Actually, interferon (IFN)-α is the first line in the treatment of chronic hepatitis B in children, but a sustained virological response is obtained in only in 40% to 45% of cases. At the end of the 1990s, a new drug, lamivudine, a negative isomer of the racemic mixture of 2-deoxy-3-thiacytidine, was shown to be a powerful inhibitor of hepatitis B virus reproduction both in wild-type chronic hepatitis and in the precore mutant form in randomized studies in Europe, North America, and Asia. The aim of this review is to show the efficacy and tolerance of lamivudine, alone or in combination with IFN-α, in children affected by chronic hepatitis B. This review shows that treatment with lamivudine led to significant improvement in the seroconversion rate of hepatitis Be antigen in children with chronic hepatitis B, but long-term therapy resulted in a high rate of lamivudine-resistant YMDD. In addition, combination therapy (lamivudine plus IFN-α) or consecutive combined therapy (induction with lamivudine alone before IFN-α) does not seem to improve HBe seroconversion. Other studies are needed to evaluate the efficacy and tolerance of other drugs such as adefovir dipivolxil and entecavir, actually used with a good efficacy in adults, in children affected by chronic hepatitis B.
Department of Pediatric, Hospital of Sondrio, Sondrio, Italy.
Address correspondence and reprint requests to Emilio Palumbo, MD, Via Dell' Arcangelo Michele 4, 71100 Foggia, Italy. E-mail: firstname.lastname@example.org.
Despite the use of hepatitis B virus (HBV) vaccine, chronic HBV infection occurs in approximately 5% of the global population. This infection, if persistent, may lead to chronic hepatitis, cirrhosis, and hepatocellular carcinoma in 25% to 40% of infected patients and is among the 10 principal causes of death throughout the world. In endemic areas such as a lot of countries in Asia and Africa, where the hepatitis B surface antigen (HBsAg) carrier rate is as high as 15% to 20%, hepatitis B is primarily a childhood disease acquired either perinatally from HBsAg-positive mothers or horizontally from infected mates or family members.1,2 In areas of intermediate endemicity such as the Mediterranean area, where 2% to 10% of the population are HBsAg carriers, infection occurs in both adults and children. In low-endemicity areas such as Northern European countries and the United States, infection in infancy and childhood is uncommon, and less than 1% of the population has chronic HBV infection. After acute infection, the probability of becoming a chronic HBV carrier is correlated to the age at infection and the efficiency of the immune system, being highest in children infected within the first year of life who tend to become immunotolerant to the virus. Thus, more than 90% of infected infants become chronic carriers as compared with 6% to 10% if the infection occurs after the sixth year of life.3-5 Chronically, HBV-infected children, particularly boys, have a high risk of progressing to cirrhosis and hepatocellular carcinoma, the likelihood of developing these complications being correlated to the length of time to achieve anti-HBe seroconversion.6-12 Spontaneous hepatitis Be antigen (HBeAg) loss in chronically infected children occurs at an annual rate of 10% to 16%, especially in Western countries, whereas spontaneous loss of HBsAg is as low as 0.6% per year, the children achieving earlier seroconversion being those with biochemical and/or histological evidence of active disease.13,14 A treatment able to speed up anti-HBe seroconversion would therefore have a major impact in avoiding the spread of infection and serious complications. Until recently, the only generally approved treatment for chronic hepatitis B in children was interferon (IFN)-α, but it has demonstrated moderate efficacy in sustained response (biochemical, virological, and histological). Hepatitis Be antigen seroconversion is achieved in approximately 40% of affected children depending on the dose and duration of therapy with IFN.15-18 At the end of the 1990s, a new drug, lamivudine, a negative isomer of the racemic mixture of 2-deoxy-3-thiacytidine, was shown to be a powerful inhibitor of HBV reproduction both in wild-type chronic hepatitis and in the precore mutant form in randomized studies in Europe, North America, and Asia. The aim of this review is to show the efficacy and tolerance of lamivudine, alone or in combination with IFN-α, in children affected by chronic hepatitis B. For this review, relevant literature was identified through searches of MEDLINE (2002 to July 2006). Search terms included, but were not limited to, lamivudine, alpha-interferon, chronic hepatitis B, HBV, therapeutic use, and sustained virological response.
In a recent study, Choe et al19 have compared the long-term therapeutic response to lamivudine with IFN-α in children with chronic hepatitis B. A total of 40 children with chronic hepatitis B who received lamivudine for at least 12 months were followed for a mean period of 39 months. Their treatment efficacy was compared with that of 19 children who had been treated with IFN-α and were followed fora mean period of 39 months. Hepatitis Be antigen seroconversion occurred in 26 (65%) of the 40 children versus 7 (37%) of the 19 children 2 years after the initiation of treatment. In the lamivudine-treated group, the results for children treated before the age of 7 versus those treated after the age of 7 were as follows: HBeAg seroconversion occurred in 17 (89%) of the 19 children versus 9 (43%) of the 21 children, whereas loss of HBsAg occurred in 8 (42%) versus 0%. This study, evidencing as long-term treatment of lamivudine, led to significant improvement in the seroconversion rate of HBeAg in children with chronic hepatitis B compared with IFN-α therapy, particularly in preschool-aged children.
In another study, 22 children have been treated with lamivudine for 4 years (3 mg kg−1 d−1, up to 100 mg d−1). After 4 years on lamivudine, only 4 patients (18%) underwent HBe seroconversion, and during the 4-year study period, a continuing decline in the participants' number was recorded mostly because of lack of compliance with treatment (41%). Only 5 children were still receiving lamivudine and showing benefit after 4 years. In 2 children, treatment termination and YMDD mutant emergence were associated with hepatitis flare. These findings suggest that continuing treatment with lamivudine for undefined periods is hard to implement and does not improve HBe seroconversion.20
Yilmaz et al21 have treated 33 children with lamivudine (3 mg kg−1 d−1) and IFN-α2a (10 MU m−2, thrice weekly). Lamivudine was initiated 3 months before IFN-α for induction in 21 patients, whereas in 12 children, both drugs were started simultaneously. End-treatment response and sustained response rates were 66.7% and 50%, respectively, in patients that underwent lamivudine induction before IFN-α and in patients that began to receive the 2 drugs simultaneously. These data propose that IFN-α2a plus lamivudine combination therapy is highly successful and safe in children, but lamivudine induction before IFN does not seem to be necessary.
In a controlled study, 59 children with chronic hepatitis B were treated with 100-mg lamivudine tablets given orally once daily for 12 months. Alanine aminotransferase (ALT) normalization occurred in 79.7% of patients, and HBeAg/anti-HBe seroconversion was achieved in 27.1% of cases. The higher rate of seroconversion was connected with lower serum HBV DNA level and longer duration of HBV infection.22
Kansu et al23 evaluated the efficacy of 2 regimens of combined IFN-α2a and lamivudine therapy in childhood chronic hepatitis B. A total of 177 patients received IFN-α2a, 9 million U thrice weekly for 6 months. In group 1, lamivudine (4 mg kg−1 d−1; maximum, 100 mg) was started simultaneously with IFN-α2a, whereas in group 2, lamivudine was started 2 months before IFN-α2a. Biochemical and virological response was 55.3% and 27.6% in groups 1 and 2, respectively. Hepatitis B surface antigen clearance was 12.5% and 4.6%, and anti-HBs seroconversion was 9.8% and 6.2% in groups 1 and 2, respectively. In this trial, combination therapy yields a higher response and earlier anti-HBe seroconversion and viral clearance than consecutive combined therapy.
In another study, 276 children who participated in a 1-year randomized, placebo-controlled study of lamivudine were enrolled in a 24-month, open-label extension. Patients were stratified into 2 groups based on HBeAg status at week 48 of the previous study: 213 HBeAg-positive children were entered into a treatment arm, and 63 HBeAg-negative children were entered into an observation arm to evaluate durability of HBeAg loss. In the treatment arm, 28 of 133 (21%) children previously treated with lamivudine and 23 of 77 (30%) children who previously received placebo achieved the primary end point: virological response (HBeAg loss and HBV DNA negativity) at month 24. The incidence of YMDD mutations at month 24 was 64% (66/103) in the children previously treated with lamivudine and 49% in those previously treated with placebo. The incidence of VR at month 24 was 5% for patients with YMDD mutant HBV and 54% for patients without. The durability of response in the observation arm was 89% at month 24. In conclusion, further clinical response was seen over the 24-month open-label study period in children who had not initially achieved a virological response after 12 months of lamivudine treatment. However, the incidence of YMMD mutations increased over time and resulted in lower response rates.24
In a controlled trial, 106 children with chronic hepatitis B were administered lamivudine (3 mg kg−1 d−1, up to 100 mg d−1, for 48 weeks. Biochemical and virological responses to antiviral therapy were simultaneously observed in 38 children (36%). Hepatitis B surface antigen was not eliminated in any of them. The response was worse in patients with a high level of HBV viremia before treatment, whereas the initial level of ALT activity did not influence the final outcome of the therapy.25
Saltik-Temizel et al26 treated 20 naive children with lamivudine (4 mg kg−1 d−1; maximum, 100 mg) alone for 3 months; IFN-α (10 μ m−1; thrice weekly) was then added to lamivudine for 6 months. After IFN-α was stopped, lamivudine alone was continued for 6 months. Therapy was stopped 6 months after HBeAg seroconversion. At the end of 15 months, virological response was achieved in 55% of patients, and 60% cleared HBeAg antigen. Therapy was well tolerated. These results seem to indicate that lamivudine and high-dose IFN-α combination therapy after a 3-month lamivudine induction may represent an effective treatment option for children with chronic hepatitis B.
In another experience, 99 children with chronic hepatitis B were treated with IFN-α (3 times a week; 5 MU) and lamivudine (4 mg kg−1 d−1) orally for 6 months. End-of-therapy response was defined as ALT normalization, HBV-DNA clearance, and HBeAg seroconversion. Partial responders were defined as patients who had ALT normalization and HBV-DNA clearance but who had not had e seroconversion. Forty-five children with partial response at the end of the sixth month continued to receive lamivudine alone. Complete response was achieved in 15.6% (7/45) and 5.6% (2/36) at the end of the first and second years, and 0% (none) at the end of the third and fourth years, respectively. Breakthrough incidence was detected in 6 (13.3%) cases at 12 months and increased to 69.4% (n = 25) and 82.4% (n = 14) at the end of the second and third years, respectively. These dates seem to demonstrate that the long-term lamivudine therapy in children with partial response after combination therapy does not induce complete response and is associated with high breakthrough incidence.27
Hartman et al28 treated 20 children with chronic hepatitis B infection who had been treated with IFN 2 to 5 years earlier with lamivudine (3 mg kg−1 d−1; maximum, 100 mg d−1) for 52 weeks. At the end of 1 year, HBV DNA declined by 95% in all patients, and 44% had sustained undetectable HBV DNA by hybridization assay. One child became HBeAg-negative. YMDD mutants were detected in 11 of 17 (65%) children after 1 year of lamivudine treatment. Among children with YMDD mutant variants, 54% maintained normal ALT values, and 45% had undetectable HBV DNA by hybridization assay. No adverse effects were observed. This study shows that lamivudine treatment resulted in an exceptionally high rate of lamivudine-resistant mutants and low HBeAg seroconversion rate.
In an American trial, children with chronic hepatitis B were randomly assigned in a 2:1 ratio to receive either oral lamivudine (3 mg kg−1 d−1; maximum, 100 mg) or placebo once daily for 52 weeks. One hundred ninety-one patients were randomly assigned to receive lamivudine and 97 to receive placebo. The rate of virological response and seroconversion to anti-Hbe at week 52 was higher among children who received lamivudine than among those who received placebo (23% vs. 13%).29
This review shows that treatment with lamivudine led to significant improvement in the seroconversion rate of HBeAg in children with chronic hepatitis B, but long-term therapy resulted in a high rate of lamivudine-resistant YMDD mutants. The incidence of YMDD mutation is 30% to 40% and 50% to 60% in adult studies after 2- or 3-year duration of treatment.30 Therefore, the incidences of YMDD mutation in some studies24,27,28 are too high that lack of compliance or enrolment of preexposed children can be suspected. In addition, combination therapy (lamivudine plus IFN-α) or consecutive combined therapy (induction with lamivudine alone before IFN-α) does not seem to improve HBe seroconversion. Other studies are need to evaluate the efficacy and tolerance of other drugs such as adefovir dipivolxil and entecavir, actually used with a good efficacy in adults, in children affected by chronic hepatitis B.
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