Long-Term Lamivudine Treatment of Children With Chronic Hepatitis B
Long-Term Lamivudine Treatment of Children With Chronic Hepatitis B
Lamivudine has been demonstrated safe and efficacious in the short term in a large cohort of children with chronic hepatitis B (CHB), but optimal duration of treatment has not been elucidated and limited data on the safety of long-term lamivudine administration have been reported. In addition, the durability of favourable therapeutic outcomes after lamivudine therapy in children has not been well characterized. The aim of this study was to examine the safety of lamivudine and the durability of clinical responses in a group of children who received up to 3years of treatment for CHB. One hundred and fifty-one children from centres in nine countries who had previously received lamivudine in a large prospective trial were enrolled. During the first year, children had been randomized to either lamivudine or placebo treatment. Subsequently, in a separate extension study, those who remained hepatitis B e antigen (HBeAg) positive were given lamivudine for up to 2years and those who were HBeAg negative were observed for additional 2years. Results of these studies have been previously reported. In this study, these children were followed for 2 additional years. Data gathered from medical record review included weight, height, signs and symptoms of hepatitis, alanine aminotransferase (ALT) levels, serologic markers, hepatitis B virus (HBV) DNA levels and serious adverse events (SAEs). Other pharmacological treatments for CHB were allowed according to the practices of individual investigators and were documented. Subjects were divided into two groups for analysis, those who had achieved virological response (VR), defined as HBeAg negative and undetectable HBV DNA by the bDNA assay by the end of the extension study at 3years, and those who had not. In those who had achieved VR by the end of the extension study, long-term durability of HBeAg seroconversion was 82% and >90% in those who had received lamivudine for 52weeks and at least 2years respectively. This compares to 75% for those who had achieved seroconversion after placebo. In those who had not achieved VR by the end of the extension study, an additional 11% did so by the end of the study; they had all received lamivudine in the previous trial, and none had received further treatment during the study. Eight children lost hepatitis B surface antigen during the study and all had received lamivudine at some point during the previous trials. Evaluation of safety data revealed no SAEs related to lamivudine. There was no effect of treatment on weight or height z scores. Clinically benign ALT flares (>10 times normal) were seen in 2% of children. Favourable outcomes from lamivudine treatment of CHB in children are maintained for at least several years after completion of treatment. Up to 3years of lamivudine treatment is safe in children.
Despite the availability of a safe and highly effective vaccine, hepatitis B virus (HBV) infection remains a global health problem. Even in countries where infant and childhood immunization is recommended, there are still new cases each year. These cases occur in high-risk subgroups, such as i.v. drug users and homosexual men, as well as in communities with large numbers of immigrants from areas of the world where HBV is still highly endemic. It is in this latter group 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.
Chronic hepatitis B (CHB) in children is most often asymptomatic and most children with the infection are clinically well and develop normally. A small number have significant liver disease during childhood or adolescence. However, serious complications such as cirrhosis or hepatocellular carcinoma (HCC) later in life may be expected in approximately 25% of individuals who acquired infection during infancy or childhood. For this reason, treatment of CHB infection is indicated in some children.
The safety and efficacy of lamivudine for 1year in children 2years of age or older has been established. In addition, further serologic and virologic responses (VR), such as hepatitis B e antigen (HBeAg) seroconversion and undetectable HBV DNA levels, have been reported in children on long-term therapy with 2 additional years of treatment. Lamivudine-associated responses have shown durability comparable with those observed in subjects who underwent spontaneous seroconversion during placebo treatment. This study was undertaken to obtain additional clinical information on children who had undergone extended lamivudine therapy in previous studies. In particular, this study was designed to collect information on the natural history of CHB in children during and following lamivudine therapy, as well as relevant long-term safety data in this group.
Summary and Introduction
Summary
Lamivudine has been demonstrated safe and efficacious in the short term in a large cohort of children with chronic hepatitis B (CHB), but optimal duration of treatment has not been elucidated and limited data on the safety of long-term lamivudine administration have been reported. In addition, the durability of favourable therapeutic outcomes after lamivudine therapy in children has not been well characterized. The aim of this study was to examine the safety of lamivudine and the durability of clinical responses in a group of children who received up to 3years of treatment for CHB. One hundred and fifty-one children from centres in nine countries who had previously received lamivudine in a large prospective trial were enrolled. During the first year, children had been randomized to either lamivudine or placebo treatment. Subsequently, in a separate extension study, those who remained hepatitis B e antigen (HBeAg) positive were given lamivudine for up to 2years and those who were HBeAg negative were observed for additional 2years. Results of these studies have been previously reported. In this study, these children were followed for 2 additional years. Data gathered from medical record review included weight, height, signs and symptoms of hepatitis, alanine aminotransferase (ALT) levels, serologic markers, hepatitis B virus (HBV) DNA levels and serious adverse events (SAEs). Other pharmacological treatments for CHB were allowed according to the practices of individual investigators and were documented. Subjects were divided into two groups for analysis, those who had achieved virological response (VR), defined as HBeAg negative and undetectable HBV DNA by the bDNA assay by the end of the extension study at 3years, and those who had not. In those who had achieved VR by the end of the extension study, long-term durability of HBeAg seroconversion was 82% and >90% in those who had received lamivudine for 52weeks and at least 2years respectively. This compares to 75% for those who had achieved seroconversion after placebo. In those who had not achieved VR by the end of the extension study, an additional 11% did so by the end of the study; they had all received lamivudine in the previous trial, and none had received further treatment during the study. Eight children lost hepatitis B surface antigen during the study and all had received lamivudine at some point during the previous trials. Evaluation of safety data revealed no SAEs related to lamivudine. There was no effect of treatment on weight or height z scores. Clinically benign ALT flares (>10 times normal) were seen in 2% of children. Favourable outcomes from lamivudine treatment of CHB in children are maintained for at least several years after completion of treatment. Up to 3years of lamivudine treatment is safe in children.
Introduction
Despite the availability of a safe and highly effective vaccine, hepatitis B virus (HBV) infection remains a global health problem. Even in countries where infant and childhood immunization is recommended, there are still new cases each year. These cases occur in high-risk subgroups, such as i.v. drug users and homosexual men, as well as in communities with large numbers of immigrants from areas of the world where HBV is still highly endemic. It is in this latter group 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.
Chronic hepatitis B (CHB) in children is most often asymptomatic and most children with the infection are clinically well and develop normally. A small number have significant liver disease during childhood or adolescence. However, serious complications such as cirrhosis or hepatocellular carcinoma (HCC) later in life may be expected in approximately 25% of individuals who acquired infection during infancy or childhood. For this reason, treatment of CHB infection is indicated in some children.
The safety and efficacy of lamivudine for 1year in children 2years of age or older has been established. In addition, further serologic and virologic responses (VR), such as hepatitis B e antigen (HBeAg) seroconversion and undetectable HBV DNA levels, have been reported in children on long-term therapy with 2 additional years of treatment. Lamivudine-associated responses have shown durability comparable with those observed in subjects who underwent spontaneous seroconversion during placebo treatment. This study was undertaken to obtain additional clinical information on children who had undergone extended lamivudine therapy in previous studies. In particular, this study was designed to collect information on the natural history of CHB in children during and following lamivudine therapy, as well as relevant long-term safety data in this group.
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