Hepatitis B and hepatitis C infections are prevalent worldwide with significant cost to the health sector, which could be substantially reduced with the implementation of few well-selected measures. The Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition (FISPGHAN) Working Group proposes 3 main priorities for medical interventions, namely universal hepatitis B immunisation, multicentric international trials on safety and efficacy of new drugs for treatment of chronic hepatitis B (CHB) and chronic hepatitis C (CHC) infections in children, and development and implementation of age- and phase-specific guidelines for management of CHB infection. Education is essential to reduce hepatitis B and hepatitis C burden, and specific programs should be provided to increase public awareness on transmission and prevention of these infections. FISPGHAN also emphasizes the development of electronic learning programs for doctors on the management of hepatitis B and C infections along with the proper referral system for these patients. FISPGHAN has endorsed research and development of new drugs on the management of hepatitis B in children besides development of an effective vaccine against hepatitis C infection. There is also a need for the development of a vaccine for nonresponders to available hepatitis B vaccine.
SUMMARY OF THE PROBLEM
Approximately 60% of the world's population live in areas where hepatitis B virus (HBV) infection is highly endemic, including China (total population 1.3 billion), Indonesia (222 million), Nigeria (132 million), and much of the rest of Asia and Africa (1).
A vaccine against hepatitis B, made of recombinant hepatitis B surface antigen (HBsAg), has proven to be extremely effective in most cases. To realise global prevention of the spread of hepatitis B, there is a need for the implementation of universal immunisation with hepatitis B vaccine, including in countries in which the immunisation is presently not provided. There is also a need for the development of an effective vaccine against hepatitis B for immunocompromised patients and for those (approximately 5%) who do not develop protective titres of antibody, despite receiving vaccine made of recombinant HBsAg.
For the timely detection of cases of hepatitis B, widespread screening programs need to be in place especially targeting pregnant women and high-risk children to prevent vertical spread and decrease morbidity and mortality. There is a need to better understand the maternal/neonatal risk factors associated with transmission of infection to babies. The treatment of hepatitis B in children mainly compromises interferon/peginterferon and antivirals, lamivudine and adefovir, which have not been effective in terms of the success rate of seroconversion. According to guidelines, the time of onset of treatment should be dependent on the immune response. Drugs should be started in the immune-responsive phase. Most children are in the immunotolerant phase, during which liver disease is likely to progress further. The longer the disease persists, the greater the likelihood of developing hepatocellular carcinoma and greater the morbidity and mortality (2,3). There is an urgent need for the development of effective drugs for the treatment of hepatitis B in children and for validating the use of drugs already approved for use in adults such as telbivudine, tenofovir, and entecavir by carrying out multicentre international trials with newer therapies for hepatitis B (4).
Hepatitis C virus (HCV) has worldwide distribution, occurring among people of all ages, sex, races, and regions of the world (5). The socioeconomic burden of HCV has not yet been defined in most countries. Where the epidemiology of hepatitis C has been studied, the consequences of CHC and end-stage liver cirrhosis have been shown to increasingly affect national health systems. Since the first reports in the early 1990s, the data on HCV prevalence remain disappointingly limited. Information is still inadequate in many countries and most prevalence studies are limited to specific subpopulations, (eg, pregnant women, blood donors, hospital inpatients), with only a few studies using sampling techniques that represent the entire population. There is an urgent need for the development of an effective vaccine against HCV infection.
HBV and HCV are transmitted through percutaneous or parenteral contact with infected blood, body fluids, and by sexual contact. Screening of blood products using nucleic acid testing in blood banks is available in most developed countries and this should be adopted by developing countries to reduce blood transfusion–transmitted infection. To optimise and improve care, international guidelines for the management of hepatitis B and C in children, which could be universally followed, are needed together with an implementation plan.
For the success of the preventive measures for hepatitis B and hepatitis C, general awareness of these infections is required. Knowledge by the public will promote the use of safe practices and hygiene to prevent the spread of infection. Awareness programs should be run on a mass scale to educate the public about these viruses, the disease caused by them, and long-term consequences. General physicians should be regularly updated through training programs and continuing medical education (CME).
In addition, to optimise care, there needs to be regional/national networks and referral systems in place so that children, and at least those with severe or complicated disease, are being managed by experts (Table 1).
Hepatitis B is one of the most common infectious diseases in the world. It is estimated that 40% of the world's population has had contact with or are carriers of HBV, which corresponds to an estimated 350 million HBV carriers. The global epidemiology of HBV infection has traditionally been described according to the 3 categories of endemic rates: high (>8%), intermediate (2%–7%), and low (<2%), depending on the proportion of the population that is seropositive for HBsAg. The HBV endemic rate often correlates with the predominant mode of transmission. Approximately 60% of the world's population live in areas where HBV infection is highly endemic, including China (total population 1.3 billion), Indonesia (222 million), Nigeria (132 million), and much of the rest of Asia and Africa. Approximately 600,000 people die each year because of the acute or chronic consequences of hepatitis B. Despite the availability of effective HBV vaccines, hepatitis B remains a major global health problem. This situation is particularly serious in developing countries, especially because a significant percentage of the population does not have access to the vaccine or does not return for the required booster doses. A number of approaches are being tested to minimise this problem including needle-free immunisation.
Treatment of Hepatitis B
The primary treatment goals for children with hepatitis B are to strengthen the immune system so that it can effectively prevent the virus from replicating, and hence achieve an undetectable HBV viral load, thus halting any liver damage. It also produces the surface antibody (HBsAb), which indicates recovery from the infection. In addition to slowing liver disease in affected children, the major goal is to eradicate the disease in the paediatric population today to prevent cirrhosis and liver cancer in the adults of tomorrow. Unfortunately, treatments available for hepatitis B infection in children so far have had limited success. There are only a handful of paediatric clinical trials taking place to test drugs on children that so far have been used only in adults. Few studies have followed large numbers of children with CHB infections and even fewer have tracked children for ≥1 decade after treatment. When to treat hepatitis B in children is also an area of debate within the medical research and treatment communities.
The only new drugs approved by the US Food and Drug Administration to treat hepatitis B in children are standard interferon, lamivudine and adefovir (for children older than 12 years), and entecavir and telbivudine (for children older than 16 years). Because presently these newer drugs are not recommended to be used on children younger than age 12 years, studies are needed in younger children. There is also a need to develop new effective drugs specifically to treat hepatitis B in children. A large proportion of infected children are in the immune-tolerant phase, in which the presently available drug therapy is ineffective. Research is needed to further study the immunological abnormalities in the immune-tolerant phase of hepatitis B and developing appropriate immunomodulatory therapies.
The major objective of hepatitis B immunisation is the prevention of chronic infection, which leads to cirrhosis and hepatocellular carcinoma because HBV-related cirrhosis and hepatocellular carcinoma usually occur in adults who were infected with HBV during their childhood. The significant benefits of HBV vaccination are therefore only seen decades later.
Taiwan is perhaps the best example of a, previously, highly endemic area where a substantial and measurable reduction in disease burden has resulted from a long-standing policy of universal childhood hepatitis B vaccination. HBsAg seroprevalence among Taiwanese children decreased from 9.8% in 1984, the year when universal infant immunisation began, to 0.7% in 1999. The average annual incidence of hepatocellular carcinoma among children ages 6 to 14 years in 1981–1986 (reflecting the prevaccine era) was 0.7/100,000, whereas in 1990–1994 (the postvaccine era) it was 0.36/100,000 (P < 0.01). In the period before routine vaccination (1974–1983) and the postvaccination era (1984–1999), mortality from hepatocellular carcinoma decreased 60% to 70% among children. In addition, mortality caused by fulminant hepatitis among infants decreased significantly. In Gambia, childhood HBsAg seroprevalence has decreased from 10% to 0.6% since the introduction of routine infant and childhood vaccination in 1986. In countries with intermediate endemicity such as Malaysia, which introduced universal infant vaccination in 1990, HBsAg seroprevalence among schoolchildren (ages 7–12 years) decreased from 1.6% in 1997 to 0.3% in 2003. Population-based surveillance data in Italy showed a decline in the incidence of acute hepatitis B from 11/100,000 in 1987 to 3/100,000 subjects in 2000. In addition, the overall prevalence of chronic HBV infection decreased from 13.4% in 1978 to 3.7% in 1997.
The most dramatic effect of hepatitis B immunisation in the United States was seen in the Alaska Native community. In Bristol Bay, Alaska, before routine immunisation, 7.6% of children had serologic evidence of resolved infection by 9 years of age and 3.2% of children were chronically infected. Ten years after the onset of routine immunisation, no child younger than 10 years was chronically infected and only 1.5% had evidence of resolved infection. Similar seroprevalence declines have been observed in other US communities with traditionally high rates of disease. In children of Asian immigrants living in Georgia, HBV seroprevalence decreased from >20% before 1992 to 1.9% in 2001. National surveillance for acute hepatitis B in the United States is also consistent with an overall decline in new HBV infections. In 2004, the incidence of acute hepatitis B was 2.1/100,000 population (6212 cases), the lowest ever reported in the United States, representing a 75% decline since 1990. The most dramatic declines have occurred in children to whom recommendations for routine infant and adolescent catch-up vaccination were applied. Hepatitis B incidence declined 94% (from 3.0/100,000 to 0.19/100,000) in subjects younger than 20 years of age from 1990 to 2004. All these mounting data strongly confirm that the promotion of universal immunisation is of the utmost importance in decreasing the prevalence of hepatitis B irrespective of the endemic rate of the region. Immunocompromised patients, however, do not produce an effective immune response to hepatitis B vaccine. There is a need to develop effective vaccines for use in these patients.
Prevention and Early Detection of Hepatitis B and C in High-risk Groups
The vertical transmission of hepatitis B and, to a less extent, of hepatitis C is high in endemic areas. Most of the children who contract hepatitis B via the vertical route become chronically infected. The chances of CHC are also higher in these children. Screening child-bearing women for HBV and HCV and putting in place appropriate measures, including exclusive breast-feeding, can prevent vertical transmission and also lead to early detection. Screening high-risk groups, such as children who are immunodeficient, those receiving chemotherapy, taking steroids, or are malnourished would lead to early detection and improved management and contribute to prevention.
Public awareness of the transmission and prevention of HBV and HCV is crucial in decreasing the incidence and prevalence of the disease. Education in various forms to increase public awareness of transmission and prevention is therefore extremely important.
The ongoing education of general paediatricians and physicians is needed to increase and update their knowledge about hepatitis B and C with the aim of optimising management of these patients, including appropriate referral to specialists. Finally, there is a need for developing and implementing evidence-based international guidelines for preventing and managing hepatitis B and hepatitis C in children worldwide.
The prevalence of hepatitis C is approximately 170 to 200 million individuals worldwide. Published data suggest that most populations in America, western Europe, and southeast Asia have prevalence rates of antibody to HCV (anti-HCV) of <2.5%. Anti-HCV prevalence rates for eastern Europe average from 1.5% to 5%, those for the western Pacific region from 2.5% to 4.9%, and those for the Middle East and central Asia from 1% to >12%. In terms of absolute numbers, the majority of infected people live in central/southeast Asia and the western Pacific regions, a pattern similar to that for CHB infection (6–8). The effect of hepatitis C on health costs is considerable.
In addition, one of the major hurdles in the eradication/reduction of the burden of hepatitis C is the lack of hepatitis C vaccine. To date, hepatitis C has been difficult to target with a vaccine because there are many different strains of the virus. In addition, like human immunodeficiency virus (HIV), the HCV mutates rapidly and exists as a complex family of mutated viruses within each infected individual, allowing the infecting virus to escape control by the immune system. This makes it difficult to identify which part of the virus should be targeted for developing an effective vaccine production.
In the United States, the present estimate of the annual costs of acute and chronic hepatitis C is estimated to exceed US$600 million, and, during the period 2010–2019, the total costs are expected to reach US$184 billion, giving an indication of how important the burden of chronic HCV infection can be for the national health systems, even in a low-endemicity country (1.8%) (9). The European Monitoring Centre for Drugs and Drug Addiction estimated the HCV-related costs in 10 European Union countries to be €50 million, excluding HCV drug therapy and monitoring, thereby demonstrating that, even with no public health action, HCV causes significant costs to society. The predicted estimates for Spain were approximately €3 billion for the period 2010–2030, and in Canada the costs are estimated at CD$150 million annually until 2040. There is, therefore, an urgent economic and medical need for the development of an effective vaccine against hepatitis C.
The present treatment of hepatitis C infection consists of a combination of peginterferon and ribavirin, and on this treatment viral eradication can be achieved in only half of all of the patients with HCV genotype 1 and in ≥90% of patients with HCV genotype 2 or 3. Treatment may take 6 to 18 months and therapy-associated adverse effects such as pancytopenia, flu-like symptoms, or depression are common and may lead to early discontinuation of drugs and treatment failure (10).
Recent improved understanding of the HCV life cycle has led to the discovery of numerous potential targets for antiviral therapy. HCV polyprotein processing and replication have been identified as the most promising viral targets; however, viral entry and fusion, RNA translation, virus assembly and release, and several host cell factors may provide alternative attractive targets for future anti-HCV drugs. Inhibitors of the HCV NS3/4A protease are presently in an advanced clinical development phase. Monotherapy with protease inhibitors has shown high antiviral activity, but it is associated with frequent selection of resistant HCV variants, often resulting in viral breakthrough; however, there is encouraging evidence, from phase 3 trials in adults, that the addition of a protease inhibitor (eg, telaprevir, boceprevir) to pegylated interferon-a/ribavirin substantially improves sustained virological response rates in both treatment-naïve and treatment-experienced patients with HCV genotype 1. Nucleotide inhibitors of the HCV NS5B polymerase have shown variable antiviral activity against different HCV genotypes, but seem to have a higher genetic barrier to resistance than protease inhibitors. In addition, several allosteric binding sites have been identified for nonnucleoside inhibitors of the NS5B polymerase (11); however, the development of a substance with high antiviral activity and a high genetic barrier to resistance seems, so far, to be difficult. Among the different host cell–targeting compounds in early clinical development, cyclophilin inhibitors have shown the most promising results. Although advances have also been made in improving interferons, combinations of antiviral agents with different mechanisms of action may lead to the eventual possibility of interferon-free regimens. Further research is warranted in developing newer antiviral drugs, including multicentre trials, not only in adults but also in children.
PLANS TO ACHIEVE THE GOALS
Medical Intervention Goals
Universal Hepatitis B Immunisation
To start, high-endemicity areas need to be targeted for mass immunisation programs. The vaccine would be administered as part of a routine immunisation program, which can reach a large part of the population. For achieving this, there would need to be strong government support along with financial support from other funding agencies. Substantial resources are needed to support manufacturing and distribution of the vaccine. The vaccine, however, should be administered free of cost to the population. For implementation of universal immunisation of the vaccine, the general population will need to be educated about the vaccine. Printed and electronic communication should be used for spreading information about the vaccine and the immunisation programs. Women of child-bearing age and children should be especially targeted with a specific immunisation program.
Multicentre International Trials on Safety and Efficacy of New Drugs for Treatment of CHB and CHC in Children
Until recently, the only drugs used for treatment of hepatitis B were interferon and lamivudine, but now there are a number of studies under way on the potential use of newer antivirals, such as telbivudine and entecavir, in the paediatric population. The results of these studies have been encouraging with regard to their safety and efficacy, although the Food and Drug Administration has still not given approval for their use in children. The only drugs approved for use in children are lamivudine and interferon. Adefovir was recently approved for use in children older than 12 years. There is a need for further development of new, effective therapies against hepatitis B and C. Large multicentre trials to validate the safety and efficacy of new drugs should be planned. International meetings, conferences, symposia CMEs, and so on are needed to generate new ideas and lead to planning of multicentre international trials on existing and new drugs for treatment of hepatitis B and C. These trials will require a large amount of funding, which should come from multiple sources such as governments, NGOs, WHO, UNICEF, the Bill and Melinda Gates Foundation, and the Wellcome Trust. The progress of the trials and monitoring will need to be tailored at the local level.
Development and Implementation of Age- and Phase-specific Guidelines for Management of Chronic HBV Infection
The guidelines available for CHB and CHC in children have been derived from adult guidelines. There are only few drugs approved for use in children compared with adults. There are no universal guidelines to manage these diseases specifically in children. Even in adults, the guidelines are not universal, although the American Association for the Study of Liver Diseases guidelines are most popularly followed. Knowledge about treatment of hepatitis B is evolving and requires further attention. Experts need to generate evidence-based guidelines on management of children with HBV and HCV and, where evidence is poor, plan large studies to guide future treatments. There should also be plans to ensure these guidelines are implemented worldwide.
Development of Effective Vaccine for HCV
HCV, as has already been mentioned, has many strains and mutates easily, making it difficult to target with a vaccine that is effective. Novel vaccine development approaches are therefore needed.
These include virus-like particle-based vaccines that have been successfully used for viral infections such as hepatitis B. An HCV virus-like particle-based vaccine approach could facilitate delivery of neutralising antibody and core-specific T-cell epitopes in a single construct resembling/mimicking HCV virions.
In theory, the delivery of major antigenic determinants in this form, rather than as linear recombinant protein or synthetic peptides, could enhance immunity. Additional strategies include molecules that induce innate immune responses, with secondary effects on adaptive responses (such as TLR-9 ligands) that are either encoded within a vaccine construct or used as a vaccine adjuvant. Qiu et al (12) prepared a fusion protein in the vector of pET-11d that included 3 conserved broadly neutralising B-cell epitopes and a series of T-cell epitopes located in the HCV NS3 region. In vivo, administration of this fusion construct resulted in specific CD8+ cytotoxic lymphocytes that recognised specific antigen sites that were detected by fluorescence activated cell sorter. An HCVcc system was established and applied to detect HCV-specific neutralising antibodies. These results suggest that the multiepitope fusion protein is immunogenic and can elicit both humoral and cellular immune responses. In particular, this fusion protein is able to elicit HCV-specific neutralising antibodies, which are critical for viral clearance. This construct may be significant for vaccine development and could be a candidate to be included in the design of a prophylactic and therapeutic vaccine against HCV.
Development of an Effective Vaccine for Nonresponders to Standard Vaccine Against HBV
Presently, there is a second-generation vaccine for hepatitis B, which is a subunit vaccine made of recombinant HBsAg. This preparation is able to generate a T-helper response but not a killer T-cell response. DNA vaccines are made of plasmids, which are genetically engineered to produce 1 or 2 specific antigen from pathogen and thus can lead to the generation of a wide range of immune responses including killer T-cell response. These vaccines need to be developed and tested for those who do not develop adequate response to the available vaccine.
Development of Newer Drugs and Other Therapies for Chronic HBV Infection
The treatment presently available for hepatitis B is mainly dependent on interferon and lamivudine, an immunomodulatory and antiviral drug, respectively. The effectiveness of both these drugs shows a broad range depending on a number of factors. Therapeutic vaccines are presently available for chronic viral infections, such as human papillomavirus, HIV, and herpesvirus. As an alternative to antiviral treatment or to support a treatment that is only partially effective, a therapeutic vaccine that would activate the patient's immune system to fight and finally control or ideally even clear the virus is needed, whereas the present success of prophylactic vaccination is based on rapid neutralisation of the invading pathogen by antibodies, virus control and elimination of infected cells require T cells. Therefore, induction of a multispecific and multifunctional T-cell response against key viral antigens is a paradigm of therapeutic vaccination and also allows activation of a humoral immune response to limit virus spread. Along with multicentre clinical trials on newer antiviral therapies novel ideas of using vaccine as supportive treatment should be considered.
Increasing Public Awareness of Transmission and Prevention of Hepatitis B Infection
Public awareness programs should be planned on a nationwide scale. These should involve printed and electronic media. There should be regular publications on the transmission and prevention of hepatitis B and C infection and there should be television coverage on the same issues. Informative campaigns should also be organised in urban and rural areas to educate the public opinion makers and media about the disease. Posters and billboards should also be used to address the issue. Prominent public figures should spread general awareness messages to the public. The government, NGOs, and international funding agencies should support the cause by offering financial assistance required for the implementation of programs.
Development of Electronic Learning Programs on Management and Appropriate Referral System for Children With CHB and Hepatitis C Infection
To ensure implementation and avoid misinterpretation of the guidelines for management of hepatitis B and C, there should be regular e-learning programs for paediatricians and general physicians. Regular updates on the topic should be sent to them and they should have free access to reading materials, including articles in journals and tutorials. The decision to start antiviral therapy and the choice of first-line drug are complex. There is a risk of spreading resistance to a drug if antiviral therapy is started without a proper understanding of indications. For this reason, experts need to be involved in managing these cases. This will require educating general physicians to refer appropriate cases to centres where the experienced specialists are involved in the management of complicated cases of hepatitis B and C. This can be achieved by holding regular CMEs with these physicians and sending them information brochures on when and how to refer the cases.
Educating Doctors and the Public on Transmission and Prevention, Including Maternal and Neonatal Risk Factors
Education to improve public knowledge and awareness of the routes of transmission including mother-to-child vertical transmission and prevention of HBV and HCV infection is crucial. The rate of HBV infection to infants is higher if the mother has acute hepatitis in the third trimester as compared with earlier in pregnancy. The presence of e-antigen is related to HBV vertical transmission and infectivity. There are studies showing that the combination of e-antigen and HBV DNA is a more sensitive marker of vertical transmission than e-antigen alone. Transmission is significantly higher in infants delivered by vaginal route than by caesarean section. This can be explained by a risk of lower microtransfusion during elective caesarean section (13).
Immunosuppression secondary to HIV co-infection implies a higher risk of transmission of hepatitis C infection, but this effect decreases by improving immunocompetence with antiretroviral treatment. Breast-feeding does not increase the risk; in fact, exclusive breast-feeding can be protective against the disease. There is a low viral content in milk, there is inactivation by gastric pH, and breast milk has proven immunological benefits. Public education and putting this knowledge into practice by the public is extremely important.
In conclusion, hepatitis B and C are major problems that affect the health of children of the world, but with major differences in rich and poor countries. The definition of priorities and pathways of medical interventions, research, and education may help decision and policy makers to promote actions that would improve the quantity and quality of millions of children.