Jia-Horng Kao

Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2012 update

Large amounts of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2005. These include long-term follow-up studies in large community-based cohorts or asymptomatic subjects with chronic HBV infection, further studies on the role of HBV genotype/naturally occurring HBV mutations, treatment of drug resistance and new therapies. In addition, Pegylated interferon α2a, entecavir and telbivudine have been approved globally. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings were discussed and debated. The earlier “Asian-Pacific consensus statement on the management of chronic hepatitis B” was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, special indications for liver biopsy in patients with persistently normal alanine aminotransferase, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patients receiving immune-suppressive medications or chemotherapy and patients in the setting of liver transplantation, are also included.

Hepatitis B Genotypes Correlate With Clinical Outcomes in Patients With Chronic Hepatitis B

BACKGROUND & AIMS Six genotypes (A-F) of hepatitis B virus (HBV) have been identified; however, the genotype-related differences in the pathogenicity of HBV remain unknown. Therefore, we investigated the prevalence of HBV genotypes in Taiwan and the association between distinct genotypes and severity of liver disease in a cross-sectional study. METHODS Using a molecular method, HBV genotypes were determined in 100 asymptomatic carriers and in 170 patients with histologically verified chronic liver disease and hepatocellular carcinoma (HCC). RESULTS All genotypes except genotype E were identified in Taiwan, and genotypes B and C were predominant. Genotype C was prevalent in patients with cirrhosis and in those with HCC who were older than 50 years compared with age-matched asymptomatic carriers (60% vs. 23%, P < 0.001, and 41% vs. 15%, P = 0.005, respectively). Genotype B was significantly more common in patients with HCC aged less than 50 years compared with age-matched asymptomatic carriers (80% vs. 52%, P = 0.03). This predominance was more marked in younger patients with HCC (90% in those aged </=35 years), most of whom did not have cirrhosis. CONCLUSIONS Our data suggest that HBV genotype C is associated with more severe liver disease and genotype B may be associated with the development of HCC in young Taiwanese. However, additional large-scale longitudinal studies are needed to confirm the relationship of HBV genotypes to liver disease severity and clinical outcomes.

Global control of hepatitis B virus infection.

Worldwide about 350 million people are chronic carriers of the hepatitis B virus (HBV). The infection can cause acute and chronic liver disease including cirrhosis and hepatocellular carcinoma (HCC). Hepatocellular injuries of HBV infection are predominantly immune-mediated, and the natural history of chronic infection can be divided into three phases based on virus-host interactions-namely, immune tolerance, immune clearance, and viral integration phases. Four serotypes (adw, ayw, adr, and ayr) and seven genotypes (A to G) of HBV have been identified, and they show some distinct geographic distributions. The HBV genotypes may have clinical relevance and are currently under investigation. On the basis of disease burden and the availability of safe and effective vaccines, the WHO recommended that by the end of the 20th century hepatitis B vaccine be incorporated into routine infant and childhood immunisation programmes for all countries. The efficacy of universal immunisation has been shown in different countries, with striking reductions of the prevalence of HBV carriage in children. Most important, hepatitis B vaccination can protect children against HCC and fulminant hepatitis, as has been shown in Taiwan. Nevertheless, the implementation of worldwide vaccination against HBV requires greater effort to overcome the social and economic hurdles. Safe and effective antiviral treatments are available but are still far from ideal, a situation that, hopefully, will be improved soon. With hepatitis B immunisation, the global control of HBV infection is possible by the end of the first half of 21st century.

Hepatitis B genotypes and the response to interferon therapy

BACKGROUND/AIMS Possible pathogenic differences among hepatitis B virus (HBV) genotypes have been observed; however, the response to interferon therapy among HBV genotypes remains unknown. We therefore analyzed the efficacy of interferon alfa in the treatment of chronic hepatitis B patients with different HBV genotypes. METHODS Fifty-eight genotype B or C infected chronic hepatitis B patients who had been treated with interferon alfa-2b were retrospectively studied. The response to interferon was defined as normalization of serum aminotransferase level, loss of hepatitis B e antigen and HBV DNA 48 weeks post-treatment. RESULTS Baseline data of both groups of patients were comparable; however, genotype C patients had a higher serum aminotransferase level and a higher frequency of core promoter mutation. The response rate was 41% and 15% in genotype B and C patients, respectively (p=0.045). In those with higher serum aminotransferase levels, the response rate was 50% and 17%, respectively (p=0.025). Additionally, younger age and genotype B infection may predict a better response to interferon alfa. CONCLUSIONS HBV genotype C, compared to genotype B, is associated with a higher frequency of core promoter mutation, and a lower response rate to interferon alfa therapy.

Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts’ personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

Hepatitis B viral genotypes: clinical relevance and molecular characteristics.

Abstract  Hepatitis B virus (HBV) infection is a global health problem and the clinical outcome of chronic HBV infection depends on the frequency and severity of hepatitis flares in the immune clearance phase. Currently, four subtypes and seven genotypes of HBV are identified and most have specific geographic distributions. The impact of HBV genotypes on the clinical outcome of chronic HBV infection has been partially clarified. In Taiwan, genotype C is associated with more severe liver disease and genotype B is associated with the development of hepatocellular carcinoma (HCC) in young non‐cirrhotic patients. In contrast, genotype B has a relatively good prognosis in Japan and China and is rarely associated with the development of HCC. Similarly, genotype D is associated with more severe liver disease than genotype A in India and may predict occurrence of HCC in young patients. Although superinfection of HBV on top of hepatitis B carriers occurs in Taiwan, it is rarely associated with acute exacerbations. As to the response to antiviral treatment, genotypes C and D are associated with a lower response rate to interferon therapy compared with genotypes B and A. In addition, the subtype adw is reported to be associated with a higher risk of lamivudine resistance than ayw. In HBV subtype adw‐infected HCC patients, genotype B responds better to embolization therapy and has a lower rate of HCC recurrence than genotype C. In summary, pathogenic and therapeutic differences do exist among HBV genotypes and determining the genotype in patients with chronic HBV infection would help gain further information for etiologic, clinical, virologic and anthropologic investigations. Further studies to clarify the molecular virological factors that contribute to these differences are awaited.

Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update

Background/Aims: A large amount of new data on the treatment of chronic hepatitis B has become available such that the 2003 consensus statement requires revision and update.

All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study

BACKGROUND An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. METHODS We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. FINDINGS This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each). INTERPRETATION Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. FUNDING Bristol-Myers Squibb.

High Levels of Hepatitis B Surface Antigen Increase Risk of Hepatocellular Carcinoma in Patients With Low HBV Load

BACKGROUND & AIMS Patients with chronic hepatitis B virus (HBV) infection have a high risk for developing hepatocellular carcinoma (HCC). Patients with lower levels of hepatitis B surface antigen (HBsAg) have higher chances of losing HBsAg than those with high levels. However, little is known about whether higher levels of HBsAg increase risk for HCC. METHODS We followed 2688 Taiwanese HBsAg-positive patients without evidence of cirrhosis for a mean time period of 14.7 years. In addition to the known risk factors of HCC, we investigated the association between levels of HBsAg and development of HCC. RESULTS Of the patients followed, 191 developed HCC, with an average annual incidence rate of 0.5%. Baseline levels of HBsAg and HBV were associated with development of HCC, and risk increased with level. Compared to HBsAg level, by receiver operating characteristic curve analysis, HBV DNA level better predicted the development of HCC during 10-year and 15-year periods (both, P < .001). However, when we evaluated hepatitis B e antigen-negative patients with levels of HBV DNA <2000 IU/mL, factors that determined HCC risk included sex, age, and levels of alanine aminotransferase and HBsAg (≥1000 IU/mL), but not level of HBV DNA. Multivariate analysis showed that the adjusted hazard ratio for HCC in patients with levels of HBsAg ≥1000 IU/mL versus <1000 IU/mL was 13.7 (95% confidence interval: 4.8-39.3). CONCLUSIONS Among patients infected with HBV genotype B or C, determinants of HCC risk include their sex, age, hepatitis B e antigen status, HBV genotype, and levels of alanine aminotransferase and HBV DNA, but not level of HBsAg. Among hepatitis B e antigen-negative patients with low viral loads, HCC risk is determined by levels of HBsAg and alanine aminotransferase and age, but not HBV DNA.

Hepatitis B surface antigen quantification: Why and how to use it in 2011 – A core group report

Quantitative HBsAg had been suggested to be helpful in management of HBV, but assays were cumbersome. The recent availability of commercial quantitative assays has restarted the interest in quantitative serum hepatitis B surface antigen (HBsAg) as a biomarker for prognosis and treatment response in chronic hepatitis B. HBsAg level reflects the transcriptional activity of cccDNA rather than the absolute amount of cccDNA copies. Serum HBsAg level tends to be higher in hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients. Among patients with a low HBV DNA (<2000IU/ml), HBsAg <1000IU/ml in genotype D HBV infection and HBsAg <100IU/ml in genotype B/C HBV infection is associated with inactive carrier state in HBeAg-negative patients. The HBsAg reduction by nucleos(t)ide analogues (NA) is not as pronounced as by interferon treatment. On peginterferon treatment, sustained responders tend to show greater HBsAg decline than the non-responders. The optimal on-treatment HBsAg cutoff to predict response needs further evaluation in HBeAg-positive patients, but an absence of HBsAg decline together with a <2 log reduction in HBV DNA at week 12 can serve as stopping rule in HBeAg-negative patients with genotype D HBV infection. A rapid serum HBsAg decline during NA therapy may identify patients who will clear HBsAg in the long-term. There are early reports among Asian patients that an HBsAg level of <100IU/ml might predict lower risk of relapse after stopping NA treatment. In clinical practice, serum HBsAg level should be used together with, but not as a substitute for, HBV DNA.