Review : Risk stratification of HBV infection in Asia-Pacific region

( Jia Horng Kao ) 대한간학회 2014 Clinical and Molecular Hepatology(대한간학회지) Vol.20 No.3

Hepatitis B virus (HBV) infection is the major etiology of chronic liver disease worldwide and thus a global health problem, especially in Asia-Pacific region. The long-term outcomes of Asian HBV carriers vary widely; however, a significant proportion of them will finally develop end-stage liver disease. Over the past decade, several host and HBV factors predictive of clinical outcomes in Asian HBV carriers have been identified. The community-based REVEAL-HBV study illustrated the strong association between HBV DNA level at study entry and risk of HCC over time, and male gender, older age, high serum alanine aminotransferase (ALT) level, positive HBeAg, higher HBV-DNA level, HBV genotype C infection and core promoter mutation are independently associated with a higher hepatocellular carcinoma (HCC) risk. Another hospital-based ERADICATE-B cohort further validated the HCC risk started to increase when HBV-DNA level was higher than 2,000 IU/mL. Of particular note, in patients with low viral load (HBV DNA level <2,000 IU/mL), HBsAg level ≥1,000 IU/mL was a new independent risk factor for HCC. With the results from REVEAL-HBV study, a risk calculator for predicting HCC in adult non-cirrhotic patients has been developed and validated by independent international cohorts (REACH-B). With the combination of HBV-DNA, HBsAg, and ALT levels, ERADICATE-B study proposed an algorithm to predict disease progression and categorize risk levels of HCC as well as corresponding management in Asian HBV carriers. The introduction of transient elastography may further enhance the predictive power. In conclusion, HBsAg level can complement HBV-DNA level for the risk stratification of disease progression in Asian adult patients with chronic HBV infection. (Clin Mol Hepatol 2014;20:223-227)

Risk Stratification of HBV Infection in Asia-Pacific Region

Jia-Horng Kao 한국간담췌외과학회 2014 한국간담췌외과학회 학술대회지 Vol.2014 No.4

Efficacy and Safety of Daclatasvir Plus Asunaprevir (DCV+ASV) in Cirrhotic and Non-cirrhotic HCV Genotype 1B Patients

Jia-Horng Kao,Jeong Heo,Boris Yoffe,William Sievert,Ira M. Jacobson,Fernando Bessone,Cheng-Yuan Peng,Stuart Roberts,Ki Tae Yoon,Justin Kopit,Misti Linaberry,Stephanie Noviello,Eric Hughes,Michael Mann 한국간담췌외과학회 2014 한국간담췌외과학회 학술대회지 Vol.2014 No.4

Elimination of HCV in Taiwan: What and How We Have Achieved from the Beginning till Today

( Jia-horng Kao ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Chronic hepatitis C virus (HCV) infection is a global health threat because of the disease burden. WHO estimated that there are 71 million people with HCV infection worldwide. Of particular note, Taiwan is a country endemic for chronic HCV infection, with ~500,000 HCV patients. Annually, ~13,000 people die of chronic liver diseases and their complications. Among them, 8000 are attributable to hepatocellular carcinoma (HCC). Because of the heavy disease burden, Taiwan has been fighting hepatitis B virus (HBV) since late 1970s and HCV since early 1990s, with successful results. Taking the control of HCV infection as an example, the Taiwan National Health Insurance system reimbursed combination therapy of pegylated interferon plus ribavirin since 2003, and before the introduction of interferon-free DAA in 2017, nearly 80,000 HCV patients were treated. When the World Health Assembly adopted the Global Health Sector Strategy on viral hepatitis in 2016, Taiwanese government began to put efforts towards the elimination of HCV. The government leaders have culminated in a consensus of reaching the WHO goals in 2025, i.e. 5 years ahead of the 2030 deadline set by WHO. Accordingly, the Taiwan Hepatitis C Policy Guideline 2018-2025 was approved. The government will provide the financial support of USD 1.7 billion within 8 years for the control of HCV infection, with the following actions: lowering the barriers of access to direct-acting antivirals (DAA); screening strategies; continuum of care; preventive measures for high-risk populations; improving liver health literacy on the prevention of new infections and reinfections; liver disease management; outcome evaluation of policy and interventions. After the implementation of Hepatitis C Policy Guideline, the number of HCV patients treated has remarkably increased year by year, from 9,500 in 2017 to 46,000 in 2019. More than 58,000 patients are anticipated to be treated in 2020. Inclusion of HCV patients already cured by peginterferon and ribavirin therapy before the DAA era, the treatment coverage of HCV patients is projected to reach 50% by the end of 2020. Thus, the elimination of HCV in Taiwan by 2025 is optimistic and thus on track. A recent study using the age-period-cohort models to estimate the mortality trends of liver diseases from 1981 to 2016 and project these trends to 2035 showed that the age-adjusted mortality rates of chronic liver disease, cirrhosis and HCC for both sexes are projected to decrease by more than 30% from 2016 to 2025 and by more than 55% from 2016 to 2035. In summary, the Taiwanese experience of the successful control of HCV infection can be shared by other countries where infections are equally prevalent and the socioeconomic status is similar.

Molecular epidemiology of Hepatitis B virus

( Jia Horng Kao ) 대한내과학회 2011 The Korean Journal of Internal Medicine Vol.26 No.3

Although safe and effective vaccines for hepatitis B virus (HBV) have been available for nearly three decades, this virus kills at least 600,000 people annually worldwide and remains the leading global cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Because the HBV reverse transcriptase lacks a proofreading function, many HBV genotypes, subgenotypes, mutants, and recombinants exist. At least 10 HBV genotypes (HBV-A through J) with distinct geographic distributions have been identified; by definition, their complete genomic sequences diverge by more than 8%. HBV genotype is increasingly becoming recognized as an important factor in the progression and clinical outcome of HBV-induced disease. Infections by HBV-C or -D are significantly more likely to lead to cirrhosis and hepatocellular carcinoma than are infections by HBV-A or -B. Additionally, the hepatitis B e antigen seroconversion response to standard or pegylated interferon is more favorable in patients with HBV-A or -B than in those with HBV-C or -D. However, therapeutic responses to nucleos(t)ide analogues are generally comparable among HBV genotypes. In conclusion, genotyping of HBV is useful in identifying chronic hepatitis B patients who are at increased risk of disease progression, thereby enabling physicians to optimize antiviral therapy for these patients.

Application of quantitative HBsAg into clinical practice

( Jia Horng Kao ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

In our clinical practice, hepatitis B surface antigen (HBsAg) is the hallmark of HBV infection and it has been qualitatively used for the diagnosis of hepatitis B virus (HBV) infection over the past decades. Virologically, HBsAg is produced by 2 pathways: from translation of transcriptionally active cccDNA molecules that serve as a template for replication and from translation of viral genes transcribed from integrated HBV DNA sequences in the host genome. Using recently developed commercial quantitative assays, qHBsAg has been shown to be helpful in the understanding and management of patients with chronic HBV infection. Studies consistently showed that HBsAg level is highest in immune tolerant phase (4.5-5.0 log10 IU/mL) and is lowest (1.5-3.0 log10 IU/mL) in low replication phase. Thus, the reduction of HBsAg for >1 log IU/mL could reflect improved host immune control against HBV infection. The combined single point quantification of HBsAg <1000 IU/mL and HBV-DNA ≤ 2000 IU/mL can identify minimal risk HBV carriers in both genotype D and non-D HBeAg negative patients. In genotype B and C dominant HBeAg-negative carriers with normal ALT, the lower the serum HBsAg level < 1000 IU/mL the higher the chance of spontaneous HBsAg seroclearance, and an HBsAg level of ≤100 IU/mL is an appropriate cut-off for predicting HBsAg loss over time. Regarding the role of qHBsAg in predicting disease progression in HBV carriers with a low viral load (< 2000 IU/mL), our recent studies indicated that a higher HBsAg level (>1000 IU/mL) is associated with a higher HCC risk. Taking these lines of evidence together, qHBsAg can complement HBV-DNA for the monitoring of HBV patients in the clinical practice. Although qHBsAg has been widely used in chronic hepatitis B patients receiving pegylated interferon therapy, serum HBsAg decline is slow and does not correlate with HBV DNA levels during treatment with nucleos(t)ide analogues (NAs). However, a rapid serum HBsAg decline during NA therapy, ideally after virological response has been achieved, may identify patients who will clear HBsAg in the long-term. A 6-12 monthly assessment of quantitative HBsAg level can be considered to monitor NA therapy. Among Asian patients infected with HBV genotype B and C, an HBsAg level of < 100 IU/ml might predict lower risk of relapse and stopping treatment can be considered. However, further larger studies are needed to validate these findings. In conclusion, qHBsAg can be integrated into future clinical practice guidelines for the management of chronic HBV infection.

New Therapeutic Perspectives for Hepatitis B Virus Cure

( Jia-horng Kao ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Current antiviral therapies have been proven to reduce the progression of chronic hepatitis B (CHB). However, covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) persists, resulting in viral relapse after the discontinuation of treatment. Several novel agents through viral and host targets approaches are under investigations towards functional cure of HBV. On one hand, direct acting antivirals (DAA) targeting virus itself, such as HBV entry inhibitor, engineered site-specific nucleases and RNA interference, could inhibit intrahepatic HBV infection and eliminate or silence cccDNA transcription. On the other hand, host targeting agents could induce non-cytolytic destruction of cccDNA or attack HBV-infected hepatocytes. With these promising approaches, we hope to reach global HBV control in the middle of this century.

Application of quantitative HBsAg into clinical practice

( Jia Horng Kao ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

In our clinical practice, hepatitis B surface antigen (HBsAg) is the hallmark of HBV infection and it has been qualitatively used for the diagnosis of hepatitis B virus (HBV) infection over the past decades. Virologically, HBsAg is produced by 2 pathways: from translation of transcriptionally active cccDNA molecules that serve as a template for replication and from translation of viral genes transcribed from integrated HBV DNA sequences in the host genome. Using recently developed commercial quantitative assays, qHBsAg has been shown to be helpful in the understanding and management of patients with chronic HBV infection. Studies consistently showed that HBsAg level is highest in immune tolerant phase (4.5-5.0 log10IU/mL) and is lowest (1.5-3.0 log10IU/mL) in low replication phase. Thus, the reduction of HBsAg for >1 log IU/mL could reflect improved host immune control against HBV infection. The combined single point quantification of HBsAg <1000IU/mL and HBV-DNA ≤ 2000IU/mL can identify minimal risk HBV carriers in both genotype D and non-D HBeAg-negative patients. In genotype B and C dominant HBeAg-negative carriers with normal ALT, the lower the serum HBsAg level < 1000IU/mL the higher the chance of spontaneous HBsAg seroclearance, and an HBsAg level of ≤100IU/mL is an appropriate cut-off for predicting HBsAg loss over time. Regarding the role of qHBsAg in predicting disease progression in HBV carriers with a low viral load (< 2000IU/mL), our recent studies indicated that a higher HBsAg level (>1000IU/mL) is associated with a higher HCC risk. Taking these lines of evidence together, qHBsAg can complement HBV-DNA for the monitoring of HBV patients in the clinical practice. Although qHBsAg has been widely used in chronic hepatitis B patients receiving pegylated interferon therapy, serum HBsAg decline is slow and does not correlate with HBV DNA levels during treatment with nucleos(t)ide analogues (NAs). However, a rapid serum HBsAg decline during NA therapy, ideally after virological response has been achieved, may identify patients who will clear HBsAg in the long-term. A 6-12 monthly assessment of quantitative HBsAg level can be considered to monitor NA therapy. Among Asian patients infected with HBV genotype B and C, an HBsAg level of < 100 IU/ml might predict lower risk of relapse and stopping treatment can be considered. However, further larger studies are needed to validate these findings. In conclusion, qHBsAg can be integrated into future clinical practice guidelines for the management of chronic HBV infection.

Treatment of HBeAg-negative Chronic Hepatitis B

( Jia Horng Kao ) 대한간학회 2007 Clinical and Molecular Hepatology(대한간학회지) Vol.13 No.5(S)

Three heads are better than two: Hepatitis B core-related antigen as a new predictor of hepatitis B virus-related hepatocellular carcinoma

( Jer-wei Wu ),( Jia-horng Kao ),( Tai-chung Tseng ) 대한간학회 2021 Clinical and Molecular Hepatology(대한간학회지) Vol.27 No.4

Patients with chronic hepatitis B virus (HBV) infection are at risk of developing hepatocellular carcinoma (HCC), and serum markers reflecting viral replication are potential predictors for HCC development. Besides the levels of serum HBV DNA and hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) quantification is an emerging serological marker for viral replication. Unlike HBV DNA and HBsAg, HBcrAg is a covalently closed circular DNA-derived protein marker, consisting of hepatitis B e antigen (HBeAg), p22cr, and hepatitis B core antigen. In treatment-naive HBV patients, higher HBcrAg levels are shown to be associated with an increased risk of HCC in several studies. More importantly, HBcrAg may complement HBV DNA level to predict HCC development. For example, an Asian treatmentnaive cohort study’s data showed that HBcrAg level of 4 log U/mL was effective to stratify HCC risk in HBeAg-negative patients with intermediate viral loads, who may not need antiviral therapy because of the low to moderate risk of HCC. In patients receiving prolonged nucleos(t)ide analogue with profound viral suppression, most data indicated that HBV DNA and HBsAg levels no longer serve as HCC predictors. However, several studies suggested on-treatment HBcrAg levels may remain as an HCC predictor. In summary, HBcrAg level can be a useful biomarker for treatment-naive patients, but its value in on-treatment patients needs validation. The next challenge is how to combine HBcrAg with the other viral markers to construct a better HCC prediction model, optimizing the management of HBV patients. (Clin Mol Hepatol 2021;27:524-534)