Pediatrics

Viral Hepatitis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has viral hepatitis? What are the typical findings for this disease?

Viral hepatitis often presents with symptoms of fever, malaise, and anorexia. In addition, many patients will also have nausea, abdominal pain or tenderness, and jaundice. However, the presentation depends on the type of virus and the age of the patients. While symptomatic hepatitis is usually characteristic of patients with hepatitis A, very young children with the infection may be asymptomatic. Children with hepatitis B rarely have acute severe hepatitis; much more commonly they are asymptomatic during childhood but are at risk for developing cirrhosis and liver cancer as adults. Likewise, children with hepatitis C are usually asymptomatic during childhood but remain at risk for progression of liver disease in adulthood.

Background

Viral hepatitis has been a global health concern and economic burden for over the past century. Great contributions have been generated from worldwide health organizations, pharmaceutical industries, and clinical and research institutions. The volume of current knowledge on viral hepatitis is high; 99,538 publications can be found by searching the phrase "viral hepatitis." This chapter will focus on important elements of hepatitis that occur from known hepatotropic viruses, including hepatitis A-E viruses (HAV, HBV, HCV, HDV, HEV), HGV and transfusion transmitted virus (TTV).

HAV is a non-enveloped, single-stranded (SS) RNA virus and belongs to the Picornaviridae family. HAV strains isolated from various parts of the world constitute a single serotype and are divided into 6 genotypes (I - VI) based on phylogenetic analysis of nucleotide sequences in the VP1/2A junction region.

HBV, an enveloped, double-stranded circular DNA virus, belongs to the Hepadnaviridae family and has 10 known genotypes (A-J) and several subtypes that vary geographically worldwide. The clinical relevance has been reported in the literature. For example, the majority of cases with perinatal transmission are associated with genotype C, which also is at higher risk for hepatocellular carcinoma (HCC).

HCV is an enveloped, SS RNA virus and belongs to the Flaviviridae family. There are 7 genotypes along with several sub-genotypes of HCV that vary geographically. Genotypes 1 and 4 are more resistant to conventional interferon-based therapy than genotypes 2 and 3. Genotype 1 represents 60-70% of patients in the United States.

HDV is a SS circular RNA virus (HBV envelope) and belongs to the Deltavirus family. It is dependent on the presence of HBV for replication.

HEV is a non-enveloped, SS RNA virus and belongs to the Caliciviridae family. There are 4 genotypes of HEV but only one serotype. Genotypes 1 and 2 infect only humans and are a major cause of water-borne outbreaks of hepatitis in developing countries, particularly during the monsoon season in Asia and Africa. Genotypes 3 and 4 infect humans and animals, especially pigs, and are the main cause of sporadic outbreaks of hepatitis in developed countries.

HGV or GBV-C is a non-enveloped, SS RNA virus, belongs to the Flaviviridae family, and is classified in five genotypes (genotype 1: West Africa; 2: North America and Europe; 3: Asia; 4: Southeast Asia; 5 South Africa).

TTV is a non-enveloped, SS circular RNA virus and belongs to the Picornaviridae family.

Clinical manifestations

HAV

HAV infection is a self-limited illness accompanied by fever, malaise, anorexia, nausea, and jaundice following an incubation period of approximately 28 days (range 15-50 days). Jaundice usually is an indicator of the diagnosis. HAV-infected young children are usually anicteric; for example, approximately 70% of infected children younger than age 6 months have mild flu-like symptoms without jaundice. Jaundice is observed in only 7% of children less than age 4 years. More than 70% of infected older children are icteric with illness.

Peak infectivity occurs during the 2-week period prior to the onset of jaundice or an elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Jaundice could last several weeks; the symptoms usually last less than 2 months. Of HAV-infected individuals, 10-15% will have prolonged or relapsing hepatitis for up to 6 months. Fecal shedding of the virus usually disappears by the time patients become symptomatic. However, the HAV virus never causes chronic disease.

HBV

Children with chronic HBV infection are asymptomatic, and most grow and develop normally. About 1/3 of older children and adolescents with acute HBV infection will develop classic symptoms of hepatitis. Cirrhosis and HCC may be anticipated in about 25% of those who acquire HBV infection during infancy or childhood. Approximately 90% of children infected as infants will develop chronic infection. The risk of chronic infection falls to 25-50% for children who become infected after early infancy but before age 5 years, and to only 5-10% for children who become infected in adolescents or adulthood.

A positive test for HBsAg for longer than 6 months defines chronic HBV infection (CHB), which is characterized by 4 immunologic phases (immune tolerant, HBeAg+ immune active, inactive HBsAg carrier, and reactivation or HBeAg− immune active). Many children will remain immune tolerant until late childhood or the second decade of life.

HCV

Infants born to HCV-positive mothers are more likely to be of low birth weight, small for gestational age, and require neonatal intensive care unit admission and assisted ventilation compared with uninfected infants. The natural history of 266 children with vertical HCV infection reported by the European Paediatric Hepatitis C Virus Network is that about 20% were able to clear the infection, 50% had evidence of chronic asymptomatic infection, and 30% had chronic active infection. In a large pediatric HCV study, 1.8% of children developed decompensated cirrhosis (mean age 9.6 years); most of these were perinatally infected with HCV genotype 1a, and most of their mothers were intravenous drug users.

HDV

HDV is a defective virus that requires the presence of HBV infection. HDV infection occurs either as a coinfection with HBV in a previously uninfected individual, or as a superinfection in an existing HBsAg carrier who may have pre-existing chronic liver disease. HDV coinfection is characterized by the simultaneous presence of markers of HDV during the acute phase of HBV infection. Individuals with HDV co-infection are more likely to develop a fulminant course than patients with isolated acute HBV infection; rarely, it progresses to chronic hepatitis. Individuals with superinfection usually present with acute or chronic hepatitis B (CHB) or mimic acute hepatitis in a previously unrecognized HBV carrier. Over 90% of patients with HDV superinfection develop chronic liver disease with an accelerated progression to cirrhosis and HCC.

HEV

The clinical course of HEV is indistinguishable from that of HAV, with the incubation period ranging from 2 - 9 weeks. The illness is a self-limited illness accompanied by fever, malaise, anorexia, nausea, and jaundice without sequelae. Case-fatality rates in the general population can vary from 0.1-3.0%. Pregnant adolescents and women often have worse outcomes, such as fulminant hepatitis and death, than non-pregnant patients. HEV has been recently reported to cause chronic infection in immunocompromised patients, which may lead to cirrhosis.

HGV or GBV-C

Individuals with HGV infection are asymptomatic. HGV can cause persistent infection in young infants with insignificant evidence of liver disease. To date, HGV has not been associated with acute or chronic hepatitis, fulminant hepatitis, or HCC.

TTV

TTV is frequently isolated from individuals with various forms of viral hepatitis. Individuals with TTV infection are asymptomatic. The mechanism of persistent TTV viremia is not well understood. Healthy children infected with TTV do not have elevated liver enzymes.

What other disease/condition shares some of these symptoms?

In the acute setting of viral hepatitis, several conditions, including bacterial, rickettsial, fungal, or parasitic infections of the liver, drug-induced liver injury, autoimmune hepatitis, metabolic liver disease such as Wilson disease, etc., can mimic viral hepatitis. In patients with chronic viral hepatitis, clinical features may not differ from patients with other types of chronic liver disease.

What caused this disease to develop at this time?

Each of the hepatotropic viruses has a different epidemiology and predisposing factors. Keys to identifying cases with viral hepatitis include a high index of suspicion, knowledge of the geographic distribution where the patients or their families have lived or travelled, personal hygiene, and risk factors, which will be discussed later.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

An abnormal hepatic panel, including ALT, AST, alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), total protein, albumin, total bilirubin (TB), and direct bilirubin (DB), has generally given clinicians a clue to the possible presence of viral hepatitis. Typically, an elevation of AST and ALT up to 10-50 times normal values suggests a hepatocellular form of viral hepatitis, whereas elevated ALP (>=3 times normal value), elevated GGT, TB, and DB suggest a cholestatic form. However, mixed forms occasionally occur. The hepatitis panel is a first-line test, which includes hepatitis A IgM (HAV IgM), hepatitis B surface antigen (HBsAg), hepatitis B core IgM (HBc IgM), and hepatitis C antibody.

An increase in the AST/ALT ratio (AST>ALT) may suggest the development of cirrhosis in individuals with chronic hepatitis B (CHB) and chronic hepatitis C (CHC).

The diagnosis of acute hepatitis A is made by detecting IgM anti-HAV in the serum. Specific antibodies rapidly develop in individuals with HAV infection. IgM anti-HAV are usually detectable 5-10 days prior to the onset of symptoms and can persist for up to 6 months after infection. IgG anti-HAV appears early in the infection, persists indefinitely, and confers lifetime protection against reinfection.

HBsAg is the initial serological marker of acute HBV infection. Early in the course of acute HBV infection, HBeAg and HBV DNA are detected and are markers of active viral replication. As the patients recover, serum HBV DNA significantly decreases but may remain detectable by polymerase chain reaction (PCR) assay for up to several decades; HBeAg to anti-HBe seroconversion occurs; and finally, HBsAg becomes undetectable. Persistence of HBsAg for longer than 6 months indicates an HBV carrier or progression to chronic HBV infection. Anti-HBc IgM is the initial antibody, which usually persists for several months. Anti-HBc IgM may be the only marker of acute HBV infection during the window period (after HBsAg is cleared and before anti-HBs is detected). The presence of anti-HBc IgG and anti-HBs indicates recovery from acute HBV infection.

CHB is indicated by the presence of HBsAg persisting for longer than 6 months and detection of anti-HBc IgG. During the early phase of CHB, HBeAg and high serum HBV DNA levels are markers of HBV replication. Over a period of time, HBV-infected individuals seroconvert from HBeAg to anti-HBe, followed by a decrease in serum HBV DNA levels.

A variety of tests are available for the diagnosis and management of individuals with acute or chronic hepatitis C. Antibody tests for detection of anti-HCV are generally the first step. At the early development of antibody tests for HCV, the average time between the onset of infection and seroconversion is 16 weeks. This window period has been shortened with newer generations of antibody tests to approximately 4-8 weeks. In contrast, HCV RNA, (the PCR assay for the viral ribonucleic acid) can be detected within 10-14 days after infection. The dynamic range of quantitative assays for HCV RNA has been developed to detect a lower limit of detection of 10-15 IU/ml; the ability to report high levels of virus is essential for successful determination of early virological response during the antiviral therapy. Since passive (transplacental) maternal antibody can persist for up to 18 months, the American Academy of Pediatrics recommends that infants born to HCV-infected mothers be screened by anti-HCV antibody at age 18 months postpartum.

Enzyme immunoassay for anti-HDV is commercially available. Negative anti-HBc IgM, positive HBsAg, and presence of anti-HDV suggest the diagnosis of HDV superinfection. Anti-HDV may take several weeks to develop. Acute and convalescent sera may be required. IgM anti-HDV is not useful since it can persist several months during chronic infection.

The specific IgM response to HEV infection is detectable at the onset of symptoms or abnormal liver function, followed shortly by anti-HEV IgG. At present, enzyme immunoassays (EIA) have been developed to detect anti-HEV IgM or IgG in infected individuals. A commercially or standardized, FDA-licensed, serological assay recently became available in the USA. Serum samples can be sent to the Centers for Disease Control and Prevention (CDC) via the microbiology laboratory department at each hospital for conventional and real-time RT-PCR assays to detect HEV RNA; however, the window of detectable viremia is narrow.

No commercially serologic testing is available for HGV. An indirect immunoassay to E2 (envelope) protein and the reverse transcription PCR method are used for detecting HGV RNA in serum samples for research purposes only. E2-specific antibodies are associated with loss of detectable HGV RNA, which indicates recovery from HGV infection. Serologic testing for TTV is not available in the clinic setting; the viral DNA can be detected by PCR.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not required to diagnose viral hepatitis; however, they can be used to assess complications of chronic viral hepatitis such as portal hypertension, cirrhosis, gallstones and other conditions that mimic viral hepatitis such as liver abscess, liver tumors, and complicated congenital hepatobiliary disorders.

Confirming the diagnosis

Table I describes children who should be screened for CHB.

Table I.

Pediatric Population: Children Who Should Be Screened for Chronic HBV Infection

Figure 1 and Figure 2 depict recommended approaches to monitoring and managing children with CHB and CHC, respectively.

Figure 1.

Recommended Approach to Monitoring and/or Managing Children with Chronic Hepatitis B Infection

Figure 2.

Recommended Approach to Monitoring and/or Managing Children with Chronic Hepatitis C Infection

If you are able to confirm that the patient has viral hepatitis, what treatment should be initiated?

Acute viral hepatitis in the pediatric population is generally a self-limited illness. The treatment is supportive. Antiviral agents have been used in the adult population for therapy of severe acute hepatitis B infection and acute hepatitis C infection. However, in the setting of fulminant hepatitis, liver transplantation is often indicated. Patients with acute liver failure secondary to viral hepatitis should always be worked up expeditiously for liver transplantation unless there is a contraindication.

Medical treatments are only available for children who are diagnosed with chronic HBV and HCV infection. In CHB, the treatment should be considered for children with HBe positive immune active status, or if liver biopsy shows moderate to severe inflammation or presence of fibrosis in children with reactivation or HBe negative immune active status.

The goal of treatment for CHB is to suppress HBV replication, reduce liver inflammation, reverse fibrosis, and prevent the development of cirrhosis and HCC. For CHB in children, there are currently six FDA-approved treatments: thrice weekly interferon (IFN) alpha for children 1 year of age and older, daily lamivudine for 16-24 weeks for children between age 2 and 18 years, adefovir dipivoxil for children 12 years and older, tenofovir disoproxil fumarate for children 12 years and older, and entecavir for children 2 years and older. Telbivudine is approved for children 16 years and older. Unfortunately, lamivudine is associated with high drug resistance rates, and for this reason is rarely used at the present time. Adefovir has about a 20% drug resistance rate after 5 years. Entecavir and tenofovir have the best drug resistance profiles, with only 1-5% drug resistance after 5 years of therapy. There have been promising results in using pegylated interferon (PEG IFN) for adults with CHB and this treatment is currently being evaluated in children.

The main goal of treatment for in CHC in children is to achieve a sustained virological response (SVR), currently defined as undetectable HCV RNA in peripheral blood 24 weeks after the end of the treatment. For chronic HCV infection, there are currently two FDA-approved treatments: interferon alpha-2b thrice weekly plus daily ribavirin for children between age 3 and 18 years, or only once weekly PEG IFN alpha-2a or -2b plus daily ribavirin for 24 weeks in HCV genotype 2 and 3 and for 48 weeks for HCV genotype 1 and 4 for children between age 3 and 18 years.

Pharmaceutical industries are currently developing new more potent agents for both HBV and HCV in adults. None of the safe and highly effective direct-acting antiviral agents (protease or polymerase inhibitors) for HCV which are currently FDA-approved for adults are approved for children. However, there are currently three clinical trials underway in the pediatric age group: the sofosbuvir-ribavirin trial for children infected by HCV genotype 2 or 3 (clinicaltrial.gov identifier NCT02175758); the ledipasvir-sofosbuvir ± ribavirin trial for children with infection by HCV genotype 1 or 4, 5, or 6 (NCT02249182); and the ombitasvir-paritaprevir-ritonavir ± dasabuvir ± ribavirin trial for children with HCV genotype 1 or 4 (NCT02486406).

The goals of treatment in HDV infection are to achieve sustained suppression of both HBV and HDV replication, to induce remission of liver disease, and to improve long-term clinical outcome by preventing cirrhosis and HCC. The effective treatment for HDV infection is eradication of HBV since the virus is unable to survive without HBV infection.

Only supportive treatment for HEV infection is recommended because it is a self-limited disease in most cases. Fulminant hepatitis may require liver transplantation to avoid fatal outcomes. Although no specific therapy is recommended, in patients who are immunosuppressed, reduction of the immunosuppressive drugs is recommended. A successful treatment with 12 months' duration of pegylated interferon alpha 2b was reported among liver transplant patients with chronic HEV that did not respond to reduction of immunosuppressive therapy. Ribavirin may also be effective in this setting.

Treatment for HGV- and TTV-infected individuals is controversial. In HCV-co-infected patients, TTV eradication was observed in some patients with interferon therapy; however, TTV DNA was detected again after completion of the treatment.

What are the adverse effects associated with each treatment option?

Interferon therapy should not be given to infants younger than age 1 year due to the risk of spastic diplegia.

Lamivudine is well tolerated in young children, but drug resistance is common, in approximately 20% of patients per year undergoing administration of lamivudine. In older children, side effects are more common. These include flu-like symptoms, gastrointestinal symptoms, neutropenia, and weight loss.

Pegylated interferon has largely replaced standard interferon since the pegylated preparation is given weekly as opposed to thrice weekly for standard interferon.

Jonas et al. reported that children who received peg-IFN-α2a had significant changes in body weight, linear growth, body mass index and body composition, which were reversible except that many had height scores that did not return to baseline. Children who received this treatment should have long-term growth parameter follow-up.

Although children who received peg-IFN-α2a and RBV infrequently developed ophthalmologic complications including potential severity of ischemic retinopathy and uveitis, a regular ophthalmologic examination should be recommended during and after the treatment. Data on long-term ophthalmologic complications do not exist for children who received interferon.

Limitations of current antiviral therapy in children include concerns of side effects, frequent injections and pill burden. When risk-benefit ratio is discussed, younger children with CHC genotype 1 who probably have milder hepatic disease and lower risk of cirrhosis and HCC development, could wait for more efficient antiviral therapy with fewer side effects.

Side effects from nucleos(t)ide analogues are minimal during clinical trials but more reports have been reported after postmarketing surveillance. These analogues have activity against human mitochondrial DNA (mtDNA) polymerase gamma and can lead to mitochondrial dysfunction. All five approved agents carry a US FDA black box warning of potential mitochondrial toxicity. Myopathy and neuropathy are commonly reported in lamivudine; nephrotoxicity is common with adefovir and tenofovir; pancreatitis with lamivudine and adefovir.

Given the teratogenic effects of ribavirin, its administration requires extreme caution in childbearing-aged adolescents with CHC.

What are the possible outcomes of viral hepatitis?

In mild cases of acute viral hepatitis, the symptoms are usually self-limiting and last less than 2 months; however, they can last up to 6 months. In the fulminant form, patients require hospitalization, and liver transplantation may be indicated. Interestingly, patients with acute HAV infection may manifest with relapsing hepatitis, which is described by intermittent symptoms of malaise, anorexia, and jaundice with a rise in AST, ALT, and bilirubin within 6 months after the onset of infection.

Infants born to mothers with CHB develop immune tolerance to HBV and have CHB. Children with CHB are generally asymptomatic. Children with genotype B and C have a high frequency of HBeAg positivity and high HBV DNA levels compared to those with other genotypes. A Taiwanese pediatric study demonstrated that HCC predominantly developed in CHB children with genotype B although in adults, genotype C is most frequently associated with HCC. Antiviral therapy for CHB children in the immune-active phase is expected to result in HBV DNA suppression and increased frequency of ALT normalization and HBeAg seroconversion compared to those without antiviral therapy. Antiviral therapy with nucleos(t)ide analogues for children in the immune-tolerant phase has not been associated with benefits but poses a risk for the development of antiviral drug resistance or adverse side effects.

Children with CHC generally are asymptomatic and have a fairly high spontaneous clearance rate under 7 years of age with normal or mild histologic findings. Only 1-2% of children with CHC progress to cirrhosis (end stage liver disease) and they rarely develop HCC. Children with chronic HCV infection genotype 2 and 3 respond very well to pegylated interferon and ribavirin. They have SVR rates up to 70-80% versus in children with genotype 1 for whom SVR rates are around 50%. However, even after successful therapy in both HBV and HCV infection, liver damage that occurred prior to the treatment may not be reversible, and cirrhosis may develop. Therefore, successfully treated patients do require clinical follow-up.

The clinical outcome of HDV infection is different between co-infection (HBV and HDV infection occur simultaneously) and superinfection (new infection on HBV carriers). Superinfection carries a higher mortality rate up to 80% versus 2-20% with co-infection in patients with chronic hepatitis D and cirrhosis.

In endemic regions, such as Africa and the Indian subcontinent, female adolescents of childbearing age who contract HEV during the second and third trimester can have fulminant hepatitis, and high mortality rates can reach up to 20%.

What causes this disease and how frequent is it?

HAV is one of the most communicable diseases, with worldwide distribution and an estimated number of recognized cases of 1.5 million annually. The rate of HAV in the United States has significantly decreased since the first availability of HAV vaccine in 1995. After the Advisory Committee on Immunization recommended routine HAV immunization for all children above age 1 year, the incidence of HAV fell to 1.2 per 100,000.

The most recent US population-based surveillance for persons at 6 US sites identified 1156 HAV cases among 29.8 million individuals under surveillance during 2005 through 2007. The overall annual incidence rate was 1.3 per 100,000 (range by site, 0.7 - 2.3). The predominant risk factor for HAV transmission was international travel (45.8%), followed by contact with a case (14.8%), employee or child in a daycare center (7.6%), exposure during a food or waterborne common-source outbreak (7.2%), illicit drug use (4.3%), and men who had sex with men (3.9%).

The fecal-oral route is the primary mode of HAV transmission in children and adolescents. Perinatal (including breastfeeding) and parenteral transmission have been rarely reported. Ingestion of contaminated shellfish has been reported as a common mode of HAV transmission. Person-to-person transmission occurs most commonly within families and among children in daycare centers. Sexual transmission occurs most frequently between men who have sex with men. Blood-borne transmission usually occurs in individuals receiving transfusion, such as hemophiliacs, and injection drug users.

For HBV and HCV, maternal-fetal transmission is currently the most common route because meticulous screening of HBV and HCV has been performed for individuals receiving transfusion of blood products. HDV infection is rare in children, but increases after the second decade of life, suggesting horizontal rather than vertical transmission. In the Mediterranean basin, the Middle East, Central and South America, Africa, and Asia, where HBV is endemic, close interpersonal contact with exchange of body fluids and sexual transmission are the most common modes of transmission. Where HBV is not endemic, as in Northern Europe and North America, injection drug use is the main route of transmission.

Regarding HBV, infants whose mothers are HBeAg positive and/or have very high serum HBV DNA (≥ 109 copies per mL) are at risk for acquiring HBV despite receiving active and passive immunization within 24 hours postpartum. One study found that, even with adherence to the combination of passive and active immune-prophylaxis immediately postpartum, 7.4% of newborn infants born to HBV-infected mothers were infected with HBV during the first year of life.

The spontaneous seroconversion rates of HBeAg (loss of HBeAg and development of anti-HBe) for children infected via perinatal transmission are less than 2% per year for those under age 3 years, and 4-5% per year in those older than 3 years, whereas children infected after the perinatal period have higher rates of spontaneous seroconversion, up to 70-80% over 20 years. The time to HBeAg clearance for individuals with HBV genotype C is longer than in patients with other genotypes. Genotypes C and F are more likely to be associated with HBeAg serology reversion after HBeAg clearance.

Adults who are immune active with persistent elevation of ALT and histologic findings of liver inflammation and fibrosis have an increased risk of cirrhosis and HCC; therefore, adolescents and young adults could be at risk for these complications if they are infected via the perinatal route.

HCV infects 170 million individuals worldwide. Of these, 7 million adults and 20,000 - 40,000 children in the United States have chronic infection. The prevalence of HCV antibody in pregnant women is 0.1-2.4%, and 60-70% are viremic. The transmission rate is 4-7% when the mother is viremic. Mothers with HCV RNA >106 IU/ml are more likely to transmit the virus to the fetus versus those with lower levels of circulating virus. HIV co-infected mothers have a 4-5-fold increased risk of transmission. The 3rd National Health and Nutrition Evaluation Survey found that, in a total estimate of 132,000 antibody-positive children, the prevalence of HCV antibody in children and adolescents was 0.2-0.4%. In a recent US census, 23,048-42,296 children were found to have CHC, with 7,200 new cases annually.

Female newborns are more likely to acquire HCV from their mothers than male newborns. A British study reported that one-third to one-half of infants had acquired HCV in utero from infected mothers. A large prospective 10-year study revealed that the viral clearance rate in children with chronic HCV infection was 8%; viral clearance occurred mostly during the 5 years of the follow-up period. In a small study of 42 children with chronic hepatitis C, the children who had serum HCV RNA below 4.5x 104 IU/mL at the time of enrollment had a higher spontaneous viral clearance rate.

HDV has a worldwide distribution, but is rare in children. In parallel with the decline of HBV infection after the implementation of universal immunization with hepatitis B vaccine, the HDV infection rate has significantly plummeted. However, an increasing prevalence of co-infection with HBV and HDV infection was recently reported in the United States.

HEV seroprevalence rates range from 15-60% in endemic areas. Anti-HEV is rarely detected in children (except in reports from Egypt, where anti HEV is detected early in young children), but rates increase to 40% in young adults, without substantial increases later in life. HEV in endemic areas is responsible for more than half of cases with acute viral hepatitis. In the United States, in certain states where animal farms are predominant, anti-HEV seroprevalence is higher than anti-HAV seroprevalence, suggesting zoonotic disease. In the National Health and Nutrition Evaluation Survey data (NHANES) in the United States, the HEV seroprevalence in the general population aged 6-19 years was 0.8% among males and 1.1% among females. Both immunocompetent and immunocompromised children with persistent elevation of transaminases should be considered for testing for evidence of HEV infection if other common causes of viral hepatitis are excluded.

The fecal-oral route is the primary mode of HEV transmission. Perinatal (including breastfeeding) and parenteral transmission have been rarely reported. HEV infection occurs as a water-borne outbreak during the rainy season. Person-to-person transmission occurs less than with HAV.

About 1-5% of volunteer blood donors in developed countries are positive for HGV, whereas in developing countries the prevalence in the general population is 10-20%. Only 0.3% of individuals with acute viral hepatitis are infected with HGV alone, and approximately 3-6% of non A-E hepatitis cases are positive for HGV.

High-risk individuals who contract HGV are those who have a history of intravenous drug use, multiple transfusions of blood products, and hemodialysis. Maternal-fetal and sexual transmission have been reported.

Approximately 50-95% of healthy individuals are TTV viremic. Interestingly, individuals with liver diseases have higher infection rates than healthy blood donors.

Although TTV transmission is predominant via parenteral and maternal-fetal transmission, fecal-oral and sexual routes have been reported. Transplacental transmission is low and independent of viral load. A report from Africa indicated significantly acquired infection in infants after age 3 months. Breastfeeding is proposed to be the mechanism of postnatal transmission, because in some children TTV has been detected in breast milk, and an increase in the positive TTV conversion rate has been seen to occur in proportion to the length of the breastfeeding period.

How do these pathogens/genes/exposures cause the disease?

  • Liver injury from most hepatotropic viruses, especially HAV, HBV, and HCV, is not a viral cytopathogenic effect, but rather, is thought to be secondary to immunopathological reactions of sensitized cytotoxic T lymphocytes against infected hepatocytes. For example, liver inflammation and damage in HCV infection is caused by the host immune response to the virus promoted by natural killer cells, neutrophils, and macrophages. Dendritic cells, as professional antigen presenting cells, induce a specific immune response from CD4-positive T helper cells, B lymphocytes, and CD8-positive cytotoxic T cells.

Other clinical manifestations that might help with diagnosis and management

Both HBV and HCV have been associated with glomerulonephritis and mixed cryoglobulinemia in adults, but these have not been reported in children with the infections.

How can viral hepatitis be prevented?

Vaccines for viral hepatitis are commercially available for only HAV and HBV. HCV vaccine is under current study. HEV vaccines were reported to be effective, but there is only one vaccine in widespread use and it is only licensed for use in China. Please consult the detailed current recommendations for HAV and HBV immunization and immune-prophylaxis at the American Academy of Pediatrics Red Book® Online (available at: http://aapredbook.aappublications.org).

HAV vaccination is recommended for individuals at increased risk for complications of HAV infection, including travelers to intermediate- and high-endemic areas, men who have sex with men, injecting drug users, and all patients with chronic liver disease.

From the time HAV vaccine was first licensed in the United States in 1995 through December 1998, more than 6.5 million doses were administered to the US civilian population, including more than 2.3 million pediatric doses (SmithKline Beecham Biologicals, unpublished data, 1999, and Merck & Co., Inc., unpublished data, 1999). During this 4-year period, the United States Vaccine Adverse Event Reporting System (VAERS) received 247 reports of unexplained adverse events within 6 weeks after HAV vaccination, including 80 among children less than 19 years old and 167 among adults (CDC, unpublished data, 1999). Approximately 1/3 of the events involved the concurrent use of other vaccines with the hepatitis A vaccine. Thirteen of the events among children (0.6/100,000 vaccine doses distributed) and 85 of the events among adults (1.4/100,000 vaccine doses distributed) were considered serious events, without regard to causality, including neurologic, hematologic, and autoimmune syndromes. However, no reported serious events could be definitively attributed to HAV vaccination, and the VAERS reporting rates were not higher than reported background rates (CDC, unpublished data, 1999).

Immunoglobulin provides protection against HAV through passive antibody transfer. When used for pre-exposure prophylaxis, a dose of 0.02 mL/kg confers protection for 1-2 months, and a dose of 0.06 mL/kg confers protection for 3-5 months. When administered within 2 weeks of exposure to HAV (post-exposure prophylaxis), 0.02 mL/kg is more than 85% effective in preventing HAV. At the present time (2011), the AAP has recommended HAV vaccine for all children 1-18 years of age.

Mother-to-child transmission is the main route for children acquiring the HBV. Mothers with CHB who breastfeed the infants should prevent bleeding from cracked nipples during the breastfeeding period. Mothers who are HBV carriers should not donate their breast milk. Despite the recommended administration of prophylaxis (hepatitis B immune globulin [HBIG] and the first dose of hepatitis B vaccine given within 12 hours of birth, and completion of hepatitis B vaccine series), the risk factors for transmission area positive HBeAg and/or a high HBV DNA level in the mother. The American Association for the Study of Liver Diseases (AASLD) suggests antiviral therapy to reduce the risk of perinatal transmission of hepatitis B in HBsAg-positive pregnant women with a high viral load. However, the exact viral load threshold and the exact week within the third trimester at which to start the antiviral therapy have not been clearly addressed. Increasing evidence on safety of infants exposed to antiviral therapy during the pregnancy is available but long-term follow-up is required.

After a routine series of the HBV vaccination, a circulating anti-HBs level of greater than10mIU/mL is considered to be seroprotective. In immune-competent individuals, seroprotective levels are achieved in at least 95% of children and 90% of adults after one course of HBV vaccine. The efficacy of HBV vaccine alone in preventing HBV infection of infants born to HBsAg+ mothers varies between 65-95%, depending on the prevalence of HBeAg and HBV DNA levels among the infected mothers. The efficacy of the combination of HBV vaccine plus HBIG is higher - up to 85-95%.

All household and sexual contacts of HBV-infected individuals should be vaccinated, in addition to individuals with high-risk behaviors, including injection drug users, men having sex with men, individuals with other sexually transmitted diseases, and persons with multiple sexual partners. For patients with end-stage liver and renal disease, immunization should be initiated early in the course of their liver or renal disease because patients vaccinated after they require liver transplantation or dialysis are less likely to respond.

Individuals who receive clotting-factor concentrates should be vaccinated as soon as they are diagnosed with clotting disorders.

Those who fail to respond to a complete HBV vaccine series will develop a protective antibody response in 15-20% after 1 additional dose, and in 50-75% after 3 additional doses. Therefore, non-responders should receive another 3-dose series of the HBV vaccine. There is no evidence that continuing beyond 6 doses would yield any benefit. Non-responders after the total number of 6 doses should be tested for HBsAg to determine if they have CHB.

The most common reported side effects are pain and erythema at the injection site, transient low-grade fever, headache, malaise and myalgia. These side effects were reported no more frequently among those receiving hepatitis B vaccines than those receiving placebo in placebo-controlled studies.

A number of conditions, such as chronic arthritis, demyelinating diseases such as multiple sclerosis, sudden infant death syndrome, autism, chronic fatigue syndrome, leukemia, and diabetes have been seen in rare patients who have received HBV vaccination; but none of these events have been proven to be related to HBV vaccines.

What is the evidence?

Jonas, MM, Kelly, D, Pollack, H. "Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to < 18 years) with chronic hepatitis B". Hepatology. vol. 47. 2008. pp. 1863-71.

(This study by Jonas et al. described 173 treatment-naive and treatment-experienced children with HBeAg+ CHB who were randomized to adefovir or placebo. The primary efficacy endpoints were the presence of serum HBV DNA <1,000 copies/mL and normal alanine aminotransferase. Adefovir demonstrated significant antiviral efficacy or was achieved in children aged 12-17 years with HBeAg+ CHB, but was not different from placebo in subjects aged 2-11 years.)

Jonas, MM, Lok, AS, McMahon, BJ, Brown, RS. "Antiviral therapy in management of chronic hepatitis B viral infection in children: A systematic review and meta-analysis". Hepatology.. vol. 63. 2016. pp. 307-18.

(Jonas et al. performed a systemic review and meta-analysis of antiviral therapy in managing children with chronic hepatitis B infection. In this systematic review, 14 studies were reviewed. The current evidence revealed that the frequency of surrogate outcomes [ALT normalization, HBeAg loss, HBV DNA suppression, HBeAg seroconversion, and HBsAg loss] are more frequently observed in children with antiviral therapy compared to those with no antiviral or placebo treatment.)

Schwarz, KB, Gonzalez-Peralta, RP, Murray, KF. "The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C". Gastroenterology. vol. 140. 2011. pp. 450-8.

(Schwarz et al. conducted a randomized, controlled trial of PEG IFN-2a; 180 μg/1.73 m2 body surface area, subcutaneously each week and ribavirin [15 mg/kg orally in 2 doses daily], compared with PEG and placebo, in children 5-17 years old with CHC. The combination of PEG IFN and ribavirin is superior to PEG and placebo as therapy for CHC in children and adolescents [SVR: 53% vs. 21%].)

Sokal, EM, Conjeevaram, HS, Roberts, EA. "Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial". Gastroenterology. vol. 114. 1998. pp. 988-95.

(The evidence for the management of HBV supports the administration of IFN-alpha and adefovir. Sokal et al. reported 144 children aged 1-17 years were randomized for either IFN-alpha 2b [6 mega units/m2 thrice weekly for 24 weeks] or no treatment. The primary endpoints were persistent loss of HBV DNA, HBe Ag 24 weeks after treatment. The secondary endpoints were loss of HBsAg and improvements in serum aminotransferase concentrations. INF-alpha2b achieved the primary endpoint in 26% of treated children versus 11% of controls. Female gender and interferon treatment were the only significant predictors of response.)

Wirth, S, Pieper-Boustani, H, Lang, T. "Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis C". Hepatology. vol. 41. 2005. pp. 1013-8.

(As evidence for the treatment of CHC, the primary endpoints are sustained virologic response [SVR] and lack of detectable HCV RNA at least 24 weeks after stopping therapy. Wirth et al. reported a combination treatment of weekly PEG IFN α-2b at a dose of 1.5 μg/kg body weight with RBV [15 mg/kg/day] for 48 weeks, which showed encouraging results in an open-labeled, uncontrolled pilot study with 62 children and adolescents [age 2-17 years]. SVR was documented in 22 [48%] of 46 patients with genotype 1, in 13 [100%] of 13 with genotype 2 or 3, in 1 of 2 with genotype 4, in 19 [70%] of 27 children.)

BIBLIOGRAPHY

Hepatotropic Viruses

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Infections with Hepatotropic Viruses

HAV

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HBV

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Ni, YH, Chang, MH, Wang, KJ. "Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma". Gastroenterology. vol. 127. 2004. pp. 1733-8.

Khungar, V, Han, S. "A Systematic Review of Side Effects of Nucleoside and Nucleotide Drugs Used for Treatment of Chronic Hepatitis B". Curr Hepatitis Rep. vol. 9. 2010. pp. 75-90.

Komatsu, H, Inui, A. "Chronic hepatitis B in children in the United States and Canada: international origins place the disease burden on children even in the era of universal vaccination". Transl Pediatr.. vol. 5. 2016. pp. 1-4.

Terrault, NA, Bzowej, NH, Chang, KM, Hwang, JP. "American Association for the Study of Liver Diseases. AASLD guidelines for treatment of chronic hepatitis B". Hepatology. vol. 63. 2016. pp. 261-83.

HCV

Bortolotti, F, Verucchi, G, Cammà, C. "Long-term course of chronic hepatitis C in children: from viral clearance to end-stage liver disease". Gastroenterology. vol. 134. 2008. pp. 1900-7.

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Pergam, SA, Wang, CC, Gardella, CM. "Pregnancy complications associated with hepatitis C: data from a 2003-2005 Washington state birth cohort". Am J Obstet Gynecol. vol. 199. 2008. pp. 38.e1-9.

HDV

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HEV

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Mast, EE, Krawczynski, K. "Hepatitis E: an overview". Annu Rev Med. vol. 47. 1996. pp. 257-66.

Khuroo, MS, Teli, MR, Skidmore, S. "Incidence and severity of viral hepatitis in pregnancy". AM J Med. vol. 70. 1981. pp. 252-5.

Pischke, S, Suneetha, PV, Baechlein, C. "Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients". Liver Transpl. vol. 16. 2010. pp. 74-82.

HGV or GBV-C

Pawlotsky, JM, Dhumeaux, D. "The G virus: the orphan virus". Presse Med. vol. 28. 1999. pp. 1882-3.

Reshetnyak, VI, Karlovich, TI, Ilchenko, LU. "Hepatitis G virus". World J Gastroenterol. vol. 14. 2008. pp. 4725-34.

TTV

Garbuglia, AR, Grasso, F, Donà, MG. "TT virus infection: role of interferons, interleukin-28 and 29, cytokines and antiviral proteins". Int J Immunopathol Pharmacol. vol. 20. 2007. pp. 249-58.

Zaki, Mel-S, el-Hady, NA. "Molecular detection of transfusion transmitted virus coinfection with some hepatotropic viruses". Arch Pathol Lab Med. vol. 130. 2006. pp. 1680-3.

Laboratory Tests

Armstrong, GL, Bell, BP. "Hepatitis A virus infections in the United States: model-based estimates and implications for childhood immunization". Pediatrics. vol. 109. 2002. pp. 839-45.

Bendall, R, Ellis, V, Ijaz, S. "Serological response to hepatitis E virus genotype 3 infection: IgG quantitation, avidity, and IgM response". J Med Virol. vol. 80. 2008. pp. 95-101.

Bendall, R, Ellis, V, Ijaz, S. "A comparison of two commercially available anti-HEV IgG kits and a re-evaluation of anti-HEV IgG seroprevalence data in developed countries". J Med Virol. vol. 82. 2010. pp. 799-805.

Carithers, RL, Marquardt, A, Gretch, DR. "Diagnostic testing for hepatitis C". Semin Liver Dis. vol. 20. 2000. pp. 159-71.

Giannini, E, Botta, F, Fasoli, A. "Progressive liver functional impairment is associated with an increase in AST/ALT ratio". Dig Dis Sci. vol. 44. 1999. pp. 1249-53.

Hadziyannis, SJ, Papaioannou, C, Alexopoulou, A. "The role of the hepatitis delta virus in acute hepatitis and in chronic liver disease in Greece". Prog Clin Biol Res. vol. 364. 1991. pp. 51-62.

Karnsakul, W, Alford, MK, Schwarz, KB. "Managing pediatric hepatitis C: current and emerging treatment options". Ther Clin Risk Manag. vol. 5. 2009. pp. 651-60.

Liaw, YF, Yang, CY, Chu, CM, Huang, MJ. "Appearance and persistence of hepatitis A IgM antibody in acute clinical hepatitis A observed in an outbreak". Infection. vol. 14. 1986. pp. 156-8.

Lin, CC, Wu, JC, Chang, TT. "Diagnostic value of immunoglobulin G (IgG) and IgM anti-hepatitis E virus (HEV) tests based on HEV RNA in an area where hepatitis E is not endemic". J Clin Microbiol. vol. 38. 2000. pp. 3915-8.

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Sheth, SG, Flamm, SL, Gordon, FD, Chopra, S. "AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection". Am J Gastroenterol. vol. 93. 1998. pp. 44-8.

Decision Algorithms

Haber, BA, Block, JM, Jonas, MM. "Recommendations for screening, monitoring, and referral of pediatric chronic hepatitis B". Pediatrics. vol. 124. 2009. pp. e1007-13.

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Mack, CL, Gonzalez-Peralta, RP, Gupta, N. "NASPGHAN practice guidelines: Diagnosis and management of hepatitis C infection in infants, children, and adolscents". J Pediatr Gastroenterol Nutr. vol. 54. 2012. pp. 838-55.

Treatment

Bourlière, M, Wendt, A, Fontaine, H. "How to optimize HC V therapy in genotype 1 patients with cirrhosis". Liver Int. vol. 33. 2013. pp. 46-55.

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Jonas, MM, Block, JM, Haber, BA. "Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options". Hepatology. vol. 52. 2010. pp. 2192-205.

Jonas, MM, Kelly, D, Pollack, H. "Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B". Hepatology. vol. 47. 2008. pp. 1863-71.

Kamar, N, Izopet, J, Tripon, S. "Ribavirin for chronic hepatitis E virus infection in transplant recipients". N Engl J Med. vol. 370. 2014. pp. 1111-20.

Karnsakul, W, Alford, MK, Schwarz, KB. "Managing pediatric hepatitis C: current and emerging treatment options". Ther Clin Risk Manag. vol. 5. 2009. pp. 651-60.

Khungar, V, Han, S. "A Systematic Review of Side Effects of Nucleoside and Nucleotide Drugs Used for Treatment of Chronic Hepatitis B". Curr Hepatitis Rep. vol. 9. 2010. pp. 75-90.

Murray, KF, Rodrigue, JR, González-Peralta, RP. "Design of the PEDS-C trial: pegylated interferon +/- ribavirin for children with chronic hepatitis C viral infection". Clin Trials. vol. 4. 2007. pp. 661-73.

Murray, KF, Szenborn, L, Wysocki, J. "Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B". Hepatology. vol. 56. 2012. pp. 2018-26.

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Schmidt, WN, Nelson, DR, Pawlotsky, JM. "Direct-acting antiviral agents and the path to interferon independence". Clin Gastroenterol Hepatol. vol. 12. 2014. pp. 728-37.

Schwarz, KB, Gonzalez-Peralta, RP, Murray, KF. "The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C". Gastroenterology. vol. 140. 2011. pp. 450-8.

Sokal, EM, Conjeevaram, HS, Roberts, EA. "Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial". Gastroenterology. vol. 114. 1998. pp. 988-95.

Possible Outcomes of Viral Hepatitis

Bortolotti, F, Cadrobbi, P, Crivellaro, C. "Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood". Gastroenterology. vol. 99. 1990. pp. 805-10.

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Bortolotti, F, Verucchi, G, Cammà, C. "Long-term course of chronic hepatitis C in children: from viral clearance to end-stage liver disease". Gastroenterology. vol. 134. 2008. pp. 1900-7.

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Karnsakul, W, Alford, MK, Schwarz, KB. "Managing pediatric hepatitis C: current and emerging treatment options". Ther Clin Risk Manag. vol. 5. 2009. pp. 651-60.

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Causes and Frequency of Viral Hepatitis

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Bortolotti, F, Iorio, R, Resti, M. "Epidemiological profile of 806 Italian children with hepatitis C virus infection over a 15-year period". J Hepatol. vol. 46. 2007. pp. 783-90.

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Hsu, EK, Murray, KF. "Hepatitis B and C in children". Nat Clin Pract Gastroenterol Hepatol. vol. 5. 2008. pp. 311-20.

Jhaveri, R, Grant, W, Kauf, TL, McHutchison, J. "The burden of hepatitis C virus infection in children: estimated direct medical costs over a 10-year period". J Pediatr. vol. 148. 2006. pp. 353-8.

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Shapiro, CN, Hadler, SC. "Hepatitis A and hepatitis B virus infections in day-care settings". Pediatr Ann. vol. 20. 1991. pp. 435-41.

Söderström, A, Norkrans, G, Lindh, M. "Hepatitis B virus DNA during pregnancy and post partum: aspects on vertical transmission". Scand J Infect Dis. vol. 35. 2003. pp. 814-9.

Wang, Z, Zhang, J, Yang, H. "Quantitative analysis of HBV DNA level and HBeAg titer in hepatitis B surface antigen positive mothers and their babies: HBeAg passage through the placenta and the rate of decay in babies". J Med Virol. vol. 71. 2003. pp. 360-6.

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Prevention

Ascherio, A, Zhang, SM, Hernán, MA. "Hepatitis B vaccination and the risk of multiple sclerosis". N Engl J Med. vol. 344. 2001. pp. 327-32.

Chen, RT. "Vaccine risks: real, perceived and unknown". Vaccine. vol. 17. 1999. pp. S41-6.

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Koff, RS. "Hepatitis A, hepatitis B, and combination hepatitis vaccines for immunoprophylaxis: an update". Dig Dis Sci. vol. 47. 2002. pp. 1183-94.

"Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP)". MMWR Recomm Rep. vol. 48. 1999. pp. 1-37.

Shrestha, MP, Scott, RM, Joshi, DM. "Safety and efficacy of a recombinant hepatitis E vaccine". N Engl J Med. vol. 356. 2007. pp. 895-903.

Szmuness, W, Stevens, CE, Harley, EJ. "Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States". N Engl J Med. vol. 303. 1980. pp. 833-41.

Wong, VC, Ip, HM, Reesink, HW. "Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis-B vaccine and hepatitis-B immunoglobulin. Double-blind randomised placebo-controlled study". Lancet. vol. 1. 1984. pp. 1-6.

Ongoing controversies regarding etiology, diagnosis, treatment

The major controversies include the treatment of immune-tolerant children with CHB (currently recommended for controlled trials only) and whether or not to treat children with mild immune active HBV or chronic HCV, given that they are asymptomatic and there is always a fear of induction of drug resistance. However, most pediatric hepatologists who care for children with these two conditions believe that the risk/benefit decisions weigh towards treatment.

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