BackgroundHepatocellular carcinoma (HCC), or liver cancer, is the third leading cause of cancer deaths worldwide, with prevalence 16–32 times higher in developing countries than in developed countr...

Global Burden of Aflatoxin-Induced Hepatocellular Carcinoma: A Risk Assessment

Chronic hepatitis B is caused by persistent infection with the hepatitis B virus (HBV), a unique DNA virus that replicates through an RNA intermediate produced from a stable covalently closed circular DNA molecule. Viral persistence appears to be due to inadequate innate and adaptive immune responses. Chronic infection has a variable course after several decades resulting in cirrhosis in up to one‐third of patients and liver cancer in a proportion of those with cirrhosis. Sensitive assays for HBV DNA levels in serum have been developed that provide important insights into pathogenesis and natural history. Therapy of hepatitis B is evolving. Peginterferon induces long‐term remissions in disease in one‐third of patients with typical hepatitis B e antigen (HBeAg) positive chronic hepatitis B, but a lesser proportion of those without HBeAg. Several oral nucleoside analogues with activity against HBV have been shown to be effective in suppressing viral levels and improving biochemical and histological features of disease in a high proportion of patients with and without HBeAg, at least in the short term. What is uncertain is which agent or combination of agents is most effective, how long therapy should last, and which criteria should be used to start, continue, switch or stop therapy. Long‐term therapy with nucleoside analogues may be the most appropriate approach to treatment, but the expense and lack of data on long‐term safety and efficacy make recommendations difficult. Clearly, many basic and clinical research challenges remain in defining optimal means of management of chronic hepatitis B. (HEPATOLOGY 2007;45:1056–1075.)

Management of hepatitis B: Summary of a clinical research workshop Potential conflict of interest: Dr. Lok is a consultant and received grants from GlaxoSmithKline, Bristol-Myers Squibb, Idenix, Gilead, Roche, and Innogenetics.

Liver diseases in the Asia-Pacific region: a Lancet Gastroenterology & Hepatology Commission.

This Review presents current epidemiological trends of the most common liver diseases in Asia–Pacific countries. Hepatitis B virus (HBV) remains the primary cause of cirrhosis; despite declining prevalence in most Asian nations, this virus still poses a severe threat in some territories and regions. Mortality resulting from HBV infection is declining as a result of preventive measures and antiviral treatments. The epidemiological transition of hepatitis C virus (HCV) infection has varied in the region in the past few decades, but the medical burden of infection and the prevalence of its related cancers are increasing. The lack of licensed HCV vaccines highlights the need for novel treatment strategies. The prevalence of nonalcoholic fatty liver disease (NAFLD) has risen in the past decade, mostly owing to increasingly urbanized lifestyles and dietary changes. Alternative herbal medicine and dietary supplements are major causes of drug-induced liver injury (DILI) in some countries. Complications arising from these chronic liver diseases, including cirrhosis and liver cancer, are therefore emerging threats in the Asia–Pacific region. Key strategies to control these liver diseases include monitoring of at-risk populations, implementation of national guidelines and increasing public and physician awareness, in concert with improving access to health care. Liver diseases exert a substantial disease burden across the Asia–Pacific region. In this Review, the authors explore the epidemiological trends in the most common liver diseases in the region, including HBV infection, HCV infection and nonalcoholic fatty liver disease, and discuss implications for preventive measures.

The changing epidemiology of liver diseases in the Asia-Pacific region.

Ten hepatitis B virus (HBV) genotypes (A-J) and 34 HBV subgenotypes have been identified so far. HBV genotypes and subgenotypes have distinct geographical distributions, and have been shown to differ with regard to clinical outcome, prognosis, and response to interferon treatment. Infection with subgenotype A2 is frequently associated with high viral load, resulting in acute infection via horizontal transmission. Genotypes A and B are more sensitive to interferon treatment than genotypes D and C, respectively. Genotype B is more frequent in acute hepatitis than genotype C, whereas genotype C (C2) is more frequently associated with an increased risk of hepatocellular carcinoma (HCC), mostly cirrhotic, as compared with genotype B (B2). Genotype mixture is associated with high viral load and worse outcome of HBV infection. HBV mutations in the S genes, especially amino acids substitution at position 145 (G145R), are associated with immune escape, whereas mutations in the PreS or S genes which impair HBsAg secretion could present a risk to blood safety. HBV variants harboring mutations in the viral polymerase gene that confer resistance to nucleoside analogs may be selected during antiviral therapy. Different genotypes have distinct mutation patterns in the PreS and EnhII/BCP/Precore regions. PreS deletions, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. HCC-associated HBV mutants may not transmit via mother-to-child transmission, and are likely generated during HBV-induced pathogenesis. Examination of HBV mutations alone or in combination and host genetic susceptibility will be helpful in classifying the HBV-infected subjects who will develop HCC and need active anti-viral treatments.

Clinical relevance and public health significance of hepatitis B virus genomic variations

Each hepatitis B virus (HBV) genotype and subgenotype is associated with a particular geographic distribution, ethnicity, and anthropological history. Our previous study showed the novel HBV subgenotypes C6 (HBV/C6) and D6 (HBV/D6), based on the S gene sequences of isolates in Papua, Indonesia. The present study investigated the complete genome sequence of 22 strains from Papua and subjected them to molecular evolutionary analysis. A phylogenetic analysis revealed that 9 out of 22 strains were classified as HBV/C6, 3 strains as HBV/D6, and 9 strains as HBV/B3. A particular strain positioned between HBV/B3 and HBV/B5 remained unclassifiable into any known subgenotypes. This strain showed high homology with HBV/C5 from the Philippines in the core region and was thought to have undergone genetic recombination with HBV/C5. Further studies are needed to determine whether this strain belongs to a new subgenotype of HBV/B. Based on the amino acid alignment, HBV/C6 has subgenotype specific variations (G18V and V47M) in the S region. HBV/C6 strains were more closely related in terms of evolutionary distance to strains from the east Asia and Pacific regions than those found in southeast Asia. HBV/D6 strains were most closely related to strains from the Western countries (HBV/D3) rather than those from Asia and Papua New Guinea. In conclusion, we have confirmed by complete sequence analysis that two novel HBV subgenotypes, HBV/C6 and HBV/D6, are prevalent in Papua, Indonesia.

Complete Genome Sequence and Phylogenetic Relatedness of Hepatitis B Virus Isolates in Papua, Indonesia

Approximately 240 million people are chronically infected with hepatitis B virus (HBV), 75% of whom reside in Asia. Approximately 600000 of infected patients die each year due to HBV-related diseases or hepatocellular carcinoma (HCC). The endemicity of hepatitis surface antigen in Indonesia is intermediate to high with a geographical difference. The risk of HBV infection is high in hemodialysis (HD) patients, men having sex with men, and health care workers. Occult HBV infection has been detected in various groups such as blood donors, HD patients, and HIV-infected individuals and children. The most common HBV subgenotype in Indonesia is B3 followed by C1. Various novel subgenotypes of HBV have been identified throughout Indonesia, with the novel HBV subgenotypes C6-C16 and D6 being successfully isolated. Although a number of HBV subgenotypes have been discovered in Indonesia, genotype-related pathogenicity has not yet been elucidated in detail. Therefore, genotype-related differences in the prognosis of liver disease and their effects on treatments need to be determined. A previous study conducted in Indonesia revealed that hepatic steatosis was associated with disease progression. Pre-S2 mutations and mutations at C1638T and T1753V in HBV/B3 have been associated with advanced liver diseases including HCC. However, drug resistance to lamivudine, which is prominent in Indonesia, remains obscure. Although the number of studies on HBV in Indonesia has been increasing, adequate databases on HBV infection are limited. We herein provided an overview of the epidemiology and clinical characteristics of HBV infection in Indonesia.

Hepatitis B virus infection in Indonesia

Universal childhood hepatitis B vaccination was introduced in Indonesia in 1997; by 2008, coverage was estimated to be 78% This study aimed to investigate the serologic status and virologic characteristics of hepatitis B virus (HBV) among the children in East Java A total of 229 healthy children born during 1994-1999 were enrolled in this study Overall, 31% were positive for hepatitis B surface antigen (HBsAg) and 236% were positive for antibody to HBsAg (anti-HBs) HBV DNA was detected in 5 of 222 HBsAg-negative carriers, which were suggested to be cases of occult HBV infection A single amino substitution (T126I) in the S region was frequently found HBV infection remains endemic, and the prevalence of anti-HBs remains insufficient among children in East Java, Indonesia

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Serologic and molecular characteristics of hepatitis B virus among school children in East Java, Indonesia.

The hepatitis virus is hyperendemic in Egypt, western Asia and Africa. In Egypt, most studies have been carried out in the regions of the upper and lower Nile Delta, and so little is known about other parts of the country. Our project aimed to clarify the carrier rate of various hepatitis viruses in the northeastern province of Ismailia. A total of 214 patients with elevated liver enzymes were enrolled in this study. Sera were collected in Ismailia hospital. We conducted a serological and molecular-based survey of hepatitis viruses, including their genetic variability and genotype-related differences. There were 10 (4.7%) cases positive for hepatitis B surface antigen (HBsAg), and 156 (72.9%) positive for anti-hepatitis C virus antibody (HCV-Ab). Phylogenetic analysis showed that genotype C of HBV and genotype 4a of HCV were prevalent. Hepatitis D virus RNA was not detected in HBsAg carriers. Although anti-hepatitis E virus IgM antibody was positive in 5 cases (2.3%), no case was positive for its RNA. Among 54 cases negative for HBsAg and HCV-Ab, HBV-DNA was detected in 35 cases (65%). Our results revealed that HBV and HCV, including occult HBV infection, are widespread and related to liver diseases in Ismailia province, Egypt.

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Molecular epidemiological study of hepatitis viruses in Ismailia, Egypt

A universal hepatitis B vaccination program for infants was adopted in Indonesia in 1997. Before its implementation, the prevalence of hepatitis B surface antigen (HBsAg)-positive individuals in the general population was approximately 5-10%. The study aimed to investigate the hepatitis B virus (HBV) serological status and molecular profile among children, 15 years after adoption of a universal infant vaccination program in Indonesia. According to the Local Health Office data in five areas, the percentages of children receiving three doses of hepatitis B vaccine are high (73.9-94.1%), whereas the birth dose coverage is less than 50%. Among 967 children in those areas, the seropositive rate of HBsAg in preschool- and school-aged children ranged from 2.1% to 4.2% and 0% to 5.9%, respectively. Of the 61 HBV DNA-positive samples, the predominant genotype/subtype was B/adw2 Subtype adw3 was identified in genotype C for the first time in this population. Six samples (11.5%) had an amino acid substitution within the a determinant of the S gene region, and one sample had T140I that was suggested as a vaccine-escape mutant type. The low birth dose coverage and the presence of a vaccine-escape mutant might contribute to the endemicity of HBV infection among children in Indonesia.

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Hepatitis B Virus Infection in Indonesia 15 Years After Adoption of a Universal Infant Vaccination Program: Possible Impacts of Low Birth Dose Coverage and a Vaccine-Escape Mutant

Yoshihiko Yano

Papers

Complete Genome Sequence and Phylogenetic Relatedness of Hepatitis B Virus Isolates in Papua, Indonesia

Hepatitis B virus infection in Indonesia

Serologic and molecular characteristics of hepatitis B virus among school children in East Java, Indonesia.

Molecular epidemiological study of hepatitis viruses in Ismailia, Egypt

Hepatitis B Virus Infection in Indonesia 15 Years After Adoption of a Universal Infant Vaccination Program: Possible Impacts of Low Birth Dose Coverage and a Vaccine-Escape Mutant