Hepatitis B in children: Complexities in management
Assistant Professor of Pediatrics and Liver Transplant, Division of Pediatric Hepatology and Recanati Miller Transplant Institute, Mount Sinai School of Medicine, New York, NY, USA
"....The importance of early intervention in children is not only disease prevention amongst family members and other social contacts in school, play and work as they are growing, but also reducing the risk of HBV related cirrhosis and HCC. As children are exposed to HBV DNA for a longer time, their cumulative risk of HCC is higher. Early intervention and elimination of 'e' antigen may considerably improve their prognosis....
..... The goal of therapy for chronic HBV infection is to eliminate or significantly suppress HBV replication and prevent the progression of liver disease to cirrhosis with the potential development of liver failure or HCC....
.... In our unit, bi-annual screening for HCC [liver cancer] with AFP (annual AFP for HBeAb-positive) and annual screening with Ultrasound is done in children with chronic HBV infection above 4 yr of age.... Children with chronic HBV infection should have their transaminases, HBV serology (HBsAg, HBsAb, HBeAg, HBeAb) and HBV DNA monitored regularly....
.... For parents who present with a child (adopted/own) newly diagnosed with chronic HBV infection, care must be taken to ensure all family members are immunized against HBV. It is also recommended that the child be immunized against hepatitis A....
.... Liver transplantation is now a viable option for those with fulminant or decompensated liver disease. With the advent of HBIG and nuclear analogues, results after liver transplantation are good...Ó
Hepatitis B is a global issue with approximately 400 million people infected with the virus worldwide. Although the US is an area of low prevalence of HBV, immigration, global travel and adoption have made HBV an important cause of morbidity and mortality. Chronic HBV infection remains a problem in spite of the fact that effective vaccination against HBV is available. This review will focus on several of the complex issues that arise in the management of childhood HBV infection such as 'Why treat?''Who to treat?''Why does chronic HBV infection develop?''How is HBV in children different?' and 'How to treat?'
Chronic hepatitis B virus (HBV) infection by definition is persistence of hepatitis B surface antigen (HBsAg) in the serum for >=6 months. The risk of developing chronic HBV infection ranges from 90% in neonates to <5% in immunocompetent adults.
HBV acquired by perinatal infection has a prolonged immune-tolerant phase, characterized by the presence of hepatitis Be antigen (HBeAg), high HBV-DNA and normal alanine aminotransferase (ALT) levels.
Efficient and multi-specific helper and cytotoxic T-cell response is essential for controlling HBV infection. Chronic HBV infection is characterized by a state of HBV-specific T-cell hyporesponsiveness.
The goal of therapy in chronic HBV infection is to eliminate or significantly suppress HBV replication and prevent the progression of liver disease to cirrhosis with the potential development of liver failure or hepatocellular carcinoma (HCC).
In adults, drugs currently licensed for treatment of HBV infection: are interferon-alpha (IFN-alpha), lamivudine (LMV) and adefovir dipivoxil (ADV), [and entecavir & Pegasys], the first two are also licensed to use in children.
IFN-alpha has the advantage of having a more durable response, fixed duration of treatment and lack of resistant mutants. The disadvantages of IFN-alpha include need for thrice-weekly injections, higher cost and more side-effects compared with the nucleoside analogues.
Nucleoside analogues can be given orally and used in decompensated cirrhosis and transplant recipients. ADV and newer drugs like tenefovir [and entecavir & Pegasys] can successfully treat mutants produced after prolonged LMV therapy. Current protocols exclude children with immunotolerant HBV.
[ED NOTE from Jules Levin: for some reason the author failed to mention two recently approved therapies for HBV-Pegasys (peginterferon) and entecavir.
Periodic screening with liver ultrasound scan and alpha-fetoprotein (AFP) in all children with chronic HBV infection is recommended.
The severe shortage of cadaveric donor organs has led to the use of marginal (including anti-HBc-positive) cadaveric donor livers in selected transplant candidates with high medical urgency; 5-10% of all liver transplants are because of HBV.
Using hepatitis B immunoglobulin and nucleoside analogues has made the outcome following liver transplantation for hepatitis B, comparable with, if not slightly better, than that in patients with other diagnoses.
Future treatments should be based on the restoration of HBV-specific T-cell responses to levels similar to that seen in subjects controlling HBV.
The answer is clear: 1.25 million Americans have chronic HBV infection and are at increased risk of developing cirrhosis and HCC (1). In the US 5-10% of all liver transplants are secondary to HBV related liver disease (2). Although the US is an area of low prevalence of HBV, immigration, global travel and adoption have made HBV an important cause of morbidity and mortality.
Who to treat?
The current guidelines recommend treatment of children with chronic HBV infection with raised transaminases for more than 6 months (3). Chronic HBV infection by definition is persistence of HBsAg for >6 months. Children are usually HBeAg-positive. A few may have the precore stop codon mutant and be HBeAg-negative. Older males typically tend to have the precore mutant with more severe necroinflammation and lower rate of sustained remission. While the presence of IgG anti-HBc indicates past exposure to HBV, the persistence of IgM anti-HBc is another clue pointing to chronic infection. The proportion of individuals with acute HBV that progress to chronic HBV infection is variable and depends on the age at infection (4). The risk of developing chronic HBV infection is 90% in neonates (highest in those whose mothers are both HBsAg and HBeAg positive): 25-30% in infants and <5% in immunocompetent adults (5). HBV DNA levels can be quantified by molecular hybridization assays (sensitivity limits of 105-106 [10,000-100,000] viral copies/mL) and PCR assays (can detect fewer than 102  copies/mL). An arbitrary value of >105 copies/mL has been chosen as the diagnostic criterion for chronic HBV infection (6). The major role of HBV DNA assays in patients with chronic HBV infection is to assess HBV replication and candidacy for/response to antiviral treatment.
Why does chronic HBV infection develop?
Efficient and strong helper and cytotoxic T-cell response is essential for controlling HBV infection. Chronic HBV infection is characterized by a state of HBV-specific T-cell hypo-responsiveness. A further immune parameter that is associated with the control of HBV is the mounting of a multi-specific CTL response - in other words, the ability of CD8 cells to recognize different epitopes located in different HBV proteins (7). Natural variants of HBV epitopes that are antagonistic to CD8 cells may be found in chronically infected patients (8). The evidence for importance of multi-specificity in control of viral infection is provided by studies done in subjects who have successfully controlled HBV (9, 10) and in chimpanzees with resolved HCV (11). Future treatments should be based on the restoration of HBV-specific T-cell responses to levels similar to that seen in subjects controlling HBV infection. It is now accepted that subjects who recover completely following acute hepatitis do not eradicate HBV infection. Several studies have shown that HBV is present (12-14) and retains the ability to replicate in the liver of patients who have cleared serum HBsAg (15). A strong virus-specific CD4-positive T-cell response with a predominant Th1 phenotype of cytokine production, is an important component of the mechanism to effectively maintain CTL responses. HBeAg is able to delete HBeAg-specific Th1 cells and skews the HBV specific T-cell response towards Th2 (16). HBeAg can cross the placenta and establish an antigen-specific T-cell tolerance (17). One important point related to the replication of HBV is that the use of reverse transcriptase results in a high rate of DNA mutations because of the lack of proofreading function by this enzyme (18). The presence of viral mutations can lead to the selection of viruses able to escape recognition of the different arms of the adaptive immune response (19). Studying subjects who develop a successful immune response against HBV vs. those who develop chronic infection can give insight regarding potential therapeutic approaches.
How is HBV infection in children different?
Children are usually diagnosed during screening and are relatively healthy unless they present with fulminant liver failure. Neonatal infections transmitted from mothers who are anti-HBe-positive are less likely to become chronic, but approximately 6% develop acute or fulminant hepatitis at 2-3 months of age (4). A recent study from Taiwan showed that within the first 15 yr of universal vaccination, HBV was found to rarely cause FHF in children over a year but remained a significant cause of FHF in infants. HBV-positive FHF was prone to develop in infants born to HBeAg-negative, HBsAg-carrier mothers if the infants had not received HBIG (20). Adults, on the contrary, tend to have evidence of chronic liver disease with or without decompensation. Chronic HBV infection acquired perinatally has a prolonged immune-tolerant phase, characterized by the presence of HBeAg, high HBV DNA and normal ALT. This phase may last for 10-30 yr (21). The rate of spontaneous HBeAg clearance is low and has been estimated to be about 2% in the first 3 yr of infection and only 15% after 20 yr (22). The importance of early intervention in children is not only disease prevention amongst family members and other social contacts in school, play and work as they are growing, but also reducing the risk of HBV related cirrhosis and HCC. As children are exposed to HBV DNA for a longer time, their cumulative risk of HCC is higher. Early intervention and elimination of 'e' antigen may considerably improve their prognosis.
How to treat?
Addressing this question is perhaps the most difficult and approaches may vary in different centres both in the US and other parts of the world. While the number of drugs available to treat HBV is on the rise, unfortunately not one is able to clear the virus permanently in all those afflicted with the virus. The degree of success of treatment varies with the regimen of drug/drugs used, the dose, the duration and whether used in combination or alone. The assessment of success of treatment in a group of patients treated with a drug can change depending on the end-point selected. The end-point (development of HBsAb vs. HbeAb vs. negative HBeAg vs. undetectable HBV DNA) used to evaluate success with a particular regime should be looked at critically when evaluating the performance of a drug or comparing drug regimens.
The goal of therapy for chronic HBV infection is to eliminate or significantly suppress HBV replication and prevent the progression of liver disease to cirrhosis with the potential development of liver failure or HCC. Two drugs are currently licensed for treatment of HBV infection in children: IFN-alpha and LMV. A third, ADV has been approved in the US for use in adults (again, Pegasys & entecavir were approved for HBV therapy in adults earlier this year). There is currently a multi-centre trial in progress regarding efficacy and safety of using ADV in children with chronic HBV infection. The opinion regarding need for performing a liver biopsy before and after therapy is debatable. While it would be optimal to perform a liver biopsy at baseline, practically speaking, in children with raised transaminase levels and positive serology, the decision regarding drug therapy is unlikely to be affected by the result. On the contrary, when the transaminases are normal and treatment is being contemplated in the so-called immunotolerant group, information obtained from biopsy may be helpful.
IFN was approved in the US to treat patients with chronic HBV infection in 1992 (23). The recommended dose of IFN-alpha for children is 6 MU/m2, duration being 16 wk for HBeAg-positive and 12 months for HBeAg-negative chronic HBV infection (3) infection. Side-effects of IFN-alpha include a transient influenza-like syndrome, bone marrow suppression, changes in personality, weight gain and sometimes marked elevation of aminotransferase levels. Elevated ALT levels and low serum HBV DNA are the best predictors of response to treatment (24). In western countries, treatment with IFN-alpha leads to loss of HBV DNA or HBeAg seroconversion in up to 58% of children (4, 25-27). Compared with nucleoside analogues, IFN-alpha has the advantage of having a more durable response, fixed duration of treatment and lack of resistant mutants. The disadvantages of IFN-alpha include need for thrice-weekly injections, higher cost and more side-effects compared with the nucleoside analogues. IFN-alpha is generally contraindicated in patients with decompensated cirrhosis (28). Peg-IFN with a polyethylene glycol moiety added to it has a prolonged half-life, reducing injections to once a week. Patients receiving Peg-IFN had a greater drop in HbeAg and HBV DNA levels than those on standard IFN (29). Pediatric studies of Peg-IFN for chronic HBV infection have not yet been published.
The nucleoside analogues LMV and ADV were found to suppress the replication of HBV in the course of treating HIV patients who were co-infected with HBV (30). The recommended LMV dose in children is 3 mg/kg/day with a maximum of 100 mg/day; duration being minimum 1 yr in HBeAg-positive HBV and longer but not yet established duration for HBeAg-negative cases (3). The main advantage of LMV is that it can be given orally and is well tolerated. Compared with IFN-alpha, LMV is more economical (if given for a year), but the durability of response appears to be lower, and long-term therapy is associated with an increasing risk of drug-resistant mutants that may negate the initial benefits and in some patients result in worsening of the disease (3). Mutations in a specific region of HBV DNA polymerase (YMDD) develop in approximately 20-25% of patients during the first year of therapy, and the rate increases to 70% by 5 yr of treatment (31). LMV therapy is associated with a 3- to 4-log reduction in serum HBV DNA levels and a loss of HBeAg in 17-32% of patients after 52 wk of treatment (32, 33). In children, virologic response was achieved in 23% of children compared to 13% of controls after 52 wk of treatment with LMV (34). Comparison with previous studies using IFN-alpha is not feasible as the endpoint in this study was loss of HBeAg and not HBeAb production. ADV is a nucleotide analogue of adenosine monophosphate and suppresses HBV replication through inhibition of DNA polymerase and by chain termination. In earlier studies ADV produced a 4-log reduction in median serum HBV DNA level after 12 wk therapy (35). ADV is excreted by the kidneys but at a dose of 10 mg in adults has significant antiviral properties without evidence of nephrotoxicity (36, 37). The recommended dose in adults is 10 mg, the dose in children is being determined. The main advantages of ADV include its activity against LMV-resistant mutants and a very low rate of ADV resistance during initial therapy. At present there are no long term follow up studies of either LMV or ADV therapy that demonstrate a significant reduction in risk of development of cirrhosis or HCC.
(ED NOTE: studies of entecavir in adults reported earlier this year found good rates of HBV DNA reduction, undetectable HBV DNA, ALT normalization loss of HBeAg.)
Combinations of nucleoside analogues and IFN with nucleoside analogues have been tried in order to improve results without much success. Studies using combination of IFN and LMV in IFN non-responders (38, 39) and IFN-na•ve (40, 41) patients have not been encouraging with minimal difference in the sustained response rate. Two studies in na•ve children with chronic HBV infection treated with IFN-alpha and LMV showed a virologic response rate between 40 and 47% (42, 43). The 'immune-tolerant' group of pediatric HBV with positive HBsAg, HBeAg, high HBV DNA and normal transaminases are notoriously difficult to treat. They have therefore been excluded from treatment in most clinical trials of chronic HBV infection in children. Unfortunately, these children represent a substantial proportion of the infected pediatric population. D'Antiga et al. (44), recently reported that a combination of LMV and IFN-alpha can be used to successfully increase the rate of anti-HBe seroconversion to 20% and anti-HBs positivity to 17%. Several newer nucleoside analogues such as entecavir, emtricitabine and telbivudine are under various phases of study (45).
HBV and HCC
Worldwide deaths from liver cancer exceed 1 million per year (46). It has been calculated that the risk of developing HCC in HBV-infected subjects is over 100-fold that of age-matched non-HBV-infected individuals (47). HBeAg-positive patients have a six times greater chance of developing HCC compared with HBeAg-negative patients (48). Periodic screening with liver ultrasound scan and AFP in children with chronic HBV infection is recommended, but there are no specific guidelines. AFP has a negative predictive value of >99%, but a positive predictive value between 9 and 30% (49). AFP can be high in pregnancy, chronic hepatitis and during seroconversion (50). Ultrasound scan is more expensive and has a false-positive rate between 28 and 82% (51). In our unit, bi-annual screening with AFP (annual AFP for HBeAb-positive) and annual screening with US is done in children with chronic HBV infection above 4 yr of age.
The Mount Sinai experience
Approximately 65 children with chronic HBV infection have been seen in our programme. Almost half of them are adopted from countries like China, Vietnam, Korea, Russia, Ukraine, Ethiopia and Cambodia. Thirty-four patients were HBeAg-positive at presentation. Ten patients have received treatment, eight with IFN-alpha, two with nucleoside analogues. Six of eight patients with raised transaminases treated with IFN-alpha achieved HBeAg seroconversion. The two patients who were treated with nucleoside analogues had transaminases <70 U/L. They were initially treated with LMV and are on ADV as they did not achieve seroconversion. Two patients have received liver transplants for HBV-related liver disease. A not so uncommonly encountered situation while managing children with chronic HBV infection is presentation with sudden rise in transaminases. While it is possible that the patient is seroconverting, other potential causes of liver disease such as hepatitis A and D infection, Wilson disease, autoimmune hepatitis drug/alcohol ingestion should be excluded. For parents who present with a child (adopted/own) newly diagnosed with chronic HBV infection, care must be taken to ensure all family members are immunized against HBV. It is also recommended that the child be immunized against hepatitis A. Adolescent patients are advised to abstain from alcohol, drugs and use barrier contraception.
Liver transplantation and HBV
The severe shortage of cadaveric donor organs has led to the use of marginal cadaveric donor livers in selected transplant candidates with high medical urgency (52). Marginal cadaveric organs are those with a higher risk of primary non-function or the potential to transmit disease. HBcAb cadaveric liver donors also are considered marginal because of the 25-90% risk for HBV transmission to the donor (53). Use of LMV and HBIG immunoprophylaxis in recipients of anti-HBc-positive cadaveric livers appears to reduce the rate of HBV transmission, but larger studies with longer follow-up are needed (54-56). A recent survey of current practice showed that as of mid-2001, of transplant medical directors in the US who responded to the survey, 57% (32/56) would accept an anti-HBc-positive donor liver for a HBV-na•ve recipient (57).
Five to 10% of liver transplants are performed for HBV-related liver disease. The outcome of liver transplantation for hepatitis B has improved significantly in the last decade, commensurate with therapeutic innovations introduced during the period. Current strategies include using a combination of HBIG and nucleoside analogues. HBIG is a polyclonal antibody preparation derived from recipients of HBV vaccine. It acts by binding to the envelope of HBV, thus preventing viral entry into uninfected viral cells and horizontal spread among hepatocytes. It is typically administered, starting at 10 000 IU during the anhepatic phase in various schedules, to maintain an anti-HBs level of >100-200 mIU/mL and even >500 mIU/mL in more aggressive protocols (58). The major drawback is cost (as high as $100 000/yr) and the fact that it may be needed indefinitely (30). Yet another drawback is that patients with active viral replication (HBeAg-positive at the time of transplant) will continue to have recurrence of disease. In the late 1990s, the use of LMV in combination with HBIG was shown to be more effective than either agent alone in prevention of recurrence even in patients with evidence of viral replication (59, 60). By the early 2000s, it was established that ADV could be used to successfully treat mutants resistant to LMV (61). Treatment with 10-mg ADV resulted in significant clinical and laboratory improvements, and improved survival in pre-OLT patients failing LMV therapy. In addition, the clinical condition improved to allow a reduction in their priority status for requiring transplantation or significantly reduced serum HBV DNA and improved clinical status to allow transplantation (45). An adjuvant HBV vaccine has recently been reported to allow stopping of HBIG in post-transplant recipients without recurrence of disease, the median follow-up of the study was 1 yr (62). The outcome following transplantation for hepatitis B, adjusting for other variables, is comparable with, if not slightly better than, that in patients with other diagnoses (63). These data support HBV as an excellent indication for liver transplantation. Trials are needed to assess the best prophylactic regime as increasing number of newer agents become available.
Managing chronic HBV infection in children is complex and therapeutic approaches vary. Children with chronic HBV infection should have their transaminases, HBV serology (HBsAg, HBsAb, HBeAg, HBeAb) and HBV DNA monitored regularly. Those with high transaminases should be considered for treatment with either IFN and/or nucleoside analogues. Children with chronic HBV infection should have regular screening for HCC using AFP and ultrasound. They should be immunized against hepatitis A virus and their family and close contacts immunized against HBV. Liver transplantation is now a viable option for those with fulminant or decompensated liver disease. With the advent of HBIG and nuclear analogues, results after liver transplantation are good and are not inferior to liver transplants performed for other indications.