|Year : 2006 | Volume
| Issue : 1 | Page : 106-127
|Management of chronic hepatitis B in children
Anna Liberek, Graeyna Luczak, Magdalena Gora-Gebka, Piotr Landowski
Department of Pediatrics, Pediatric Gastroenterology and Oncology, Medical University of Gdańsk, Poland, Ul. Nowe Ogrody 1-6, 80-803 Gdańsk, Poland
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| Abstract|| |
Chronic hepatitis B remains a major public health problem, affecting approximately about 350 million people globally. The number of hepatitis B virus (HBV) infected children has not been fully documented. The natural history of HBV infection reflects the dynamic host-virus interactions related to the condition of the host immune system; hence, the clinical course of HBV differs between children and adults. The immaturity of immune system in young children is responsible for the fact that nearly 90% of HBV infections acquired in infancy and 40-70% HBV infections before the age of 3 years result in chronic carrier state of the virus. Therefore a large population is in need of effective and save treatment of this disease. Significant advances have been made during the last decades in the treatment of chronic hepatitis B. The epidemiological situation of HBV infection, its natural history, clinical outcome with its serious long-term consequences and therapeutical approach in children are reviewed in the paper.
|How to cite this article:|
Liberek A, Luczak G, Gora-Gebka M, Landowski P. Management of chronic hepatitis B in children. Hep B Annual 2006;3:106-27
| Introduction and natural history of chronic hepatitis B|| |
The infection with hepatitis B virus (HBV) is a serious epidemiological problem worldwide due to its high incidence and the consequences of the chronic infection, including chronic hepatitis B associated with the risk of liver cirrhosis and primary liver cancer. There are approximately 350 million people chronically infected with HBV in the world. Even upto 40% of these individuals can be expected to develop serious hepatic complications.,,
Over one million patients die each year from complications of the infection. Low (less than 2% of the population seropositive for HBsAg), intermediate (2-8%) and high prevalence (more than 10%) areas are recognized. This problem is particularly important in the Asia, Africa and the Western Pacific region where the prevalence is very high (from 5-20% to 80% of all infected people in the world). The majority of HBV infection in this area is acquired perinatally or in early childhood. In North America and Western Europe, the disease affects less than 2% of the population and infection is usually transmitted by blood transfusion, intravenous drug abuse or sexual contacts.
The number of HBV infected children has not been fully documented. This fact is associated with the asymptomatic course of the disease and the lack of large epidemiological studies as the determination of serological markers of HBV infection is not performed in children on routine basis. Indirect evidence for a large number of infected children comes from reports on the incidence of accidentally diagnosed hepatitis in children who are hospitalized for other reasons.
The natural history of HBV infection reflects the dynamic host-virus interactions related to the condition of the host immune system; hence, the clinical course of HBV differs between children and adults. The course of this infection in children depends mainly on the age at infection. Children who were infected perinatally undergo an immunotolerant phase with high HBV-DNA levels (usually >10 7 copies/mL) and normal or minimally elevated alanine aminotransferase (ALT) levels. This pattern is typical in highly endemic regions of the Far East.,, The immunotolerant phase may last for 10-30 years after perinatal infection. In some patients it may be followed by an immunoactive phase of infection with the elevation of serum aminotransferases levels and a decrease in serum HBV-DNA load. Seroconversion HBeAg to anti-HBe may occur following a sudden, asymptomatic elevation of serum aminotransferases. The immaturity of immune system in young children is responsible for the fact that nearly 90% of HBV infections acquired in infancy and 40-70% HBV infections before the age of 3 years result in chronic carrier state of the virus., Chronic hepatitis B is defined as the persistence of HBsAg in serum, elevated level of ALT and characteristic inflammatory and necrotic changes in the liver for more than 6 months. This disease usually causes variable pattern of inflammatory and necrotic changes in the liver, elevated aminotransferases level and viremia in serum.
The risk of liver cirrhosis increases with the duration of the infection, amounting to around 10 years on the average.,, In children, HBV usually progresses with few symptoms or is asymptomatic, which hinders the determination of HBV duration until the occurrence of liver cirrhosis. There are cases of liver cirrhosis related to HBV infection, diagnosed in children aged 3-6 or in infants.,,, Primary liver cancer is usually of cirrhotic background and it often develops several years after infection. However, some authors have reported on the occurrence of this neoplasm even in small children with HBV infection.,
Spontaneous HBV remission with the inhibition of virus replication reflected in HBeAg/anti-HBe seroconversion is rare among children - it has been observed in 8-19% of cases.,,,, Full recovery with the elimination of all viral antigens and the presence of anti-HBs is recorded rather sporadically, in around 2% of children with chronic HBV hepatitis.
Therapy aims at the complete virus elimination and the development of immunity to reinfection. Practically, this effect can be obtained relatively very rare.,, The drugs used so far allow solely for the inhibition of HBV replication. This usually presents with clinical, biochemical and histological remission of the disease.
Several strategies have been evaluated for treatment of chronic HBV infection with the goal of eliminating persistent viral replication and preventing progression to chronic active hepatitis and its complications.,
Interferon-α therapy of chronic hepatitis B
Till now Interferon-a (IFN-α) is the therapy of first choice for children with chronic hepatitis B. Treatment with IFN-α significantly accelerates HBV DNA clearance and HBeAg/anti-HBe seroconversion. The effectiveness of the IFN-α therapy in children varies from 17-19% of cases in predominantly vertically infected Chinese children, to 30-50% of cases reported from Europe.,,,, The elimination of HBeAg and HBsAg, considered equal with full recovery, is relatively rarely observed, usually in less than several percent of children (<20%).,,
Since the introduction of widespread use of IFN-α in the treatment of chronic hepatitis B and finding it effective only in a limited group of patients, there has been a search for epidemiological and clinical factors that might be of importance for positive response to therapy. They aim at the optimal selection for IFN-α treatment only of patients who are likely to recover. This is determined not only by economical considerations but also, particularly in the case of children, by the need not to expose patients to long-term unnecessary treatment and possible side effects. Small number of children forming study groups treated with IFN-α in various centers did not allow for detailed analysis of the factors predicting successful treatment., In 1997, the experiences of several European hepatologists and pediatricians who had treated overall more than 1000 children with chronic hepatitis B were collected to reach a consensus on the guidelines for the use of IFN-α.
According to the consensus, children with HBeAg and HBV DNA positive hepatitis are candidates for IFN-α treatment. IFN-α should be administrated to children older than 2 years. This therapy in younger children can cause growth retardation during a period of life when growth is crucial. However, some authors who treated children younger than 2 years did not observe significant growth retardation. Young children usually have very mild transaminase elevation in serum and liver lesions and thus do not need treatment, although shortening the period of HBV replication may be important even in these cases.
Candidates for IFN-α treatment should have elevated ALT levels. It seems to be better to treat only children with ALT at least twice the normal level or higher. However, there are also suggestions to treat children with normal ALT, if they have histological features of inflammation in the liver.,,
Children treated with IFN-α should have intermediate or low levels of HBV DNA in serum (usually <1000 pg/mL), according to the method of HBV DNA quantification used in each laboratory. In children with high viremia, it is better to delay the treatment until viremia tends to decrease. It is also possible to start the treatment and evaluate the therapy influence on HBV DNA level after 4 months, eventually withdrawing the therapy in the case of persistent high viremia.
Liver biopsy is important for assessing severity and stage of liver damage as a guide to treatment and a parameter of evaluating response to therapy. Some authors suggest delaying treatment in children with minimal hepatitis.
Treatment with IFN-α can be considered in case of cirrhosis due to chronic hepatitis B in children with Child-Turcotte-Pugh class A and HBeAg persistent in serum. In these cases liver function must be monitored very carefully. IFN-α is contraindicated in the cases of liver function impairment (prolonged prothrombin time, hypoalbuminemia) and cytopenia caused by hypersplenism.,
Interferon-α therapy is contraindicated in the autoimmune disorders especially with the presence of antibodies to liver and kidney microsomal antigens type 1 (LKM 1) because IFN can exacerbate liver damage. Low titers of other autoantibodies (e.g., antinuclear or anti-smooth muscle) without other manifestation of autoimmunity are not contraindications for treatment.
IFN-α therapy is contraindicated in children with organ transplant, because it enhances the risk of rejecting the organ. This therapy is also contraindicated in patients with renal or cardiac failure or severe function disturbances.
Neurological diseases are contraindications for IFN-α therapy although few children with well-controlled epilepsy were treated without complications. Children with a history of febrile seizures should be treated above the age of risk or provided temperature is carefully monitored. Repeated febrile seizures during treatment require therapy cessation.,
The standard treatment schedule is 5 MU/m 2 IFN-α administered subcutaneously or intramuscularly three times a week for 6 months. Lower doses seem to have lower efficacy while higher doses significantly increase the incidence of side effects.,
A response to IFN-α therapy is regarded as seroconversion from HBeAg to anti-HBe, normalization of ALT level in serum and HBV-DNA clearance during the treatment or within 6 months after treatment. In some cases this response is observed 6-12 months after completion of therapy. HBsAg to anti-HBs seroconversion is rare after IFN-a treatment.
Numerous clinical studies were designed to establish optimal interferon-a treatment of chronic HBV.,,, The studies conducted point to the existence of pre-treatment parameters predisposing for positive response to IFN-a treatment. ALT level (twice the norm or higher) and low HBV DNA level (<100 pg/mL) are regarded as the main predictors of seroconversion. Greater IFN-α effectiveness in patients with high ALT activity has been confirmed in studies on both children and adults.,,,,, Only few authors have not observed such a correlation., The other parameters as: high activity of inflammatory changes in the liver, short duration of HBV infection, older age, the onset of infection in adulthood and being female are taken under consideration, but the significance of these factors is not well-established.,,,,, Our findings did not differ from other reports. The results in respect of the frequency of HBeAg elimination in relation to patients' gender are ambiguous. Some authors report better response to IFN-a in older children, while other researchers do not confirm this claim. Lower IFN-α effectiveness in children infected in very early childhood, reported in the literature, is ascribed to poorer immune response of the young immature organism.,, The observations of many authors indicate that better results are obtained in patients with shorter HBV duration. The majority of the investigators suggest that better response to IFN-α is observed with higher inflammatory activity in the liver,,,,,, while others do not agree with this opinion.,, Reported worse response to treatment with greater intensity of changes might be related to irreversibility of fibrosis and the remodeling of liver parenchyma, although some authors have observed good outcome of IFN-a therapy even in patients with cirrhotic changes in the liver., This might be due to the interferon-induced inhibition of the ongoing inflammation and further development of cirrhosis., There are some data reporting different response in children receiving one of two subtypes of recombined interferon: alpha 2a and alpha 2b. Antonelli et al . observed lower frequency of seroconversion in patients on IFN-α-2b when compared to those receiving IFN-α-2a, which was ascribed to more frequent formation of neutralizing antibodies against interferon after IFN-α-2b administration. On the other hand, some authors found more frequent production of antibodies against IFN-α-2a. There were no differences between the frequencies of HBeAg elimination in children who received different interferon-a subtypes in our study.
There are still no available data showing beneficial effect of IFN-α on the long-term prognosis. Relatively short follow-up in the majority of patients after treatment termination does not allow to define factual, crucial results of treatment such as complete withdrawal of inflammatory changes and lower risk for the development of liver cirrhosis and cancer.
The indications for check-up liver biopsy in children should be established very carefully. It is necessary to consider not only scientific but also ethical aspects of repeated invasive examination. Liver biopsy is performed under general anesthesia in children, which is an additional risk for young patients. Another histological assessment does not alter further management, particularly in children with clinical and serological remission of the disease. Additionally, before treatment most children displayed low activity and advancement of liver changes, thus the improvement should be reflected in complete withdrawal of inflammatory changes, which is rather unlikely in a short observation period., In children with persistent HBV infection, repeated biopsy may be necessary when the application of the new therapy of chronic HBV becomes possible. The decision to perform another liver biopsy in children should include all the factors indicating the necessity for morphological examination of the liver and the benefits of liver biopsy to the patient. When these doubts are not cleared out, it will be difficult to persuade children' parents that another invasive examination is necessary. The effectiveness of a performed check-up histological assessment of liver specimens is still being discussed.
The interferon-a therapy is related to a number of side effects with flu-like symptoms, abdominal pain and fatigue being most commonly reported.,,,, Most of these symptoms usually subside spontaneously after 2 weeks of treatment., Other side effects are hematological disorders, infections, neuropsychiatric complication, autoimmunologic reactions and non-specific general symptoms.,, The treatment with IFN-a is also uncomfortable to receive (especially in children).
In many clinical trials, fever is the most commonly observed side effect of IFN therapy. In the majority of cases, it occurred at the beginning of treatment.,,, In young children febrile seizures may occur. Percentage of seizure episodes in IFN-treated patients is estimated between several and 20%., Flu-like syndromes such as muscle and joints pain, malaise and fatigue during the IFN-a therapy are observed in almost a half of cases.,, Some authors report even higher number of flu-like syndrome: in 75-90% of cases. Headaches and loss of appetite are also relatively often observed.,, There are various studies reporting the incidence of various types of behavioral disorders (like drowsiness, irritability or depression).,, However, severe psychotic symptoms or depression during the interferon therapy are commonly described rather in adult patients., Local discomfort after interferon injection (pain, redness and swelling in the place of injection) is observed only sporadically in clinical studies.,
The incidence and intensity of clinical side effects usually do not differ between groups of children with positive or with no response to the interferon therapy. It appears that the presence and intensity of side effects have no prognostic value for the outcome of the therapy. Some data suggest higher incidence and severity of side effects may be connected with high dose of IFN-α, but other studies do not confirm that observation.,
Analysis of blood count is usually recommended during IFN therapy because of its potential suppressive effect on hematopoetic system. The significant but transient leukocyte count decrease is frequently observed.,,,, Leucopoenia and severe infectious diseases as a result of IFN- administration were reported previously, particularly in patients with advanced liver dysfunction., Significant but transient thrombocytopenia is commonly observed especially at the beginning of the therapy.,, Hematological disorders mentioned above are usually not life-and health threatening. However, thrombocytopenia and leucopoenia observed by Ruiz-Moreno et al . was so severe that it resulted in interferon dose reduction or even discontinuation of the therapy. It could have been caused by relatively high interferon doses of 10 MU/m 2 . The presently recommended dose is much lower - 5 MU/m 2 . Reports on red blood count and hemoglobin level decrease are rare. These changes, similarly to other hematological disorders, are transient. It may suggest relatively lower effect of IFN-α on red cell system in bone marrow.
In a number of papers the possibility of autoimmune reactions during the IFN-α therapy is suggested. HBV infection itself may be the cause of autoimmune processes or they may result directly from the IFN-α therapy. Thus, serum immunoglobulin level should be monitored during therapy and in some cases serum autoantibodies titers should be evaluated. Various autoantibodies in low titers were found relatively often by some authors.,, Significant but transient increase of immunoglobulin levels, an intensive autoimmune reactions and severe autoimmunological hepatitis were also described.
It is reported that IFN-α may induce different, persistent thyroid dysfunction in adults. Thyroid dysfunction might be the result of IFN-α induced antithyroid antibodies production., Thus, monitoring of thyroid gland function during INF-a therapy is advocated.
In conclusion, the IFN-α therapy enhances HBV DNA clearance, HBeAg elimination and ALT normalization is children with chronic hepatitis B. Side-effects of this treatment are common, but usually transient and mild.
For the adult patients with chronic hepatitis C and/or B pegylated interferon is recommended.,, The addition of polyethylene glycol (PEG) molecule to IFN produces a product with significantly longer half-life and more sustained interferon activity. In the multi-center study in patients with chronic hepatitis B significantly higher rate of HBeAg seroconversion in the pegylated IFN groups was observed in comparison to the standard IFN group.
Lamivudine therapy and other new anti-viral agents in chronic hepatitis B
In the recent years the nucleotide analogue - lamivudine treatment for chronic hepatitis B has been recommended especially for patients who did not respond to IFN-a therapy or with contraindications to this therapy., Lamivudine is the first oral antiviral agent approved for the treatment of chronic hepatitis B. Positive results of this treatment in adult patients, comfortable route of administration and good tolerance have been very promising for use of lamivudine therapy in children with chronic hepatitis B.,,
The results of multi-center controlled trial conducted on the group of 286 children, aged 2-17 years, with chronic hepatitis B proved that the 52-weeks course of lamivudine therapy resulted in the significantly higher rate of viral response comparing to placebo (23 vs. 13%). Furthermore, sustained virologic response (SVR) was also observed more often than in the control group. There are also some other data confirming positive biochemical and virologic response in children with chronic hepatitis B treated with lamivudine than in the control groups.
Our research on the group of 59 children with chronic hepatitis B demonstrated that 12 months of 100 mg lamivudine treatment resulted in 24% of SVR. Special stress must be put on the fact that 86% of these patients had not responded to prior IFN-a therapy. Many authors investigating lamivudine therapy effectiveness demonstrated rate of viral response of 22-44%. However, Kocak et al . observed HBeAg/anti-HBe seroconversion only in 5% of cases while in 90% of cases viral load significantly decreased. Most trials on the effectiveness of lamivudine therapy in both adults and children with chronic hepatitis B show that ALT normalization is significantly more frequent even though it is often not associated with the viral response.,,,,
The majority of authors suggest that pretherapy ALT level and active histological disease are the most important predictors of lamivudine-induced HBeAg loss.,, In children with chronic hepatitis B seroconversion rate is higher in those with pre-treatment ALT >2 times normal (34 vs. 16%).
ALT normalization was observed in the most of children treated with lamivudine., Jonas et al . showed in their research that median time of ALT normalization was 24 weeks.
One year of lamivudine therapy for naοve patients seems to be as effective as the standard course of IFN-a and adverse events are similar for the lamivudine and placebo groups.
Due to small number of data on the representative groups of patients establishing the optimal dose of lamivudine especially for children under the age of 12 years appears to be still an important problem. Most authors claim it should be 3-4 mg/kg/24 hours, maximum 100 mg/24 hours. It appears that increase in the daily dose or in the frequency of its administration does not improve the results of lamivudine therapy.,, Recommended dose of lamivudine in children results in the serum concentration of the drug similar to that in adults receiving 100 mg daily. Due to some years of experiences in treatment in adults with chronic hepatitis B, this dose of lamivudine seems to be satisfactory.
No particular side effects were observed in the group of patients with chronic hepatitis B treated with lamivudine., However Lebensztejn et al . reported a case of a child with chronic hepatitis B treated with lamivudine who developed thrombocytopenia. Withdrawal of lamivudine caused normalization of platelets count, while reintroduction of the drug resulted in repeated thrombocytopenia. Some authors report on the risk of liver dysfunction and even acute liver failure after cessation of lamivudine therapy especially in patients with advanced liver fibrosis or cirrhosis.
As many data show, duration of lamivudine therapy increases not only the rate of positive viral response, but also the risk of YMDD mutations, which appears to rise upto 60% in patients treated with lamivudine for more than 4 years.,, However, besides the high percentage of viral mutants, lamivudine is still capable of induction of HBeAg/anti-HBe seroconversion and improvement of histopathological changes within liver tissue in the treated patients., One year lamivudine therapy has been proved effective, save and well tolerated therapy in children with chronic hepatitis B.
Data on the results of combined IFN-a and lamivudine therapy vary and this treatment does not seem to be more effective than monotherapy with either IFN-a or lamivudine.,,,
Several other new antiviral agents have been shown to be effective in inhibiting HBV replication in vitro as well in phase I as in phase II clinical studies. In order to effectively manage the problem of the treatment of chronic hepatitis B, alternative therapies need to be efficacious against both wild-type and lamivudine resistant mutants.
Adefovir has been the most thoroughly studied and approved for use in patients with chronic hepatitis B in the USA and Europe. Adefovir dipivoxil is an orally bioavailable pro-drug of adefovir, a nucleotide analogue of adenosine monophosphate. It can inhibit both the reverse transcriptase and DNA polymerase activity and is incorporated into viral DNA causing chain termination.,,, Adefovir at a dose of 10 mg per day has been approved for use for adult patients with chronic hepatitis B. It has been shown to be effective in suppressing not only wild type but also lamivudine resistant HBV mutants.,
Other drugs, which were tried in therapy of chronic hepatitis B in adults, are e.g.: Famciclovir, Entecavir, Clevudine., They are not widely accessible for pediatric patients.,
Lamivudine, one of the two approved nucleoside analogous with efficacy against HBV, has however, some well-documented serious limitations, in particular the emergence of HBV drug-resistance. Although lamivudine therapy results in a rapid decline of serum HBV DNA levels and normalization of transaminases levels in the majority of patients, the risk of the emergence of drug resistant mutants appears especially during prolonged treatment.,, Prolonged lamivudine therapy is required to induce sustained remission as it has been proved that lamivudine has no activity against the covalently closed circular (ccc) HBV DNA responsible for the viral persistence, which may be destroyed only by the death of infected hepatocytes (the half-life of infected hepatocyte is about 100 days)., Drug-resistant mutants have been detected in 14-32% of HBeAg positive patients after 1 year of lamivudine treatment.,,, Some data show the rates of drug-resistant mutations to be 38, 49, 66 and 69% after 2, 3, 4 and 5 years of therapy, respectively. High pre-treatment serum HBV DNA levels, high pre-treatment ALT levels, male gender and high body mass index were recognized by some authors as factors correlating with the emergence of lamivudine resistance.,
Lamivudine resistance is usually manifested as reappearance of HBV DNA in serum after its initial disappearance. In vitro assays have confirmed that the some mutations confer reduced susceptibility of HBV to lamivudine., Furthermore, some experiments also suggested that drug-resistant mutants had reduced replicative efficiency in the absence of lamivudine, compared with wild-type HBV. The diminished replication capacity of the mutants accounts for the rapid outgrowth of the wild-type virus upon cessation of lamivudine treatment. Flares in hepatitis owing to the re-emergence of wild-type virus have been reported in patients after withdrawal of lamivudine therapy. Thus it is recommended by some authors to maintain patients with breakthrough infection on lamivudine treatment to suppress residual wild-type virus especially in patients with advanced fibrotic changes within liver tissue.,
Genome variability of HBV is one of the mechanisms involved in viral persistence. HBV replicates its genome by means of a reverse transcriptase activity., The reverse transcriptase/DNA polymerase region can be divided into five domains. Domains A, C and B are involved in nucleoside triphosphate binding and catalysis, while domains B and E may participate in the positioning of the RNA template and the primer, relative to the catalytic site. Lamivudine resistance is associated with the appearance of HBV variants with mutations in the highly conserved tyrosine, methionine, aspartate, aspartate (YMDD) and motif in the C domain of the viral polymerase. Three types of such mutants in which the methionine (rtM204, YMDD) is replaced by valine (rt204, YVDD), isoleucine (rt204, YIDD) or serine (rtS204, YSDD) were described.,, Recently, YLDD and YMED mutants were detected. YIDD is the only single mutation, while YVDD and YSDD mutations are accompanied by other changes in either the B or A domains of the HBV polymerase.,, The biological role of particular mutations within polymerase gene has not been fully elucidated yet, however, their clinical importance since nucleoside analogous were used for the treatment of HBV infections, has been increasing. The presence of some less recognized mutations may point at the problem of some overlapping resistance.
The approach in the treatment of HBV infection is not only to look for monotherapy with particular effective immunomodulatory or antiviral drugs, but also to use a combination of agents that have additive or synergistic effects. Thus the cross-resistance of HBV mutants to some antiviral agents appears to be relevant for the future therapeutic policies in patients with chronic hepatitis B. The future for effective therapy for chronic hepatitis B is probably the combined therapies: two or more anti-viral agents or anti-viral agents and IFN-a together with virologic, immunologic and clinical characterization of the individual patient.
However, having in mind still high incidence of hepatitis B infection and lack of fully effective treatment of chronic hepatitis and its serious complications, the prevention of the infection by vaccination of the populations at risk becomes especially important.
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Department of Pediatrics, Pediatric Gastroenterology and Oncology, Medical University of Gdańsk, Poland, Ul. Nowe Ogrody 1-6, 80-803 Gdańsk
Source of Support: None, Conflict of Interest: None
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