During the last 30 years, pediatric hepatology has been transformed by advances in our understanding and management of a wide spectrum of liver diseases. Globally however, viral hepatitis remains one of the most important causes of liver disease in children. Major advances in this field include the discovery of the hepatitis C (HCV) and hepatitis E virus (HEV), the implementation of hepatitis B virus (HBV) and hepatitis A virus (HAV) vaccination, definition of the immunologic phases of HBV infection, and the development of treatments for chronic HBV and HCV infections. Advances in virology, epidemiology, and therapeutics have led to considerable progress in understanding and managing chronic HBV and HCV infection in childhood. Recent clinical guidelines provide evidence-based best practices for diagnosis and management of viral hepatitis in children (1–3).
In developing countries, where routine HAV vaccination is not available, HAV infection is still common and is a leading cause of acute liver failure (ALF). This is in stark contrast to developed countries where the infection risk is now low.
HBV infection remains a global public health problem. Although vaccination has reduced the prevalence of chronic hepatitis B infection in many countries, it is still high in areas such as Western Africa and Asia. Human immunodeficiency virus (HIV) coinfection has added to the complexity of managing these children. Although less common than HAV and HBV infection, increasing numbers of children with HCV are presenting for treatment.
Despite the recent advances, optimal management is constrained by limited knowledge of important aspects such as the natural history of chronic infection, the effect of comorbid disease (such as nonalcoholic fatty liver disease and HIV), the management of immune-tolerant HBV infection, the role of combination therapy, and predictors of response to treatment. In developing countries, universal vaccination against hepatitis A and B, and Hepatitis E in high-risk areas, should be a health priority.
The following articles from 6 continents focus on these infections and their contribution to liver disease in children.
HEPATITIS IN CHILDREN IN NORTH AMERICA
Key advances have been made in the diagnosis, prevention, and treatment of chronic HBV and HCV infection in childhood (1–3).
HBV vaccine has dramatically reduced the incidence of infection in US children younger than 15 years with a 98% reduction of acute HBV infection from 1990 to 2006. All of the infants in the United States should be vaccinated beginning at birth (and all of the children younger than 19 years who have not been vaccinated) and at 2 and 6 months, and those born to hepatitis B surface antigen (HBsAg)-positive mothers should receive vaccine plus one dose of hepatitis B immunoglobulin within 12 hours of birth (1,2). Approximately, 90% of HBV-infected infants and 20% to 25% of those infected before 5 years of age will develop chronic infection, compared with 5% for teens or adults. Four immunologic phases of infection have been defined, with most children remaining in the immune-tolerant phase throughout early childhood. For vertically transmitted cases, spontaneous seroconversion of hepatitis B e antigen (HBeAg) to anti-HBe is below 2% per year for those younger than 3 years and 4% to 5% for those older than 3 years. Horizontal transmission is associated with a higher (70%–80%) rate of seroconversion by age 20 years (1). Adults who acquired HBV during infancy or childhood have a 15% to 25% premature liver-related death rate (4).
Treatment for HBV must be initiated at the proper time to achieve its full effect. Endpoints for treatment are undetectable serum HBV DNA levels, long-lasting HBeAg seroconversion, normalization of alanine transaminase (ALT), and improved liver histology. Although there are 7 US Food and Drug Administration–approved drugs for HBV in adults, only 4 are presently approved for children: adefovir dipivoxil for 12 years of age and older, entecavir for 16 years and older, interferon α-2b for 12 months and older, and lamivudine for 3 years and older. Adefovir and lamivudine are less potent, have few side effects, but may be associated with high rates of viral resistance (eg, 65% resistance rate for children receiving lamivudine for 36 months), thus potentially affecting future treatment options. Interferon-α, which must be injected subcutaneously, yields 26% seroconversion for HBeAg and 10% for HBsAg, and is not associated with development of viral resistance. Its use is hampered by significant side effects. Pegylated (PEG)-interferon is not approved in the United States for this indication; however, it is used in other countries with similar results but requiring fewer injections. Interferons are contraindicated in those with cirrhosis because it has precipitated hepatic failure and death. Antiviral therapy is reserved for those with active liver disease (elevated ALT and abnormal liver histology) who do not spontaneously seroconvert. The testing and hopefully future approval of more effective and less viral resistance–inducing nucleoside(tide) analogues (eg, entecavir and tenofovir) for younger children will add these to the armamentarium of treatment options. Children in the immune-tolerant phase should presently not be treated because present therapies are not effective and may induce viral resistance.
HCV has a higher propensity (70%–80%) to chronic infection at all ages of acquisition than HBV (3). Serologic evidence of earlier or present HCV infection is present in 1.0% to 1.5% of North American adults and 0.17% of 6- to 11-year-olds and 0.39% of 12- to 19-year-olds (5). Most pediatric cases are acquired by vertical transmission at birth or needle transmission during adolescence. There is no effective vaccine to prevent HCV transmission. The risk of vertical transmission from HCV-positive mothers is 5% to 7% for HIV-negative mothers and twice as high if it is for HIV-positive mothers. It is now clear that the genotype of HCV (types 1a and 1b most common in North America) and the genotype of the host (eg, interleukin-28B receptor) (6) have major effects on the natural history of HCV and the response to antiviral therapies.
Present treatment for HCV in children should be considered when there is persistent elevation of ALT or those with progressive fibrosis on liver biopsy. PEG-interferon and ribavirin in combination are approved for pediatric use in North America and yield sustained viral response rates of up to 30% to 40%, with duration of therapy and response rate dependent on genotype. New direct-acting antivirals, which have been approved for triple therapy in adults, are being tested in children and offer the promise for double the response rates, and to even avoid interferon therapy eventually. The reduction of perinatal transmission should also be a goal of future therapeutic strategies.
HEPATITIS IN CHILDREN IN EUROPE
Hepatotropic viruses and drugs are the most common cause of hepatitis in children. In the last 2 decades, however, obesity has doubled worldwide and nonalcoholic fatty liver disease has emerged as the most frequent cause of chronic hepatitis in children and adolescents (7) in developed countries.
Notwithstanding the above, viral hepatitis remains the principal focus of research and public health interventions in pediatric hepatology. In the last decade, no aspect of hepatology has attracted more attention in the scientific community than viral hepatitis. Governments in the United States, Europe, Japan, and Australia actively support research and the pharmaceutical industry has made major investments in the prevention and treatment of this group of diseases that affects 500 million patients worldwide and promises to be an incredibly rewarding market for antiviral drugs (8).
Viral hepatitis in childhood is largely caused by infection with hepatotropic viruses including HBV, HCV, HEV, and hepatitis D virus (HDV). HAV infection is relatively uncommon in Europe, although some countries such as Romania have an intermediate risk of transmission.
Clinical presentation of acute hepatitis, regardless of the etiology, generally includes jaundice and vague abdominal pain, although some children may present with vomiting and fever. These symptoms are reported to be milder and the disease course shorter in children compared with adults (9); however, children with chronic hepatitis are usually asymptomatic. The incidence of viral hepatitis varies according to geographical areas as well as the immunization regime employed in different countries that in turn depends on factors such as socioeconomic conditions and local outbreaks.
HBV infection poses a global health burden; >350 million people worldwide have been infected with long-term liver infections (10). In 1992, the World Health Assembly recommended the inclusion of HBV vaccine in all national immunization programmes. Substantial progress has been made worldwide to introduce the vaccine. Within Europe, following the introduction of the vaccine, the incidence of acute hepatitis B has decreased markedly, from 6.7/100,000 in 1995 to 1.5/100,000 in 2005, although there is wide variation within Europe in the rates of chronic infection (11).
Approximately 170 million people worldwide are presently infected with HCV. In Europe, the seroprevalence of HCV infection in pregnant woman is estimated to be between 0.15% and 2.4% and may be higher in other regions of the world (12). Several factors influence the clinical course of HCV infection, but recent data from adolescent and young adults indicate that alcohol abuse and intravenous drug consumption remain the major risk factors of progression to cirrhosis in HCV-infected subjects (13).
Issues in the management of HBV and HCV infection, which still require clarification, are who and when to treat, what medication to use, and anticipating the need for liver transplantation and other interventions for end-stage liver disease.
HEV infection is an enteric infectious agent that differs from HAV and HBV. It is endemic in Asia and Africa, where the prevalence of HEV IgG antibody could be as high as 50%; however, in recent years, enhanced surveillance has detected an increasing number of nontravel-associated HEV infections, especially in Europe and Japan (14). These patients should be treated with ribavirin because prolonged viremia has been associated with the development of liver cirrhosis and hepatic failure (15).
Approximately 15 million people are infected with HDV worldwide, but areas with the highest prevalence include southern Italy, North Africa, and the Middle East (16). The disease is asymptomatic and not progressive in a minority of cases, but has a severe and rapidly progressive course to cirrhosis in most patients. The present immigration to Europe of HDV-positive subjects will lead to an increase in the reservoir of HDV infection.
It is clear that both HBV and HCV infections represent high-risk factors for liver cancer development (17). Therefore, strategies to improve screening and detection of infected patients, to reduce viral transmission (HBV vaccination of infants and susceptible adults and treating patients with chronic HBV and HCV infections) and address cofactors for progression (alcohol intake and metabolic syndrome in adolescent) are urgently needed.
HEPATITIS IN CHILDREN IN AUSTRALIA
The management of viral hepatitis in children during the last 30 years has matured considerably, from a state of ignorance of its presence, to pre-emptive diagnostic testing, an understanding of the natural history, and response-guided treatment paradigms based on a combination of adult and pediatric clinical trials.
HCV infection in children is now acquired predominantly by the perinatal route with approximately 60% to 80% of children becoming chronic carriers of the virus (3). The prevalence varies from extremely low (0.22/105 in Australia (18), 0.17% of 6 to 11 year olds in North America (5)) to 5.8% in Egypt (19). The natural history of perinatally acquired HCV has been clarified by long-term studies, which suggest that children are generally well with mildly abnormal liver function tests. Cirrhosis is rare in childhood (1%–2%); however, liver transplantation for end-stage disease has been required (3). Treatment paradigms have changed rapidly and standard of care is now peglyated interferon and ribavirin, which are approved for use in children in many countries. For this therapy, the role of viral genotype is imperative to predicting response. HCV genotype 1 has consistently lower response rates (50%) than genotype 2 and 3 (80%–100%) in several pediatric studies (20). More recently, at least 2 polymorphisms of interleukin-28B have allowed a subdivision of genotype 1 patients into those who are more likely to response to PEG-IFN ribavirin therapy (80% vs 30%). Data in children regarding the use of this polymorphism are awaited. Response-guided therapy paradigms presently used in adults allow early termination of therapy (at 12 weeks) in those unlikely to respond. Newer oral antivirals presently available for adults have further increased response rates in genotype 1 patients and eventually these may replace the present interferon-based therapies. The question regarding which children should be treated presently remains controversial, although the ability to cure HCV is an attractive individual and global health goal.
Hepatitis B remains a significant global health issue with >350 million people infected worldwide. Prevalence rates vary globally from high (>8%; eg, Asia-Pacific) to low (<2%; eg Western Europe, North America) (21). The predominant route of transmission in endemic areas is perinatal where >90% of infants become chronic carriers. Horizontally acquired HBV during childhood may also account for the increasing prevalence during childhood in some populations, for example, Euro-Mediterranean and African countries (22); however, an overall reduction in prevalence has been achieved with universal immunization programs in many countries (23). The risk of cirrhosis during childhood is low and likely to be related to other risk factors such as concomitant infection with HCV and HDV. Fibrosis, however, is much more common, and approximately 15% to 40% of people with chronic HBV may eventually develop end-stage liver disease (24).
Therapy remains difficult, and although a number of therapies including PEG-interferon and some nucleoside analogues are licensed for use in children, the “holy grail” of therapy, eradication of CCC DNA, remains elusive. Children should be monitored for the development of hepatocellular carcinoma (HCC) regardless of the phase of HBV infection, although data to guide the frequency and nature are lacking. At this stage, yearly measurement of α-fetoprotein and liver ultrasound seem reasonable if available. A more pressing issue is the lack of response to vaccination, which may be related to genotype, an immunocompromised host, or the emergence of vaccine-resistant mutants.
Although the approach and management of viral hepatitis in children have progressed considerably during the last 30 years, there is still much to be achieved particularly in terms of streamlining treatment paradigms in HCV and prevention and treatment of hepatitis B–related liver disease.
HEPATITIS A AND B IN SOUTH AMERICA
Owing to poor hygiene and sanitary conditions, HAV was highly endemic in South America for most of the 20th century with almost universal infection of children by the age of 10 (25). During the last 2 decades, as conditions have improved, there has been a shift to intermediate endemicity, with lower rates of seropositivity in schoolchildren and in adolescents. For example, during the 1990s and the beginning of 2000, the rate of seropositivity in children 6 to 10 years old was 30% in Chile and approximately 50% in Brazil and Argentina (26). A systematic review published in 2010 (25) found that all of the regions in South America had an intermediate endemicity. This included Andean countries (Peru and Bolivia), which had the highest rates of hepatitis A in the region, and tropical (Brazil, Paraguay) and southern countries (Chile, Argentina, Uruguay), which had the lowest rates in the region. At the beginning of 2000, HAV was found to be the most common cause of ALF in children from Argentina, Brazil, Chile, and Colombia, comprising 45% of the cases (27).
Several countries have shown a large reduction in HAV infection owing to improved living conditions; however, these improvements are not uniform across each country. Although Chile and Brazil have national seroprevalence rates lower than 10/100,000, there are areas within these countries where the rates are >10 times higher (data provided by the Ministry of Health, Chile, and Brazil).
Although it is widely accepted that intermediate endemicity, with its burden on the public health system, is the best scenario for introducing routine vaccination and several local pharmacoeconomic studies have shown that this policy is cost-effective in the region, only 2 South American countries have introduced the HAV vaccine in their immunization programs to date.
Argentina has developed world-leading experience in the successful use of 1 dose of HAV vaccine. In 2005, vaccination of 12-month-old infants was introduced. Coverage was 95% in 2006 and 100% after 2008. The incidence of HAV infection decreased from 70 to 173/100,000/year during 1995 and 2004 to 10/100,000/year in 2007, representing an 88% reduction (28). Moreover, no liver failure cases owing to HAV have been observed since 2008. Uruguay introduced a 2-dose vaccination schedule in 2008 for children at 15 and 21 months; infection rates fell from 34 and 57/100,000 in 2005 and 2006 to 4.5 and 2.78/100,000 in 2009 and 2010, respectively (data provided by the MOH, Uruguay).
HBV infection is a major public health concern worldwide. Recently, studies measuring HBsAg in children (5–9 years old) showed a high intermediate prevalence (5%–7%) in Bolivia, Peru, and Ecuador; the rest of the South American countries had low intermediate or low prevalence. In adults (19–49 years old), all of the South American countries had a low intermediate or low prevalence (29). The most prevalent genotype in South America is genotype F, with 4 subgenotypes, which exhibit a geographic distribution (30).
In South America, HBV vaccine has been introduced increasingly since 1997 and presently all countries include the vaccine in their routine immunization schedules. Countries that previously had the highest prevalence of HBV in South America (Brazil 7.9% and Venezuela 3.2%) incorporated the first dose of HBV vaccine in the newborn period. The coverage for the 3rd dose of HBV vaccine is 75% worldwide and up to 85% in the Americas. A recent multistage household cluster survey of 17,749 children in Brazil showed that 40% received a birth dose within 1 day of birth, 95% received at least 1 dose, and 87% completed the 3-dose series by 12 months of age (31), showing an improvement in coverage. The pentavalent vaccine (DTPw + Hib + Hep B) is the most frequently used modality of administration in South America.
Despite persistent problems with vaccine cover in some countries, vaccination strategies have led to an impressive decline in chronic HBV infection in the region. For example, in areas of Brazil with high endemicity before the introduction of the HBV vaccine, preliminary results of a National Survey of HBV estimate that the prevalence of HBV infection is 0.11% and 0.5% among 10- to 19-year-olds and 20- to 69-year-olds, respectively, in the northeast region and 0.17% and 0.75% in these same age groups in the central-west region, demonstrating great efficacy.
VIRAL HEPATITIS IN CHILDREN IN ASIA
Viral pathogens are the main cause of hepatitis in Asian children. Of these viruses, HBV infection remains a major health hazard in Asia because of its high prevalence and the severe complications of chronic infection. This problem persists in children even in the era of HBV vaccination.
HAV (South and South-East Asia) and HEV (Central and South-East Asia) are endemic in parts of Asia. HAV and HEV are transmitted through the fecal-oral route and transmission is significantly associated with poor hygiene (32,33). HAV and HEV infections are generally mild and self-limiting diseases in immune-competent children, although rarely ALF may occur.
The efficacy and safety of HAV vaccine have been confirmed and vaccination is recommended for high-risk subjects such as those with chronic liver diseases or travellers to HAV endemic areas. Whether or not to include the vaccine in the routine childhood immunization schedule depends on the local level of risk for children. In Asia, China has introduced HAV vaccination into routine childhood immunization schedule (other non-Asian countries that have introduced HIV vaccination are Israel, the United States, and Argentina).
Genotype 3 HEV infection can be a zoonosis from animal reservoirs in industrialized countries, and chronic HEV infection has been described in immune compromised patients. In a phase III clinical trial, HEV vaccine had a 94% to 100% efficacy in adults (33).
To date, many Asian countries are categorized as HBV endemic areas. The first universal HBV vaccination program in the world was launched in Taiwan in 1984. After the introduction of this program, the seroprevalence of HBsAg in Asian children declined to <2% in most endemic areas. The incidence in children of HBV-associated acute hepatitis, fulminant liver failure, nephropathy, and HCC decreased after the vaccination program. HBV vaccine is the first human cancer-preventive vaccine (34). Although the HBV vaccine is extremely effective, approximately 10% of infants born to HBeAg-positive mothers were still infected (35). The main causes of vaccine failure are high maternal viral load and vaccine escape mutants. During chronic HBV infection, clearance of HBeAg and HBsAg are markers of a favorable outcome. Differences in the age of onset of puberty, cytokines, and toll-like receptor polymorphisms are important predictors of HBeAg and HBsAg seroclearance and seroconversion (36). Of the 10 HBV genotypes in the world, the main genotypes in Asia are B, C, and D. Subjects chronically infected with genotype B have earlier HBeAg seroconversion than those with genotype C or D. Presently approved anti-HBV drugs in children are lamivudine, adefovir (12–17 years), and conventional interferon, whereas the entecavir, tenofovir, and PEG-interferon trials are ongoing or to be initiated in children. Future strategies to increase the global HBV immunization rate and to interrupt mother-to-infant transmission are needed to eradicate HBV.
HDV is transmitted through infected body fluid or blood products. HDV super-infection may aggravate the clinical course of chronic HBV infection and lead to cirrhosis and even hepatic insufficiency (37). Genotypes I and IV HDV are the main types in Asia, and genotype I is associated with a higher risk of fulminate hepatitis, liver cirrhosis, and HCC than genotype IV (37). Presently, interferon monotherapy is the drug of choice for chronic HDV infection, although efficacy is limited. Better therapy for hepatitis D is anticipated. Successful HBV vaccination can protect HDV infection.
In most Asian countries, the average prevalence of HCV infection, as indicated by anti-HCV antibodies, is <2.5% in adults and is generally extremely low (<0.2%) in children, except in high-risk groups or in some localized hyperendemic areas. Six genotypes of HCV have been identified and genotype 1, 2, 3, and 6 are most common in Asia. The main transmission routes include the administration of contaminated blood products, intravenous drug use, tattooing, acupuncture, mother-to-infant or sexual transmission, accidental needle-stick injury, and household contact. Mother-to-infant transmission becomes the main route of transmission after the introduction of blood product screening for anti-HCV antibodies and the use of disposable needles and syringes. Because of the lack of an effective vaccine, interruption of HCV transmission still depends on the prevention of transmission, such as the implementation of blood donor anti-HCV screening, the use of disposable or sterile medical instruments, and the avoidance of high-risk behaviors (38). The use of combined PEG-interferon α-2a and ribavirin is superior to PEG-interferon α-2a alone for chronic hepatitis C in children (39).
VIRAL HEPATITIS IN CHILDREN IN AFRICA
Viral hepatitis remains the most important cause of acute (HAV infection) and chronic (HBV infection) liver disease in children in Africa.
Despite the limitations of available data, it is clear that the HBV infection rate is high in many parts of Africa. Of the 470 million people living on the continent, about 50 million are carriers of the virus, while 25% of these are at risk for dying from the illness. Studies from Western African countries such as Liberia, the Gambia, Mali, and Senegal show that transmission is predominantly horizontal and usually occurs in childhood. The prevalence of infection increases rapidly after the age of 6 months, and by 2 years, 40% of children have been infected with 15% of children developing chronic infection. By 10 years, 90% of children in some regions have been infected and 20% have become chronic carriers (40). The situation in other parts of Africa is similar to that described in West Africa. In some regions such as South Africa however, the prevalence is relatively low: only 0.97% of children in Soweto, Johannesburg, are HBsAb-positive and the prevalence in Cape Town is <3% (41).
Because transmission of HBV in African children is predominantly horizontal, routine HBV vaccination in infancy dramatically reduces the incidence of infection. In countries that have introduced HBV vaccination in infancy, the incidence of hepatitis B–associated complications has decreased (42). In a recent survey, 28 of 30 respondents from Africa reported that they had a HBV vaccination policy (43). In most of these countries, the policy was aimed at infant vaccination, although some included health care workers. None of the countries covered adolescents and only 1 provided routine vaccination to high-risk groups. Other preventative measures such as passive prophylaxis at birth and adolescent counseling have been employed with variable success in Africa.
Transmission through blood products is an important route of infection in some areas. Life-saving blood transfusions are often required, particularly in areas with a high incidence of malaria; however, in 2004, blood was not screened for HBV and HCV in 22% and 51%, respectively, of African countries surveyed (43).
Sub-Sahara Africa has the highest prevalence of HIV in the world, and HBV and HIV coinfection occurs in as many as 19% of HIV-infected children (44). The response to HBV vaccination in HIV-infected children is poor (45), placing them at increased risk for horizontal transmission. Additional doses of the vaccine (46) and antiretroviral therapy may improve the response rate. In addition, coinfected patients have higher HBV DNA levels, are less likely to clear HBeAg, are more likely to develop chronic hepatitis and liver fibrosis, and have more drug toxicity and liver-related mortality.
There are a number of challenges to the treatment of coinfected children: interferon therapy is less effective and few coinfected children are suitable candidates for this treatment, the choice of antiviral agents in children is limited, and, in contrast to adults, there are no clear guidelines for their management.
Primary health care strategies are the most cost-effective approach to reducing the burden of HBV infection. Effective screening of blood donors, improving the implementation of immunization programmes, immunization of health care workers, and cheaper vaccines are priorities that should be addressed.
Most children living in poor socioeconomic conditions in Africa will be infected with HAV before adulthood; in some areas, almost 100% of children have serological evidence of HAV infection by the age of 6 years. In these areas, HAV is the leading cause of ALF and the most common cause of hepatitis requiring hospitalization. Unfortunately, no African country provides routine HAV vaccination to children.
The seroprevalence of HCV infection is low (<1%) in Southern Africa, whereas the adult prevalence in some Western African regions (47) is high. Presently, no data are available on the prevalence of HCV infection in African children.
Sub-Sahara Africa is a region with a high HBV prevalence. Poverty and ignorance contribute to the high infection rate and subsequent complications such as liver failure, cirrhosis, and HCC. Routine vaccination of children against HBV and HAV should be a priority.
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