Hepatitis B: A comprehensive prevention, diagnosis, and treatment program – past, present, and future

The management of hepatitis B virus (HBV) infection presents us with many challenges. Disease prevention, as well as supervision of chronic carriers of the infection, remains a key concern. Despite a rapid increase in the Expanded Program on Immunization (EPI) coverage, the global disease burden remains high. It is estimated that around 2 billion individuals worldwide have evidence of present or past infection with HBV.1 Of these, approximately 350 million are chronic carriers of the virus,1 and it is expected that between 15% and 25% of them will die as a result of HBV.2 Disease progression can take up to 30 years; therefore an estimated 1 million individuals will die each year from chronic hepatitis, cirrhosis, or hepatocellular carcinoma.2 Globally, chronic hepatitis B (CHB) is widespread (Fig. 1); approximately 45% of the global population live in areas of high prevalence HBV. These areas include sub-Saharan Africa, aboriginal Australia, the East Mediterranean, South-east Asia (although Singapore, Taiwan and Malaysia are rapidly becoming areas of low/intermediate prevalence as a result of vaccination1), South America, the Pacific Islands (excluding Japan), and the Inuit communities of Canada. It is expected that more than 8% of the population in these areas are positive to hepatitis B surface antigen (HBsAg).3 In high prevalence regions, the lifetime risk of HBV infection is greater than 60%, and most infections are acquired at birth or during early childhood when the risk of developing chronic infection is greatest. Because most infections in children are asymptomatic, very little acute disease related to HBV occurs, but rates of chronic liver disease and liver cancer in adults are very high. The geographic distribution of chronic hepatitis B virus infection. Areas of intermediate prevalence include the countries that formed the old USSR, Eastern Europe, Japan, South-west Asia, Israel, and the Amazon Basin of South America. Approximately 43% of the global population live in areas of intermediate prevalence, with 2–7%3 of the population being hepatitis B surface antigen (HBsAg)-positive. The lifetime risk of being infected is 20–60% and infections occur in all age groups. Acute disease related to HBV is common because many infections occur in adolescents and adults; however, the high rates of chronic infection are maintained primarily by infections occurring in infants and children. Only 12% of the population live in areas with low prevalence and less than 2% of this population is HBsAg-positive.3 In low prevalence areas (e.g. North America, Canada, Mexico, Western Europe, Australia, and New Zealand [with the exception of the Maori population]), the lifetime risk of infection is less than 20%. Most HBV infections in these areas occur in adults in relatively well-defined risk groups, including injecting drug users, homosexual men, and household contacts of HBV carriers. In 1992, the World Health Organization (WHO) recommended the integration of vaccination against hepatitis B in the EPI. By early 2002, 126 countries had incorporated the hepatitis B vaccine into their routine mass infant immunization programs.4 This currently leaves 65 countries unprotected, including India and sub-Saharan Africa.4 It is expected that with the help of the Global Alliance for Vaccines and Immunization (GAVI) – a coalition of public and private institutions – more of the remaining countries will initiate mass infant vaccination programs in the near future. There are still a considerable number of people who have not received the vaccine due to economic reasons, even though the cost of vaccination has dropped significantly in the 20 years since it was first introduced. As a result, there are still missed opportunities for vaccination where private initiatives could help to supplement routine national vaccination programs. Up until now, the treatment of HBV has been a reactive process, with carriers receiving antiviral treatment only after the onset of symptomatic disease. As early stages of the disease are often asymptomatic this proves to be a significant problem in disease control – a proactive approach would significantly reduce the morbidity or mortality associated with HBV, as both effective prevention and treatment options are now available. The current vaccination program is not functioning at its optimum, as it is usually targeted towards infants within a specific age group. This means that many individuals that were born before the vaccination guidelines were put in place have not been immunized. This problem could be addressed by the introduction of ‘catch-up’ vaccination programs aimed at those children and adolescents who were too old to be included in the current mass infant vaccination programs. As children are more at risk of infection of HBV, vaccination of all primary and secondary school children should be implemented to ensure that all of the target population is accounted for. There is a need to create more awareness of HBV infection in the general population, as even physicians do not realize the extent of the global threat that HBV poses to health. Current figures on the number of global HBV chronic carriers were thought by many to be a gross exaggeration; however, it can now be seen that the figures are correct. Issues to be addressed include the identification of either chronic carriers in need of treatment or non-immune individuals in need of vaccination. This will involve contacting those individuals who would not normally seek medical care, mostly due to socioeconomic status. The initiation of public education and screening programs will help to increase awareness of the disease, and of vaccination and treatment options. A database of chronic carriers should be initiated to ensure the successful monitoring of patients, their close contacts, and disease management. The provision of easier access to vaccination and treatment, and more integration of diagnostics, prevention and treatment are required. This will allow the identification of people in need of treatment and offer tailor-made prevention and/or treatment options. Uncontrolled screening can generate anxiety among the general public, so information and education about the objectives of screening must be provided simultaneously. Along with increased public education, screening programs can greatly increase public awareness of HBV. This initiates contact with those individuals not normally seeking medical care and allows for the creation of a database so treatment can be managed effectively. However, there are many problems associated with current methods of screening that may account for the lack of target population awareness. Currently, screening of the general population has not been favored. The screening methods available take some time to detect antibodies and antigens, and results are not available immediately. This can cause anxiety during the waiting period for individuals tested, and they will often have to be recalled for the outcome of the screen. This can result in individuals not returning for consultation or proper follow-up. The high laboratory costs associated with screening is another factor that reduces the willingness to screen the general population. The rapid test is a screening method that is able to discriminate an infected individual from an uninfected subject within minutes is greatly beneficial to the proactive management of HBV. This rapid diagnostic test facilitates screening and helps raise awareness of hepatitis B (Fig. 2). The test allows the initiation of treatment or immediate vaccination, reducing the potential loss of follow-up when results are not available straight away. Rapid diagnostic test for the detection of hepatitis B surface antigen (HBsAg) and hepatitis B early antigen (HBeAg). The rapid test consists of an assay that is able simultaneously to detect HBsAg and hepatitis B e-antigen (HBeAg), allowing the distinction to be made between those who might benefit from an antiviral treatment (HBsAg-positive and HBeAg-positive), those who are likely to be less receptive to therapy (HBsAg-positive and HBeAg-negative), and those who require vaccination (HBsAg-negative and HBeAg-negative). The test is based on immunochromatographic technology and is designed to use whole blood, serum or plasma obtained by finger or heel puncture. The test has been evaluated at Ghent University Hospital, Ghent, Belgium, in which serum samples were obtained from patients with biopsy-proven chronic HBV infection.5 These sera all tested positive for HBsAg and HBV-DNA. HBV-free serum and whole blood samples were obtained from HBV-free healthy volunteers. To carry out the test, 60 µL of serum or 100 µL of whole blood was used.5 The test was found to have 99.75% clinical sensitivity for HBsAg and 96.37% sensitivity for HBeAg. An overall specificity of 99.63% for HBsAg (99.32% in serum and 100% in whole blood), and 99.37% for HBeAg (98.99% in serum and 100% in whole blood) was recorded. On samples taken from HBV-free individuals, the test displayed a clinical specificity for HBsAg and HBeAg of 99.63%.5 The test was found to be very effective in detecting HBV carriers even in populations of intermediate endemicity, it was also able to provide information on viral presence and replicative activity. Overall, this screening tool was found to be robust, easy to use, with a positive result visible within 2–10 min. The result was also stable for at least three hours following completion of the assay, allowing further review to be made at a later time. No evidence of cross-reactivity was noted.5 The rapid screening test could be incorporated successfully into a disease management program. The test allows for the proactive screening of HBV carriers, and further action can be taken when necessary. Those individuals who are found to be HBsAg-positive will be recommended to undergo further blood testing to confirm that they are chronic carriers and, if confirmed, physicians will advise these patients to: have a hepatitis A vaccination to protect against hepatitis A super-infection (HAV). This is of great value since chronic carriers of HBV or those with chronic liver disease are likely to suffer more severe or even fulminant hepatitis disease if co-infected with HAV. Mortality rates among chronic hepatitis B carriers are 10 times higher than those of HBV-free individuals when coinfected with hepatitis A; bring his or her close contacts (family members and sexual partners) to the hospitals to be tested and vaccinated if necessary. Close contacts of carriers can be vaccinated against both HBV and HAV, as can non-immune individuals. Among HBsAg positive individuals, a significant number is likely also to be HBeAg-positive, indicating active virus replication. This is the group that will be recommended for antiviral treatment. Those people who test negative for hepatitis B markers will be recommended for vaccination. These non-immune individuals should be educated about the danger of hepatitis A as well, and be recommended for vaccination preferably with a combined hepatitis A and B vaccine. The disease management program will begin with public awareness campaigns to encourage people to ‘get tested’. The target population will consist of individuals between 16 and 35 years of age. Pre-testing activities will also include education and data collection on health and immunization history. In order successfully to manage hepatitis B disease, a more proactive approach to screening and vaccination must be taken. The objective of the hepatitis B management program is to seek out those who require treatment or prophylaxis, thus lowering the overall disease burden. By using the rapid screening test, individuals who need either prophylaxis or treatment can be identified at an early stage. Cost-effectiveness and population epidemiology determine the need for antibody testing. According to the Advisory Committee on Immunization Practices, the decision to undertake prevaccination testing of adults should include an analysis of cost-effectiveness, to determine whether the costs of testing balance the costs of vaccine saved by not vaccinating already-infected persons.6 The rapid test is a relatively inexpensive method of screening; its use has already begun in a pilot study in Malaysia. It is hoped that the test will be offered either free of charge or at a very low cost that reflects each country's economic status. The overall disease management program will need to be supported by hepatitis B awareness campaigns to encourage public education and the distribution of information. The data that are generated as a result of the program will have to be managed effectively to achieve even greater benefits.

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