Toward elimination and eradication of hepatitis B

Hepatitis B virus (HBV) causes important human health problems. It has infected one-third of the world's population and approximately 360 million people are chronic carriers. Worldwide, 0.5–1.2 million deaths are attributed to HBV infection annually. Therefore, global control of HBV infection is important. HBV infection can be intervened by interrupting routes of transmission, treating the chronically infected, and preventing the susceptibles with immunoprophylaxis. All these measures are effective. Nevertheless, although pegylated interferons or nucleos(t)ide analogs are effective for the treatment of chronic hepatitis B, chronic carriage of HBV is not easy to eliminate, as revealed by the frequent persistence of hepatitis B surface antigen, despite satisfactory responses to these treatments. On the other hand, hepatitis B vaccination has been shown to preclude HBV infection effectively. This is particularly true for pre-exposure prophylaxis. Worthy of note is the universal vaccination of newborn infants. This is the most effective means of preventing HBV infection, especially for those born to HBV carrier mothers. To eliminate and eradicate hepatitis B, first, HBV in the chronically infected should be eradicated or strongly and efficiently suppressed, so that the infection does not spread rampantly. Second, all the transmission routes should be interrupted. Lastly, but most effectively, is to immunize all susceptibles. The difficulties and possible solutions of each approach are discussed. In conclusion, the existing means to prevent and treat HBV infection render our goal toward eliminating and eradicating hepatitis B possible, although it will take much time and effort to achieve this objective.     

Legend of hepatitis B vaccination: the Taiwan experience

Hepatitis B, a disease entity currently affecting more than 350 million persons worldwide, is also a serious health problem in Taiwan. Liver cirrhosis and hepatoma, which are both closely correlated with hepatitis B, are among the 10 leading causes of death in Taiwan. A mass hepatitis B vaccination program, conducted by the government of Taiwan, was started in 1984. Prior to this vaccination program, a series of viral epidemiological surveys, transmission pattern studies, and pilot immunization trials proved the clinical, economic, and strategic benefits of mass immunization, thus providing the impetus for the implementation of this mass vaccination program. The success of this program has led to a decline in hepatitis B carrier rates among children in Taiwan from 10% to <1%. Furthermore, the mortality rate of fulminant hepatitis in infants and the annual incidence of childhood hepatoma have also decreased significantly in recent years. This is one of the most remarkable success stories in the field of public health.     

Economic evaluation of chronic hepatitis B treatments in Taiwan

Background and Aims: Chronic hepatitis B (CHB) and its sequelae are major health problems in Taiwan. The purpose of the present study was the economic evaluation of short‐duration treatments of CHB and longer duration antiviral treatment for up to 5 years. Methods: Ten‐health state CHB disease progression Markov models were used for hepatitis B e antigen (HBeAg)‐positive and HBeAg‐negative CHB patients, respectively, that included the emergence of antiviral resistance. The perspective of this economic evaluation was the Taiwan health‐care system. Costs and benefits were discounted at 3% per annum. Results: Short‐course therapies of up to 1‐year treatment had limited impact on improving patient survival. Long‐term viral suppression with lamivudine and adefovir sequential rescue therapies (including add‐on therapies) for up to 5 years were found to be highly cost‐effective by international standards (estimated to be NT$580 000 per quality adjusted life year [QALY] for Taiwan). When Taiwan‐specific model inputs were used for HBeAg‐positive CHB, the cost per QALY for lamivudine plus adefovir sequential antiviral therapy increased by approximately 100% over the base‐case estimate, but was still well within the estimated NT$580 000 per QALY threshold. Conclusions: In Taiwan, treatment of CHB patients with lamivudine and adefovir sequential antiviral therapies for up to 5 years results in survival benefits and is highly cost‐effective.     

The natural course of hepatitis B surface antigen-positive chronic active hepatitis in Taiwan

A prospective study on the natural course of hepatitis B surface antigen (HBsAg)-positive chronic active hepatitis (CAH) in 84 patients was conducted at the Taiwan Veterans General Hospital in Taipei. On presentation, 36% of the patients had jaundice and 94% had elevated serum transaminase activity in addition to clinical symptoms. Of the 84 patients with HBsAg-positive CAH, 76 were followed for an average of 46 months, and at the time of the last visit 46% either had evidence of progressive liver disease or had died. Of the 15 deaths, nine were due to complications of liver disease and six were due to primary hepatocellular carcinoma (PHC), alpha-Fetoprotein levels of greater than 400 ng/ml were found only in patients in whom PHC was detected. The course of HBsAg-positive CAH in this predominantly male Asian population was progressive, and deaths occurred either by liver failure, by bleeding esophageal varices, or by progression to PHC.     

Adefovir combined with hepatitis C virus treatment may prevent hepatitis B reactivation after hepatitis C virus eradication in hepatitis B and C virus carriers

This observation reports that a hepatitis B virus (HBV) reactivation, as the result of hepatitis C virus (HCV) eradication on a dominant HCV coinfected HBV/HCV patient, was subsequently prevented by treating both viral infections together. This finding raises the question as to whether preemptive HBV treatment should be prescribed along with HCV treatment to prevent HBV from being reactive after HCV eradication in coinfected HBV/HCV patients.     

Prospects for hepatitis B virus eradication and control of hepatocellular carcinoma

Hepatitis B virus infection is the most common cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. In areas hyperendemic for HBV infection, the related complications occur mostly during adulthood. However, nearly half of all primary infection in chronic carriers occurs in the perinatal period through maternal transmission, the other half arising from horizontal transmission mainly through intrafamilial spread or injection using unsterilized needles. A universal vaccination programme is better than immunization for at-risk groups. Hepatitis B vaccination should be integrated into the Expanded Programme on Immunization in children. Universal immunization against hepatitis B virus has proved to be effective in reducing the hepatitis B carrier rate to one-tenth of the prevalence before the vaccination programme in highly endemic areas, and the incidence of hepatocellular carcinoma in children has also been shown to be significantly reduced. Continued efforts to implement universal vaccination programmes worldwide will very likely reduce the incidence of hepatitis B virus-related diseases, particularly liver cirrhosis and hepatocellular carcinoma.     

Natural history of chronic hepatitis B virus infection in Taiwan: studies of hepatitis B virus DNA in serum

Hepatitis B virus DNA (HBV DNA) in serum was measured by a Spot hybridization technique in a consecutive series of 79 cases with chronic HBV infection from Taiwan. HBV DNA was found in 96.3% (52/54) of HBeAg-positive, 66% (2/3) with neither HBeAg or anti-HBe and in 63.6% (14/22) of anti-HBe positive patients. The levels of HBV DNA in the HBe-Ag-positive patients were significantly higher than in the anti-HBe positive patients (median, 944 vs. 58 pg per ml, p less than 0.001). The mean ages increased from 28.7 years for the cases with high levels of HBV DNA, to 34.7 years for those with low levels (p less than 0.01) and to 41.0 years in those without HBV DNA in serum (p less than 0.05 when compared with those with low level of HBV DNA). Ninety per cent of patients (27/30) with high levels of HBV DNA showed only minor hepatic inflammatory activity, as did 91% (10/11) of those without HBV DNA. In contrast, histologic signs of chronic active hepatitis or chronic lobular hepatitis were demonstrated in 76% of cases (29/38) with low levels of HBV DNA. These data are consistent with the hypothesis that liver damage occurs during the period of clearance of hepatocytes supporting HBV replication, and are inconsistent with the view that HBV may be directly cytopathic. Thus, the natural history of chronic HBV infection may be divided into three phases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic hepatitis B in Italy: new features of an old disease--approaching the universal prevalence of hepatitis B e antigen-negative cases and the eradication of hepatitis D infection.

We evaluated 1336 hepatitis B surface antigen-positive subjects consecutively observed in 79 Italian hospitals over a 6-month period. The proportion of hepatitis B e antigen-negative cases was 86.4%, that of patients coinfected with hepatitis D virus was 9.7%, and the rate of patients coinfected with hepatitis C virus was 16.8%. Multiple logistic regression analysis showed that age >49 years, alcohol abuse, and anti-hepatitis D virus and anti-hepatitis C virus positivity were independent predictors of progression to liver cirrhosis.     

Towards the eradication of hookworm in an isolated Australian community

Hookworm (Ancylostoma duodenale) and other enteric parasites such as Giardia and Hymenolepis are common in Aboriginal communities in northem Australia, and their presence is associated with iron deficiency, anaemia, and failure to thrive. We report the outcome of a sustained, community-based control programme that used regular albendazole in one isolated community. Whereas hookworm has been effectively controlled by the programme, no sustained effect on the prevalence of Giardia and Hymenolepis was seen; the control of these parasites will depend on improvements in health education. This programme might serve as a model for community-based or population-based drug treatment programmes elsewhere.     

Fulminant hepatitis in infants in Taiwan: Strong association with hepatitis B e antigen-negative but antibody-positive maternal hepatitis B surface antigen carriage

This study examined the virologic profiles and pathologic features in 10 infants with fulminant hepatitis and aged 2–7 months. Nine male infants were related to hepatitis B virus infection: as evidenced by positive anti-HBc IgM (4 cases); positive serum HBsAg, and/or liver HBcAg (4 cases); or born to an HBsAg carrier mother (1 case). Only one female infant had presumed non-A non-B fulminant hepatitis, but none had hepatitis A. The mothers of eight infants with HBV-ralated fulminant hepatitis were all positive for serum HBsAg, and most (5/6) were negative for HBeAg but positive for anti-HBe. These findings suggest that infants born to HBsAg carrier mothers, particularly those who are negative for HBeAg, may contract fulminant hepatitis B in infancy in Taiwan. Six infants studied had massive hepatic necrosis and all died, whereas four had submassive or bridging hepatic necrosis and all survived, suggesting a close correlation between the extent of liver necrosis and the patient's outcome. None of the infants had hepatocyte HBsAg, although four had cytoplasmic HBcAg. Anti-HBc IgM was commonly detected (4/6), in sharp contrast to the constant negativity in infants who had contracted an asymptomatic HBV infection. These findings suggest that cytoplasmic HBcAg and anti-HBc IgM may be related to the occurrence of severe liver disease.     

De novo hepatitis B virus infection in hepatocellular carcinoma following eradication of hepatitis C virus by interferon therapy

Epidemiological studies have revealed that hepatocellular carcinoma (HCC) is still observed in hepatitis C virus (HCV)‐positive patients with a sustained response to interferon (IFN) treatment, although a substantial decrease in the incidence of hepatocellular carcinoma (HCC) has been achieved in those patients. Why HCC develops in patients who have a complete clearance of HCV remains unclear. Here, we provided evidence of latent hepatitis B virus (HBV) infection in an initially HCV‐positive chronic hepatitis patient who developed HCC after the complete eradication of HCV by IFN therapy. Although he was initially negative for anti‐hepatitis B surface antigen (HBsAg) or circulating HBV DNA but positive for anti‐hepatitis B core antigen (anti‐HBc) in his sera, he developed HBsAg and HBV DNA during the course of the management of a series of cancers. HBV DNA was detectable in the liver tissues before HBV reactivation and the viral sequences derived from his anti‐HBc‐positive liver showed 100% homology to that from the serum after HBsAg appearance. These findings indicates that HCV‐positive individuals who are positive for anti‐HBc in the absence of HBsAg could have latent HBV infection in their liver tissues and intrahepatic HBV infection may play a pivotal role in the development of HCC after the IFN‐mediated eradication of HCV.     

Subgenotypes of hepatitis B virus genotype C do not correlate with disease progression of chronic hepatitis B in Taiwan.

BACKGROUND: Hepatitis B virus (HBV) genotype C (HBV/C) has two subgenotypes: HBV/Cs and Ce. The prevalence and clinical implications of subgenotype Cs and Ce in Taiwanese HBV carriers remain unknown. METHODS: Subgenotypes of HBV/C were determined in 242 Taiwanese HBV carriers with various stages of liver disease. The clinical as well as virologic features between patients with HBV/Cs and HBV/Ce infection were further compared. RESULTS: HBV/Ce was the predominant subgenotype in Taiwan. The prevalence of HBV/Ce was 93.6% in the inactive carriers group, 84.2% in chronic hepatitis patients, 81.2% in cirrhosis patients, 92.5% in hepatocellular carcinoma (HCC) patients without cirrhosis and 91.9% in HCC patients with cirrhosis. There was no significant difference in the distribution of the HBV/C subgenotypes among patients with different stages of liver disease. CONCLUSIONS: Subgenotypes of HBV/C may not have a clinical impact on the disease progression of chronic hepatitis B in Taiwan.     

Long-term immunogenicity and efficacy of universal hepatitis B virus vaccination in Taiwan

The long-term immunogenicity of universal hepatitis B virus (HBV) vaccine is seldom studied in large-scale prospective community-based populations, especially in adolescents. This study enrolled 1200 children aged 7 years with complete HBV immunization in infancy and determined HBV surface antigen (HBsAg), its antibody (anti-HBs), and HBV core antibody (anti-HBc) annually until the children were aged 14 years. Eleven children had new HBV infections with anti-HBc positivity as the only marker. None became positive for HBsAg or had detectable HBV DNA by polymerase chain reaction. The percentage of protective anti-HBs in 951 children without booster vaccination gradually decreased from 71.1% at age 7 years to 37.4% at age 12 years. Only 1 of the 200 children in the booster group and 2 of the 258 children in the nonbooster group developed new anti-HBc positivity. The results suggest that routine booster vaccination may not be required to provide protection against chronic HBV infection before age 15 years.