Despite the availability of safe and highly effective vaccines, Hepatitis B virus (HBV) infection is still a global health problem. Even in the United States, where universal infant and childhood immunization has been implemented, there are still new cases each year. These occur primarily in identifiable high-risk groups, such as intravenous drug users and homosexual men, and in communities with large numbers of immigrants from parts of the world where HBV is still highly endemic, such as the Far East, and large parts of Africa. It is in this population that most new childhood infections are found, either in the immigrant children themselves, children born to immigrant women who are infected, or children who acquire HBV by horizontal transmission within these households or enclaves.
The number of children with acute HBV infection, as detected by the Sentinel Counties Study of the Centers for Disease Control, decreased from the first to the second study period, 1982-1988 to 1994-1998 (13.8 and 3.3 cases per 100,000 population, respectively). The incidence of HBV infection in the 10-19 year age group declined by 72.5 % (1). However, these are reports of acute infection and do not include children who were infected perinatally, the largest group of new pediatric infections. Infants and children who become infected with HBV present challenges distinct from those of adults, because the likelihood of chronic HBV infection in children is inversely proportional to the age of acquisition. Chronic infection develops in 90% of infants vertically infected, 25-50% in children infected between ages 1 to 5 years and 6-10% of older children.
NATURAL HISTORY AND CLINICAL FEATURES
Chronic HBV infection in infants often begins with an immune tolerant phase, with high HBV DNA levels and HBeAg in serum for years, into late childhood, adolescence or even into adulthood. Alanine aminotransferase (ALT) levels are usually normal during this phase, with minimal liver disease (2). The presence of hepatitis B e antigen (HBeAg) is typical of this phase, and HBV DNA levels are usually high, indicating active viral replication. Spontaneous HBeAg seroconversion rates in these children are low, occurring in fewer than 2% per year in children less than 3, and 4-5% in children greater than 3 years (3). Children infected after the perinatal period have higher rates of HBeAg seroconversion. Longitudinal studies of children with predominantly horizontally acquired, HBeAg positive, infection in Italy and Spain demonstrated 70-80% seroconversion of HBeAg to anti-HBe over 1-20 years (4,5).
Most children with chronic infection are clinically well and grow and develop normally. Chronic HBV infection is most often asymptomatic or rarely associated with fatigue and vague right upper quadrant abdominal pain. Generally, symptoms of chronic HBV infection in children are not apparent unless complications develop. In some children, the only or presenting sign is nephrotic syndrome, because of membranous glomerulonephritis (6-8). This extrahepatic manifestation of chronic HBV often responds to antiviral treatment.
Hepatocellular carcinoma (HCC) is a recognized sequel of chronic infection with HBV. HCC in children with HBV infection has been reported in both Asian (9,10) and Western (11,12) populations. Children infected with HBV who develop HCC seem to have undergone rapid progression from hepatitis to cirrhosis (11,13). Fortunately, vaccination has had a major positive impact on the incidence of childhood HCC, as demonstrated in Taiwan. The average annual incidence of HCC in children aged 6 to 9 years declined from 0.7 per 100,000 children between 1981 and 1986, to 0.57 in the period 1986-1990 and declined even further to 0.36 between 1990 and 1994 (14).
Inflammatory changes are often mild in liver biopsies from children with chronic hepatitis B. However, fibrosis may be significant. In a recent study of 76 children with chronic HBeAg-positive HBV and elevated ALT (age 1-19 years, mean 9.8 years), at least half had moderate to severe fibrosis, with 35% having either bridging fibrosis with lobular distortion or cirrhosis (15).
It has become apparent that some children with chronic HBV infection require treatment to prevent serious sequelae, such as cirrhosis and HCC, in young adult life. Management of children with chronic HBV infection involves education and counseling, surveillance for HCC and antiviral therapies in some cases. Children with HBV should be allowed to participate in all regular activities of childhood. There is no need to exclude infected children from regular school and sports participation (16). HBV-infected children should receive Hepatitis A vaccine. Household contacts should receive HBV immunization and be tested to ensure vaccine efficacy. They should be counseled not to share items that may be contaminated with blood and to carefully dispose of such items. Adolescents need to be informed of the risks of transmission of HBV by sexual activity and needle sharing. General principles of management and monitoring are outlined in Table 1.
The goals of antiviral therapy in chronic HBV infection include cessation or decrease in viral replication, normalization of aminotransferases and liver histopathology and prevention of cirrhosis and HCC. Neither of the medications currently licensed in the United States fulfils these goals for all children. For this reason, appropriate patient selection is critical so that children who are most likely to benefit from therapy are identified. Children selected for treatment should have evidence of chronic HBV infection, that is, detectable serum HBsAg for at least 6 months, and HBeAg and/or HBV DNA (in case of HBeAg negative HBV infection). In addition, children most likely to respond to treatment are those with consistently abnormal ALT values. Before starting treatment, a liver biopsy is useful to establish the extent and stage of liver disease, and to rule out any other potential disease processes. Rates of spontaneous seroconversion must be considered in making a decision regarding whom and when to treat.
Interferon-alfa (INF-α) has been used in children with chronic HBV for about 10 years. Success rates of INF-α treatment in children have varied significantly in different regions of the world. Response rates have been highest in western countries, where treatment with INF-α results in loss of HBV DNA or HBeAg seroconversion in 20-58% compared with 8-17% in untreated controls. In contrast, only 3-17% of children treated with INF-α in Asian countries clear HBV DNA or seroconvert from HBeAg to anti-HBe. However, if aminotransferases are elevated, there may be no difference in response rates between children born in Asian countries (22%) and those from Europe and North America (26%) (17). Children most likely to respond to INF α-2b, regardless of ethnicity, are of younger age with elevated aminotransferases and low HBV DNA levels. A large multinational randomized controlled trial of INF-α was performed in 144 children with chronic HBeAg positive infection and ALT greater than twice the upper limit of normal (17). Treated patients received INF-α, 6 megaunits (MU) per square meter of body surface area, thrice weekly for 24 weeks. Serum HBeAg and HBV DNA became negative in 26% of treated children in comparison to 11% of untreated controls. In addition, 10% of treated children lost HBsAg in comparison to 1% of controls.
Variables that have been examined for association with response to INF-α are listed in Table 2. A recent study indicated that INF treatment might be more effective in eliciting both HBeAg and HBsAg loss in children less than 5 years of age (18). Studies including high dose INF-α (10 mMU/m2) or prednisone priming of standard doses of INF-α have not improved response rates and are not routinely recommended (19,20).
Side effects of INF-α in children include the flulike symptoms of fever, myalgia, headache, arthralgia and anorexia. Neutropenia may occur in up to 39% of children during treatment, sometimes requiring dose adjustments. Discontinuation of the medication for side effects is rare (21). Children have weight loss as do adults, but may also have decreased growth velocity during treatment. These side effects are reversible, resolving at least 6 months after treatment is complete (22). Mood disturbances may be significant, and younger children may have personality changes, irritability and temper tantrums (17,21).
Contraindications to INF-α in children are similar to those in adults and include decompensated cirrhosis, pregnancy, underlying autoimmune disorder, organ transplant or serious neuropsychiatric disease. INF-α is currently recommended for children aged 2 years and over with consistently abnormal ALT values, at 6 MU/m2 thrice weekly for 24 weeks. HBeAg seroconversion may occur during or up to 12 months after the completion of therapy. ALT flares during treatment do not mandate cessation of therapy if there are no signs of decompensation; these flares often herald impending seroconversion. There is a small but reproducible rate of HBsAg seroconversion after successful INF-α therapy that is rarely seen in untreated children.
Lamivudine is an oral nucleoside analog that is approved in the United States for treatment of childhood HBV. In 2002, a multicenter randomized, double blind, placebo-controlled 52-week trial was reported (23). All children had been HBsAg positive for at least 6 months, were positive for HBeAg, had detectable HBV DNA in serum, ALT greater than 1.3 times the upper limit of normal but less than 500 IU/L and evidence of inflammation on liver biopsy. Children received lamivudine 3 mg/kg (100 mg maximum) or placebo daily. Clearance of HBeAg and HBV DNA at 52 weeks occurred in 23% of treated children in comparison to 13% of controls (23). In children whose baseline ALT was at least twice normal, this response rate increased to 35%. Subsequently, open label lamivudine given to nonresponders showed a cumulative 3-year virologic response (loss of HBeAg and undetectable HBV DNA) rate of 35%. HBsAg loss occurred in 3% of patients. HBeAg seroconversion from the first year was durable in 88% of patients at 36 months (24). Factors associated with likelihood of virologic response to lamivudine in children are shown in Table 2.
The necessary duration of treatment with lamivudine seems to be at least 1 year, and the medication should be continued for at least 6 months after documentation of HBeAg seroconversion. Treatment for longer than 1 year has been associated with a risk of resistance (25,26). Lamivudine resistance by development of the YMDD mutant was evident in 19% of children treated for 1 year, and only 1 of these patients subsequently lost HBeAg (23). Continuation of lamivudine once resistance is noticed is controversial. It has been recommended that lamivudine be continued whereas HBV DNA remains suppressed, but discontinued in the child who has virologic breakthrough and no serious underlying liver disease. Children in whom lamivudine is discontinued should be closely monitored for several months for post-treatment "flares" of hepatitis that may be quite severe.
Lamivudine is safe for children with hepatitis B, and it is well tolerated. Serious side effects were not reported after 3 years of continuous treatment (24). In comparison to treatment with INF-α, decreased height velocity and weight loss were not observed.
Combination therapy with INF-α and lamivudine has been reported in 2 studies of Turkish children (27,28). These studies compared combination with monotherapy and response rates using different schedules of combination therapy. Neither study documented improved long-term virologic response compared with that achieved with INF-α monotherapy.
The Food and Drug Administration (FDA) has approved 2 additional nucleotide/nucleoside analogs and peginterferon α-2a for the treatment of chronic HBV in adults. These medications seem to induce less viral resistance than lamivudine. Other medications are either being used off-label or are in various stages of development at this time.
Adefovir dipivoxil is an oral nucleotide analog that inhibits both HBV reverse transcriptase and DNA polymerase activity. It has been shown to be effective in suppressing both wild-type HBV and its lamivudine-resistant mutants (29,30). Adefovir dipivoxil, taken for 48 weeks, results in improvement in histology, HBeAg loss (12%), normalization of ALT, and reduction of HBV DNA in adults (29). In comparison to lamivudine, adefovir dipivoxil seems to induce significantly less viral resistance, with a frequency of approximately 3% at 3 years, and no cross-resistance between the 2 medications (31). A multicenter, randomized, placebo-controlled trial of adefovir dipivoxil is currently being conducted in children 2-17 years of age with chronic HBV.
Entecavir, an oral guanosine nucleoside analog, inhibits HBV polymerase at 3 different steps. Phase 3 trials in adults have shown HBV DNA suppression and histologic improvement in nucleoside naive HBeAg positive or HBeAg negative patients, and patients who were lamivudine nonresponders. There is, however, some cross-resistance between lamivudine and entecavir. The FDA recently licensed entecavir for the treatment of chronic HBV infection in adults. There are no data available regarding its use in children.
Peginterferon α-2a was recently approved by the FDA for the treatment of HBeAg-positive and HBeAg-negative HBV infection in adults. Several multicenter studies have documented greater frequency of virologic and histologic responses 24 weeks after a 48-week course of either peginterferon monotherapy or combination therapy with lamivudine when compared with lamivudine alone. There was no benefit over peginterferon monotherapy with the addition of lamivudine (32,33). These studies again showed a measurable rate of HBsAg loss (7%) with peginterferon therapy. There are as yet no data available regarding the use of peginterferon for chronic HBV infection in children.
To date, there have been 8 genotypes (A-H) and 2 subtypes (Aa/Ae and Ba/Bj) of HBV identified. Genotype has been clearly linked with the propensity to HBeAg seroconversion, downregulation of HBeAg expression and response to antiviral therapy (34). Analyses from Asia have shown that genotype B has a higher rate of spontaneous HBeAg seroconversion than genotype C (35), and a greater likelihood of response to INF-α (36,37). No difference was seen between genotypes B and C in response to lamivudine (38,39) or adefovir dipivoxil (40) treatment. Studies from Europe have shown that genotype A responds better than genotype D to INF-α (41). This rapidly accumulating knowledge of HBV genotype differences may soon be used to tailor treatment decisions.
At this time, there are no recommendations regarding the best treatment of children with coinfections, such as hepatitis C or human immunodeficiency virus, because these coinfections are rare in pediatric patients.
Optimal treatment for children with chronic HBV should be individualized, depending on clinical and histologic status, comorbid conditions, ability to take medications, contraindications and family concerns. The goal of treatment should be suppression of HBV DNA and durable HBeAg seroconversion, indicating cessation of active viral replication, to prevent the long-term consequences of inflammation and fibrosis, which include cirrhosis and HCC. Appropriate patient selection and understanding of the strengths and limitations of each of the therapeutic options are key to successful treatment.
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