Hepatitis B Annual

: 2006  |  Volume : 3  |  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

Correspondence Address:
Anna Liberek
Department of Pediatrics, Pediatric Gastroenterology and Oncology, Medical University of Gdańsk, Poland, Ul. Nowe Ogrody 1-6, 80-803 Gdańsk


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;3:106-127

How to cite this URL:
Liberek A, Luczak G, Gora-Gebka M, Landowski P. Management of chronic hepatitis B in children. Hep B Annual [serial online] 2006 [cited 2022 Dec 9 ];3:106-127
Available from: https://www.hepatitisbannual.org/text.asp?2006/3/1/106/32775

Full Text

 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.[1],[2],[3]

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.[4] 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.[5]

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.[6],[7],[8] 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.[7] 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.[9],[10] 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.[11] 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.[4],[12],[13] 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.[14],[15],[16],[17] 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.[18],[19]

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.[20],[21],[22],[23],[24] 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.[25]

Therapy aims at the complete virus elimination and the development of immunity to reinfection. Practically, this effect can be obtained relatively very rare.[24],[26],[27] 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.[28],[29]

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.[6] The effectiveness of the IFN-α therapy in children varies from 17-19% of cases in predominantly vertically infected Chinese children[22],[30] to 30-50% of cases reported from Europe.[31],[32],[33],[34],[35] The elimination of HBeAg and HBsAg, considered equal with full recovery, is re­latively rarely observed, usually in less than several percent of children ( 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.[6],[34],[36]

Children treated with IFN-α should have intermediate or low levels of HBV DNA in serum (usually 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.[39],[40]

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.[6]

Numerous clinical studies were designed to establish optimal interferon-a treatment of chronic HBV.[26],[41],[42],[43] 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 ( 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.[45] On the other hand, some authors found more frequent production of antibodies against IFN-α-2a.[39] There were no differences between the frequencies of HBeAg elimination in children who received different interferon-a subtypes in our study.[35]

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.[46] 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.[41],[47] 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.[46]

The interferon-a therapy is related to a number of side effects with flu-like symptoms, abdominal pain and fatigue being most commonly reported.[35],[38],[48],[49],[50] Most of these symptoms usually subside spontaneously after 2 weeks of treatment.[23],[42] Other side effects are hematological disorders, infections, neuropsychiatric complication, autoimmunologic reactions and non-specific general symptoms.[23],[35],[50] 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.[20],[23],[35],[44] In young children febrile seizures may occur. Percentage of seizure episodes in IFN-treated patients is estimated between several and 20%.[41],[46] 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.[2],[23],[35] Some authors report even higher number of flu-like syndrome: in 75-90% of cases.[44] Headaches and loss of appetite are also relatively often observed.[23],[35],[44] There are various studies reporting the incidence of various types of behavioral disorders (like drowsiness, irritability or depression).[23],[35],[46] However, severe psychotic symptoms or depression during the interferon therapy are commonly described rather in adult patients.[23],[42] Local discomfort after interferon injection (pain, redness and swelling in the place of injection) is observed only sporadically in clinical studies.[35],[46]

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.[6],[35]

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.[23],[24],[35],[49],[50] Leucopoenia and severe infectious diseases as a result of IFN- administration were reported previously, particularly in patients with advanced liver dysfunction.[23],[37] Significant but transient thrombocytopenia is commonly observed especially at the beginning of the therapy.[24],[49],[50] 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 .[22] 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.[23]

In a number of papers the possibility of autoimmune reactions during the IFN-α therapy is suggested.[23] HBV infection itself may be the cause of autoimmune processes or they may result directly from the IFN-α therapy.[51] 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.[35],[51],[52] Significant but transient increase of immunoglobulin levels, an intensive autoimmune reactions and severe autoimmunological hepatitis were also described.[53]

It is reported that IFN-α may induce different, persistent thyroid dysfunction in adults.[54] Thyroid dysfunction might be the result of IFN-α induced antithyroid antibodies production.[51],[54] 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.[28],[55],[56] 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.[55]

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.[57],[58] 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.[59],[60],[61]

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.[57] 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.[62]

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.[63] Many authors investigating lamivudine therapy effectiveness demonstrated rate of viral response of 22-44%.[62] However, Kocak et al . observed HBeAg/anti-HBe seroconversion only in 5% of cases while in 90% of cases viral load significantly decreased.[61] 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.[60],[61],[62],[64],[65]

The majority of authors suggest that pretherapy ALT level and active histological disease are the most important predictors of lamivudine-induced HBeAg loss.[66],[67],[68] In children with chronic hepatitis B seroconversion rate is higher in those with pre-treatment ALT >2 times normal (34 vs. 16%).[57]

ALT normalization was observed in the most of children treated with lamivudine.[57],[63] Jonas et al . showed in their research that median time of ALT normalization was 24 weeks.[57]

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.[69]

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.[57],[64],[70] Recommended dose of lamivudine in children results in the serum concentration of the drug similar to that in adults receiving 100 mg daily.[70] 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.[57],[63] 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.[71] 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.[59]

As many data show, duration of lamivudine therapy increases not only the rate of positive viral response, but also the risk of YMDD mutations,[59] which appears to rise upto 60% in patients treated with lamivudine for more than 4 years.[65],[72],[73] 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.[74],[75] 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.[69],[76],[77],[78]

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.[2],[28],[79],[80] 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.[79],[80]

Other drugs, which were tried in therapy of chronic hepatitis B in adults, are e.g.: Famciclovir, Entecavir, Clevudine.[28],[29] They are not widely accessible for pediatric patients.[65],[81]

Lamivudine-resistance HBV

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.[60],[82],[83] 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).[84],[85] Drug-resistant mutants have been detected in 14-32% of HBeAg positive patients after 1 year of lamivudine treatment.[28],[82],[86],[87] 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.[28] 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.[28],[66]

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.[2],[88] 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.[73],[89]

Genome variability of HBV is one of the mechanisms involved in viral persistence. HBV replicates its genome by means of a reverse transcriptase activity.[90],[91] 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.[83],[92],[93] Recently, YLDD and YMED mutants were detected.[94] 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.[83],[92],[93] 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.[28]

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.


1Esteban R. Management of chronic hepatitis B: An overview. Semin Liver Dis 2002;22:1-6.
2Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225-41.
3McMahon BJ. Hepatocellular carcinoma and viral hepatitis. In : Wilson RA, editor. Viral hepatitis. Marcel Dekker: New York; 1997. p. 315-30.
4Liaw YF, Leung N, Guan R, Lau GK, Merican I, McCaughan G, et al . Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2005 update. Liver Int 2005;25:472-89.
5Lok AS, Heathote EJ, Hoofnagle JH. Management of hepatitis B: 2000- summary of a workshop. Gastroenterology 2001;120:1828-53.
6Jara P, Bortolotti F. Interferon-a treatment of chronic hepatitis B in childhood: A consensus advice based on experience in European children. J Pediatr Gastroenterol Nutr 1999;29:163-70.
7Dusheiko G. Candidates for therapy: HBV. J Hepatol 2006;44:S84-9.
8Bortolotti F, Jara P, Crivellaro C, Hierro L, Cadrobbi P, Frauca E, et al . Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period. J Hepatol 1998;29:184-90.
9 Shapiro CN. Epidemiology of hepatitis B. Pediatr Infect Dis J 1993;12:433-7.
10McMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP, et al . Acute hepatitis B virus infection: Relation of age to the clinical expression in disease and subsequent development of carrier state. J Infect Dis 1985;151:599-603.
11 Davis GL. Chronic hepatitis. In : Neil Kaplowitz, editor. Liver and biliary diseases. Williams and Wilkins: 1996. p. 327-39.
12 Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, et al . Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology 1995;21:77-82.
13Louis-Jacques O, Olson AD. Cost-Benefit Analysis of Interferon Therapy in Children with Chronic Active Hepatitis B. J Pediatr Gastroenterol Nutr 1997;24:25-32.
14 Bortolotti F, Calzia R, Cadrobbi P, Giacchini R, Ciravegna A, Armigliato M, et al . Liver cirrhosis associated with chronic hepatitis B virus infection in childhood. J Pediatr 1986;108:224-7.
15Dupuy JM, Kostewitz E, Alagille D. Hepatitis B in children. J Pediatr 1978;98:17-20.
16Ruiz Moreno M, Camps T, Aguado JG, Porres JC, Oliva H, Bartolome J, et al . Serological and histological follow up of chronic hepatitis B infection. Arch Dis Child 1989;64:1165-9.
17 Shinozaki T, Saito K, Shiraki K. HBsAg-positive giant cell hepatitis and cirrhosis in a 10-month-old infant. Arch Dis Child 1981;4:34-6.
18Chang MH, Chen PJ, Chen JY, Lai MY, Hsu HC, Lian DC, et al . Hepatitis B virus integration in hepatitis B virus-related hepatocellular carcinoma in childhood. Hepatology 1991;13:316-20.
19 Cheah PL, Looi LM, Lin HP, Yap SF. Childhood primary hepatocellular carcinoma and hepatitis B virus infection. Cancer 1990;65:174-6.
20Bortolotti F, Cadrobbi P, Cirivellaro C, Guido M, Rugge M, Noventa F, et al . Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood. Gastroenterology 1990;99:805-10.
21 Evans AA, Fine M, London WT. Spontaneous seroconversion in hepatitis B e antigen-positive chronic hepatitis B: Implications for interferon therapy. J Infect Dis 1997;176:845-50.
22Ruiz Moreno M, Rua MJ, Molina J. Prospective, randomized trial of interferon-alpha in children with chronic hepatitis B. Hepatology 1991;13:1035-9.
23 Ruiz-Moreno M. Chronic hepatitis B in children. Natural history and treatment. J Hepatol 1993;17:S64-6.
24Torre D, Tambini R. Interferon-a therapy for chronic hepatitis B in children: A meta-analysis. Clin Infect Dis 1996;23:131-7.
25 Hsu HY, Chang MH, Lee CY, Chen JS, Hsu HC, Chen DS, et al . Spontaneous loss of HBsAg in children with chronic hepatitis B virus infection. Hepatology 1992;15:382-6.
26Brook MG, Chan G, Yap I, Karayiannis P, Lever AM, Jacyna M, et al . Randomized controlled trial of lymphoblastoid interferon alfa in Europid men with chronic hepatitis B virus infection. BMJ 1989;299:652-6.
27 Lau DT, Everhart J, Kleiner DE, Park Y, Vergalla J, Schmid P, et al . Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology 1997;113:1660-7.
28 Conjeevaram HS, Lok AS. Management of chronic hepatitis B. J Hepatol 2003;38:S90-103.
29Craxi A, Antonucci G, Camma C. Treatment options in HBV. J Hepatol 2006;44:S77-83.
30Schalm SW, Heathcote J, Cianciara J, Farrell G, Scherman M, Willems B, et al . Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: A randomized trial. Gut 2000;46:562-8.
31 Barbera C, Bortolotti F, Crivellaro C, Coscia A, Zancan L, Cadrobbi P, et al . Recombinant interferon-a2a hastens the rate of HBeAg clearance in children with chronic hepatitis B. Hepatology 1994;20:287-90.
32Giacchino R, Main J, Timitilli A, Giambartolomei G, Facco F, Cirillo C, et al . Dual-centre, double-blind, randomized trial of lymphoblastoid interferon alpha with or without steroid pretreatment in children with chronic hepatitis B. Liver 1995;15:143-8.
33 Ruiz Moreno M, Jimenez J, Porres JC, Bartolome J, Moreno A, Carreno V. A controlled trial of recombinant interferon-alpha in Caucasian children with chronic hepatitis B. Digestion 1990;45:26-33.
34Ruiz-Moreno M, Camps T, Jimenez J, Lopez R, Castillo I, Bartolome J, et al . Factors predictive of response to interferon therapy in children with chronic hepatitis B. J Hepatol 1995;22:540-4.
35Liberek A, Luczak G, Korzon M, Szlagatys-Sidorkiewicz A, Bako W, Gora-Gebka M, et al . Tolerance of interferon-alpha therapy in children with chronic hepatitis B. J Paediatr Child Health 2004;40:265-9.
36Liberek A, Łuczak G, Bako W, Korzon M, Rytlewska M, Sikorska-Wiśniewska G, et al . Prognostic factors in the treatment of chronic hepatitis B with interferon alpha in children. Med Sci Monit 2001;7:127-37.
37Hoofnagle JH, Di Bisceglie AM, Waggoner JG, Park Y. Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology 1993;104:1116-21.
38Shakil AO, Di Bisceglie AM, Hoofnagle JH. Seizures during alpha interferon therapy. J Hepatol 1996;24:48-51.
39Brook MG, McDonald JA, Karayiannis P, Caruso L, Forster G, Harris JR, et al . Randomised controlled trial of interferon alfa 2A (rbe) (Roferon-A) for the treatment of chronic hepatitis B virus (HBV) infection: Factors that influence response. Gut 1989;30:1116-22.
40 Utili R, Sagnelli E, Gaeta GB, Galanti B, Nardiello S, Felaco FM, et al . Treatment of chronic hepatitis B in children with prednisone followed by alfa-interferon: A controlled randomized study. J Hepatol 1994;20:163-7.
41Perrillo RP. The management of chronic hepatitis B. Am J Med 1994;96:34S-40S.
42 Schalm SW. Treatment of chronic hepatitis B. Neth J Med 1994;44:103-9.
43Utlili R, Sagnellini E, Galanti B, Aprea L, Cesaro G, Digilio L, et al . Prolonged treatment of children with chronic hepatitis B with recombinant alpha 2A interferon: A controlled randomized study. Am J Gastroenterol 1991;86:327-30.
44 Lai CL, Lok AS, Lin HJ. Use of recombinant alpha 2 interferon (r-IFN) with or without steroid in Chinese HBsAg carrier children: A prospective double-blind controlled trial. Gastroenterology 1989;96:618.
45 Antonelli G, Currenti M, Tutriziani O, Dianzani F. Neutralizing anti-bodies to interferon-alpha: Relative frequency in patients treated with different interferon preparations. J Infect Dis 1991:63:882-5.
46Woynarowski M, Socha J. Results of interferon alfa therapy in children with chronic viral hepatitis type B. Experiences of Polish centres 1990-1997. Ped Pol 1998;10:1031-41.
47Brook MG, Petrovic L, McDonald JA, Scheuer PJ, Thomas HC. Histological improvement after anti-viral treatment for chronic hepatitis B infection. J Hepatol 1989;8:218-25.
48Renault PF, Hoofnagle JH, Park Y, Mullen KD, Peters M, Jones DB, et al . Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987;147:1577-80
49Sata M, Yano Y, Yoshiyama Y, Ide T, Kumashiro R, Suzuki H, et al . Mechanisms of thrombocytopenia induced by interferon therapy for chronic hepatitis B. J Gastroenterol 1997;32:206-10.
50Iorio R, Pensati P, Botta S, Moschella S, Impagliazzo N, Vajro P, et al . Side-effects of alpha-interferon therapy and impact on health-related quality of life in children with chronic viral hepatitis. Pediatr Infect Dis J 1997;16:984-90.
51Czaja AJ. Extrahepatic immunologic features of chronic viral hepatitis. Dig Dis 1997;15:125-44.
52di Cesare E, Previti M, Russo F, Brancatelli S, Ingemi MC, Scoglio R, et al . Interferon-alpha therapy may induce insulin autoantibody development in patients with chronic viral hepatitis. Dig Dis Sci 1996;41:1672-7.
53Socha J, Pawłowska J, Woynarowski M, Burczyρska B, Madaliρski K, Janowicz W, et al . Results of alpha-interferon treatment in children with chronic viral hepatitis type B. Ped Pol 1992;69-74.
54Deutsch M, Dourakis S, Manesis EK, Gioustozi A, Hess G, Horsch A, et al . Thyroid abnormalities in chronic viral hepatitis and their relationship to interferon alfa therapy. Hepatology 1997;26:206-10.
55Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al . Peginterferon a-2a (40 kDa): An advance in treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepatitis 2003;10:288-305.
56Fried MV, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales Jr FL, et al . Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-82.
57Jonas MM, Mizierski J, Badia IB, Areias JA, Schwarz KB, Little NR, et al . Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med 2002;346:1706-13.
58 Leung N. Clinical experience with Lamivudine. Liver Dis 2002;22:15-21.
59Dixon JS, Boehme RE. Lamivudine for the treatment of chronic hepatitis B. Acta Gastro-Enterologica Belgica 2000;63:348-56.
60Dienstag JL, Schiff ER, Wright TL, Perillo RP, Hann HW, Goodman Z, et al . Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256-63.
61Koηak N, Ozen H, Saltik IN, Gurakan F, Yuce A. Lamivudine for Children with Chronic Hepatitis B. Am J Gastroenterol 2000;95:2989-90.
62Hartman C, Berkowitz D, Shouval D, Eshach-Adiv O, Hino B, Rimon N, et al . Lamivudine treatment for chronic hepatitis B infection in children unresponsive to interferon. Pediatr Infect Dis J 2003;22:224-9.
63Liberek A, Szaflarska-Poplawska A, Korzon M, Luczak G, Gora-Gebka M, Los-Rycharska E, et al . Lamivudine therapy for children with chronic hepatitis B. World J Gastroenterol 2006;12:2412-6.
64Lebensztejn DM, Skiba E, Sobieniec-Lotowska M, Kaczmarski M. The HBe/antiHBe seroconversion as a result of lamivudine treatment in children with chronic hepatitis B unresponsive to previous interferon alfa therapy. Pol Merkuriusz Lek 2004;16:557-9.
65Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, et al . A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol 2004;2:87-106.
66 Perrillo RP, Lai CL, Liaw YF, Dienstag JL, Schiff ER, Schalm SW, et al . Predictors of HBeAg loss Lamivudine treatment for chronic hepatitis B. Hepatology 2002;36:186-94.
67Chien RN, Liaw YF, Atkins M. Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B. Hepatology 1999;30:770-4.
68Hom X, Little NR, Gardner SD, Jonas MM. Predictors of virologic response to Lamivudine treatment in children with chronic hepatitis B infection. Pediatr Infect Dis J 2004;23:441-5.
69Schalm SW, Heathcote J, Cianciara J, Farrell G, Scherman M, Willems B, et al . Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: A randomized trial. Gut 2000;46:562-8.
70Sokal EM, Roberts EA, Mieli-Vergani G, McPhillips P, Johnson M, Barber J, et al . A dose ranging study of the pharmacokinetics, safety and preliminary efficacy of lamivudine in children and adolescents with chronic hepatitis B. Antimicrob Agents Chemother 2000;44:590-7.
71Lebensztejn DM, Kaczmarski M. Lamivudine-associated thrombocytopenia. Am J Gastroenterol 2002;97:2687-8.
72Sokal E. Drug treatment of pediatric chronic hepatitis B. Paediatr Drugs 2002;4:361-9.
73Hussain M, Lok AS. Mutations in the hepatitis B virus polymerase gene associated with antiviral treatment for hepatitis B. J Viral Hepat 1999;6:183-94.
74Liaw YF, Lai CL, Leung NW, Chang TT, Guan R, Tai DI, et al . Two-year lamivudine therapy in chronic hepatitis B infection: Results of a placebo controlled multi-centre study in Asia. Gastroenterology 1998;114:1289.
75Leung N. Liver disease - significant improvement with lamivudine. J Med Virol 2000;61:380-5.
76Selimoglu MA, Aydogdu S, Unal F, Zeytinoglu A, Yuce G, Yagci RV. Alpha interferon and lamivudine combination therapy for chronic hepatitis B in children. Pediatr Int 2002;44:404-8.
77Rosenberg PM, Dienstag JL. Therapy with nucleoside analogues for hepatitis B virus infection. Clin Liver Dis 1999;3:349-61.
78Dikici B, Bosnak M, Bosnak V, Dagli A, Davutoglu M, Yagici RV, et al . Comparison of treatment of chronic hepatitis B in children with lamivudine and alpha-interferon combination and alpha-interpheron alone. Pediatr Int 2002;44:517-21.
79 Marcellin P, Chang TT, Lim SG, Sievert W, Tong M, Jain A, et al . Adefovir dipixovil (ADV) 10 mg for the treatment of patient with HBeAg(+) chronic hepatitis B: continued efficacy beyond 48 weeks. Hepatology 2002;36:373A.
80Gilson RJ, Chopra KB, Newell AM, Murray-Lyon IM, Nelson MR, Rice SJ, et al . A placebo controlled phase I/II study of adefovir dipixovil in patients with chronic hepatitis B virus infection. J Viral Hepatol 1999;6:387-95.
81Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al . Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology 2003;38:1419-27.
82Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al . A one year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998;339:61-8.
83Niesters HG, de Man RA, Pas SD, Fries E, Osterhaus AD. Identification of a new variant in the YMDD motif of the hepatitis B virus polymerase gene selected during lamivudine therapy. J Med Microbiol 2002;51:695-9.
84Papatheodoridis GV, Hadziyannis SJ. Diagnosis and management of pre-core mutant chronic heapatitis. J Vir Heapat 2001;8:311-21.
85Moraleda G, Saputelli J, Aldrich CE, Averret D, Condreay L, Mason WS. Lack of effect of antiviral therapy in non-dividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus. J Virol 1997;71:9392-9.
86Liaw YF, Leung NW, Chang TT, Guan R, Tai Di, Chien RN, et al . Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroentrology 2000;119:172-81.
87Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, et al . On behalf of the Asia Hepatitis Lamivudine Study Group. Extented lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: Results after 3 years of therapy. Hepatology 2001;33:1527-33.
88Zoulim F. Assessing hepatitis B virus resistance in vitro and molecular mechanisms of nucleoside resistance. Semin Liver Dis 2001;22:23-31.
89Chayama K, Szuki Y, Kobayashi M, Kobayashi M, Tsubota A, Hashimoto M, et al . Emergence and takeover of YMDD motif mutant hepatitis B virus during long term and re-takeover by wild type after cessation of therapy. Hepatology 1998;27:1711-6.
90Honkoop P, de Man RA, Heijtink RA, Schalm SW. Hepatitis B reactivation after lamivudine. Lancet 1995;346:1156-7.
91Kreutz C. Molecular, immunological and clinical properties of mutated hepatitis B viruses. J Cell Mol Med 2002;6:113-43.
92Niesters HG, Honkoop P, Haagsama EB, de Man RA, Schalm SW, Osterhaus AD. Identification of more than one mutation in the hepatitis B virus polymerase gene arising during prolonged lamivudine treatment. J Infect Dis 1998;177:1382-5.
93Ogata N, Fuji K, Takigawa S, Nomoto M, Ichida T, Asakura H. Novel patterns of amino-acid mutations In the hepatitis B virus polymerase in association with resistance to lamivudine therapy in Japanese patients with chronic hepatitis B. J Med Virol 1999;59:270-6.
94Ohishi W, Chayama K. Rare quasispecies in the YMDD motif of hepatitis B virus detected by polymerase chain reaction with peptide nucleic acid clamping. Intervirology 2003;46:355-61.