Long‐term lamivudine treatment of children with chronic hepatitis B: durability of therapeutic responses and safety

Abstract

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 3 years of treatment for CHB. One hundred and fiftyone 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 2 years and those who were HBeAg negative were observed for additional 2 years. 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 3 years, 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 52 weeks and at least 2 years 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 3 years of lamivudine treatment is safe in children.

Treatment of special populations with chronic hepatitis B infection

“…Studies using conventional IFN-a have demonstrated increases in the rate of HBsAg and HBeAg loss, but most of the children suffered from adverse events, such as hair loss and changes in personality [101]. LAM was safe when given to children and induced HBeAg loss in almost a fifth of them, but continuous treatment resulted in the development of tyrosine-methionineaspartate-aspartate (YMDD) mutants (19-24% after 1 year, 49-59% after 2 years and 64% after 3 years of treatment) [102]. However, 82% and >90% of the children who lost HBeAg and were treated with LAM for 52 weeks and for at least 2 years consequently, remained HBeAg -for at least 2 years after treatment cessation [102].…”

“…LAM was safe when given to children and induced HBeAg loss in almost a fifth of them, but continuous treatment resulted in the development of tyrosine-methionineaspartate-aspartate (YMDD) mutants (19-24% after 1 year, 49-59% after 2 years and 64% after 3 years of treatment) [102]. However, 82% and >90% of the children who lost HBeAg and were treated with LAM for 52 weeks and for at least 2 years consequently, remained HBeAg -for at least 2 years after treatment cessation [102]. Moreover, adefovir given for 48 weeks to children 2-17 years of age had similarly good results, which were better in the group of children older than 12 years [103].…”

Long-term prognosis of chronic hepatitis B virus infection in the childhood

“…In the study of Kuloğlu et al (21), it was stated that treatment with lamivudine for a mean period of 18 months would be sufficient. Jonas et al (22) showed that lamivudine could be used safely up to three years. Genetic study directed to lamivudine resistance was not performed in any of the patients who did not give response to lamivudine treatment.…”

Phase I, Open-Label, Single-Dose Study To Evaluate the Pharmacokinetics and Safety of Telbivudine in Children and Adolescents with Chronic Hepatitis B

“…This treatment, however, has significant side effects, including flu-like symptoms, neutropenia, nausea, and psychiatric effects. Use of nucleoside and nucleotide analogues, while effective in viral suppression, is associated with development of viral resistance and return of detectable HBV over time (3,(5)(6)(7).…”

“…This treatment, however, has significant side effects, including flu-like symptoms, neutropenia, nausea, and psychiatric effects. Use of nucleoside and nucleotide analogues, while effective in viral suppression, is associated with development of viral resistance and return of detectable HBV over time (3,(5)(6)(7).Telbivudine (LDT600, Sebivo, Tyzeka) is the unmodified Lenantiomer of the naturally occurring nucleoside thymidine and has been approved for the treatment of chronic HBV infection in adults. In the phase III GLOBE study of 1,370 patients Ն16 years of age, treatment with telbivudine (600 mg/day) for 52 weeks resulted in undetectable serum HBV DNA levels in 60% of HBeAgpositive and 88.3% of HBeAg-negative patients; lamivudine (100 mg/day) treatment achieved the same response in 40.4% and 71.4% of each group, respectively (8).…”