucleos(t)ide analog therapy cohorts. However, there is no information about anti-HBc levels in the natural history of CHB. This study aimed to define anti-HBc levels of different phases in the natural history of CHB. Two hundred eleven treatment-naive CHB patients were included in the study. They were classified into 4 phases: immune tolerance (IT) phase (n = 39), immune clearance (IC) phase (n = 48), low or no-replicative (LR) phase (n = 55), and HBeAg-negative hepatitis (ENH, n = 69). Fifty patients who were HBsAg negative and anti-HBc positive were also recruited as past HBV infection (PBI) control group. Anti-HBc levels were measured by a newly developed double-sandwich immunoassay. Correlation of anti-HBc levels with alanine aminotransferase (ALT) and other HBV-related markers within each phase was performed. Serum anti-HBc levels were statistically significant between patients in different phases of CHB (P < 0.001). The median anti-HBc levels were: IT (3.17 log 10 IU/mL), IC (4.39 log 10 IU/mL), LR (3.29 log 10 IU/mL), ENH (4.12 log 10 IU/mL), and PBI (0.61 log 10 IU/mL). There existed a strong correlation in IC (r = 0.489, P < 0.001), a poor correlation in ENH (r = 0.275, P = 0.042), and no correlation in patients with ALT reached 5 times upper limit of normal (r = 0.120, P = 0.616). Anti-HBc levels show significant differences during the natural course of CHB. These results may provide some potentially useful insights into hepatitis B pathogenesis and immune activation against hepatitis B virus.

Interferon for Chinese patients with chronic hepatitis B e antigen-positive diseases-the controversy arises again?

In 2014, seven drugs were registered for the treatment of chronic hepatitis B (CHB) infection. Two were immunomodulatory agents, conventional interferon(IFN)-a and pegylated IFN-a2a, and five were direct antiviral nucleos(t)ide analogs (NUCs), lamivudine, adefovir dipivoxil, telbivudine, entecavir and tenofovir disoproxil fumarate. Due to the high resistance barrier of entecavir and tenofovir as compared to the other NUCs, only these two drugs are now in practical use in most parts of the world [1]. For chronic hepatitis B e antigen (HBeAg)-positive patients, HBeAg seroconversion, defined as the loss of HBeAg with the appearance of anti-HBe, is often associated with clinical remission and a transition to inactive liver disease. Accompanying HBeAg seroconversion, there is a reduction in liver fibrosis and a lower incidence of cirrhosis and hepatocellular carcinoma. HBeAg seroconversion, whether spontaneous or treatment induced, is also associated with a higher probability of hepatitis B surface antigen (HBsAg) loss and seroconversion, which is considered to be a more permanent clinical remission of liver disease. Thus, the achievement as well as maintenance of HBeAg seroconversion, in association with low serum hepatitis B virus (HBV) DNA levels (\3–4 log IU/ml), is an important goal in the management of patients with HBeAg-positive CHB [2]. Based on evidence demonstrating HBeAg seroconversion is an important hallmark event of a durable clinical remission of liver disease, most hepatology society treatment guidelines have adopted HBeAg seroconversion with sustained suppression of HBV DNA as an end point for treatment in patients with HBeAgpositive CHB who do not have cirrhosis or decompensated liver disease [1]. Previously, the conflicting data related to the importance of HBeAg seroconversion were largely related to the existence of a group of HBeAg seroconverters with a high HBV DNA viral load. In fact, this merely represented a transition from chronic HBeAgpositive disease to chronic HBeAg-negative disease, with little impact on the natural history of CHB. This important point was emphasized by a recent study in Taiwan, which included 2,946 chronic CHB Chinese patients. It was shown that high serum HBV DNA levels at the seroclearance of HBeAg could explain the nonsignificant association between HBeAg seroclearance and HCC risk [3]. Among the various forms of treatment, 1-year treatment with pegylated IFN-a2a yielded the highest rate of HBeAg seroconversion (around 40 %); among them, one-tenth further benefited from HBsAg seroconversion. On the other hand, treatment with NUCs achieved a much lower rate of HBeAg seroconversion; hence, more prolonged therapy is required when one has started treating CHB patients with NUCs. Hence, one of the key questions is related to the durability of HBeAg seroconversion with the various forms of therapy. This will affect the physician’s decision when choosing a therapy for our chronic HBeAg-positive patients between nucleos(t)ide analogs (NUCs) or pegylated IFN. Clinically, this has always led to a painful choice between either life-long medication with NUCs with a high genetic barrier (entecavir or tenofovir disoproxil fumarate) or lasting remission with a relatively short duration but sometimes side effect-prone therapy with 48 weeks of pegylated IFN. Previously, two large-scale clinical studies in Chinese subjects demonstrated that treatment with G. K. K. Lau (&) Humanity and Health GI and Liver Centre, Hong Kong, Hong Kong SAR e-mail: gkklau@netvigator.com

Viral factors and outcome of chronic hepatitis B revisited.

Virus-host interactions during chronic hepatitis B virus (HBV) infection allow the distinction of several phases, defined according to virological, biochemical and histological profiles: immune-tolerant (IT) [HBeAg-positive, very high serum level of HBV DNA, normal serum alanine aminotransferase (ALT) level without significant liver necroinflammation activity and fibrosis], immune-reactive (HBeAg-positive, high HBV DNA and ALT levels with moderate to severe liver activity and fibrosis) and the inactive carrier state, which follows HBeAg seroconversion and reflects host immune control of the HBV infection (HBeAg-negative, low HBV DNA level, normal ALT level without liver damage in most cases). An HBeAg-negative chronic hepatitis B (CHB) phase (HBeAg-negative, HBV DNA level above 2,000–20,000 IU/mL, normal/high ALT level and histological signs of CHB) occurs in patients who have achieved HBeAg seroconversion or in inactive carriers due to HBV reactivation [1]. Basal core promoter (BCP) mutations have been reported to possibly modulate HBV replication [2–4] and could thus impact the natural course of CHB. In addition, BCP mutations (the more common are the BCP A1762T/G1764A dual mutations) and precore G1896A mutation lead to the impairment and abolishment, respectively, of HBeAg production [5], and they have been reported in patients with HBeAg-negative CHB occurring under immune pressure to control HBV infection. Importantly, the more common BCP dual mutations have been shown to increase the risk of developing hepatocellular carcinoma (HCC) [6, 7]. Turyadi et al. [8] carried out a cross-sectional study to characterize the relationships between viral factors and the natural history of CHB within the Indonesian population. In their study, Turyadi et al. assessed the correlations between viral parameters [serum HBsAg, HBeAg and HBV DNA levels, HBV genotype and BCP (A1762T/G1764A)/ precore (G1896A) mutations] in different stages of HBV infection within a cohort of 152 treatment-naive Indonesian patients. Patients were categorized into the four phases of CHB, denoted IT, immune-clearance (IC, i.e, immunereactive phase), low/non-replicative (LR, i.e., inactive carrier state) and HBeAg-negative CHB (ENH). The authors showed that HBsAg and HBV DNA serum levels were both at a high level and strongly correlated in the early phases of CHB (i.e., IT and IC), but a tendency to separate from one another occurred after HBeAg seroconversion. A moderate correlation between serum HBV DNA and serum HBsAg titers was found in the ENH phase, and no correlation was observed in the LR phase. These important results are consistent with previous studies [9, 10] and suggest that the control of HBV replication by the immune system does not hamper HBsAg production. In this study, a temporal relationship between HBeAg seroconversion and an increase of prevalence of patients with This is an editorial to the article available at doi:10.1007/s12072-0139438-z

Update in the management of chronic hepatitis B

To review the recent developments in the management of chronic hepatitis B (CHB) based on the articles published between January 2012 and January 2013. International guidelines have been updated to include recent discoveries in the natural history of CHB, how to determine who should be treated, recommendations of management of special populations, and support of highly potent medications with high genetic barrier to resistance as the first-line therapy. Sustained response rates to interferon may be influenced by the IL28B genotype and can be predicted by on-treatment monitoring of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA. Long-term viral suppression can be obtained by entecavir and tenofovir even in cases of multidrug resistance, leading to decreased rates of hepatocellular carcinoma and death. Current therapies suppress, but rarely eradicate hepatitis B. Drug resistance remains a barrier to success in the long-term treatment of CHB, especially in resource-poor areas and in previously treated patients. Quantitative hepatitis B surface antigen in addition to other clinical data may provide personalized treatment decisions based on risk and response. There remains a need for novel therapies targeting HBV replication and immune system for CHB cure.

Update of chronic hepatitis B

We review here new developments in chronic hepatitis B (CHB) treatment, based on review of published articles between December 2009 and November 2010. It is estimated that two-thirds of US CHB patients have not been identified, evaluated and appropriately treated, largely due to lack of knowledge and awareness of CHB among medical professionals and at-risk populations. Seven medications have been approved to treat CHB in adults, but only four medications have been approved to treat CHB in children.Hepatitis B e antigen (HBeAg) seroconversion is still an important treatment endpoint in HBeAg-positive patients. Durability of nucleoside analogue treatment-related HBeAg seroconversion is still questionable. Hepatitis B surface antigen (HBsAg) seroclearance has been achieved in some patients with antiviral therapy. HBsAg quantitation and kinetics is now being studied to determine its role in the natural history of CHB and whether these measures may predict future response to current antiviral therapy. Great advances have been made in understanding the HBeAg seroconversion durability. The clinical significance of serum HBsAg kinetics has been recognized in naive CHB patients and patients with antiviral therapy. More education programs are needed to improve the public awareness of the importance of CHB to the health of whole population.

Update on HBV treatment and Management of Antiviral Resistance

Chronic hepatitis B (CHB) is a major public health problem affecting up to 400 million people globally. Complications of CHB including liver failure and hepatocellular carcinoma result in 1.2 million deaths per year, making CHB the 10 th leading cause of mortality worldwide. The natural history of CHB is variable and complex. The past decade witnessed important developments for the therapy of hepatitis B and marked the new era of oral therapy. The ultimate goal of CHB therapy is to arrest the progression of liver injury and to prevent the development of liver failure and hepatocellular carcinoma. Currently, six agents are approved for the treatment of CHB. Each of these agents, given as monotherapy, has been shown to produce virological, biochemical and histological benefits for both HBeAg positive and negative CHB. There are, however, limitations in spite of their efficacy. The significant sideeffect profile of interferon, for example, limits its longterm use. The approved oral agents are tolerable with prolonged use but drug resistance could limit long-term monotherapy. To date, combination therapy with nucleoside analogue and pegylated interferon or two nucleos(t)ide analogues given for one year does not show superiority in durability of response compared to monotherapy. Ongoing research effort is critical to identify the ideal hepatitis B therapy that is safe, effective and produces durable response with a finite course of therapy. It is equally important to conduct a well designed, prospective natural history study to identify predictors of disease progression. This will accurately guide treatment strategy for this important disease. [N A J Med Sci. 2011;4(1):35-43.]

Review: Current status of antiviral therapy for hepatitis B

Chronic hepatitis B (CHB) is a major public health problem affecting up to 400 million people globally. Complications of CHB including liver failure and hepatocellular carcinoma result in 1.2 million deaths per year, making CHB the 10th leading cause of mortality worldwide. The natural history of CHB is variable and complex. The past decade witnessed important developments for the therapy of hepatitis B and marked the new era of oral therapy. The ultimate goal of CHB therapy is to arrest the progression of liver injury and to prevent the development of liver failure and hepatocellular carcinoma. Currently, six agents are approved for the treatment of CHB. Each of these agents, given as monotherapy, has been shown to produce virological, biochemical, and histological benefits for both HBeAg positive and negative CHB. There are, however, limitations in spite of their efficacy. The significant side-effect profile of interferon, for example, limits its long-term use. The approved oral agents are tolerable with prolonged use but drug resistance could limit long-term monotherapy. To date, combination therapy with nucleoside analogue and pegylated interferon or two nucleos(t)ide analogues given for one year does not show superiority in durability of response compared to monotherapy. Ongoing research effort is critical to identify the ideal hepatitis B therapy that is safe, effective, and produces durable response with a finite course of therapy. It is equally important to conduct a well designed, prospective natural history study to identify predictors of disease progression. This will accurately guide treatment strategy for this important disease.