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See article on page 715
Advances in the understanding of hepatitis B viral infection are a major accomplishment in modern hepatology. In three decades we have progressed from rather vague clinical concepts to a remarkably complete virology of hepatitis B virus (HBV), primary prevention with recombinant vaccines, and some effective antiviral treatments. This progress is especially important for children because it provides hope for preventing severe HBV associated liver disease. It is already evident that the best way to deal with hepatitis B infection is to avoid it altogether. The effectiveness of neonatal active with passive vaccination in preventing vertical transmission of HBV infection is on the order of 90–95%. Studies from Taiwan show that universal immunisation leads to reduced prevalence of HBV infection and a significantly lower incidence of hepatocellular carcinoma (HCC) in childhood.1
What about children who already have chronic HBV infection? Treatment with interferon α is effective in approximately one-third, where success denotes that active viral replication has ceased, HBeAg (hepatitis B e antigen) to anti-HBe (antibody to HBeAg) seroconversion has taken place, and serum HBV DNA is undetectable by hybridisation techniques. In a large randomised controlled paediatric clinical trial,2 18 of 70 (26%) children had HBeAg seroconversion during the 24 weeks of treatment or within 24 weeks of stopping treatment. Over the same 48 weeks, eight of 74 untreated control patients had spontaneous HBeAg seroconversion. An additional five children in the original treatment group had seroconversion 49–72 weeks after starting treatment: thus the overall response rate was 35%. There were no late spontaneous responses in the control group but the numbers were very small due to trial design. Drug induced and spontaneous HBeAg seroconversion were equally durable.
Interferon α treatment has limitations. It is most effective if commenced when serum alanine aminotransferase (ALT) levels have been consistently elevated to at least twice normal for several months, indicating that the host immune response against HBV is active but proving ineffective. Many younger children do not meet this treatment criterion. Treatment for children usually lasts for 24 weeks and may have unpleasant side effects. In children they are similar to those in adults, including transient “flu-like” syndrome, anorexia with weight loss, neutropenia, and hair loss.3 In teens it may be difficult to differentiate typical adolescent moodiness from interferon induced affective disorders; school work may deteriorate temporarily. Febrile seizures can be problematic and require stopping treatment. Interferon induced diabetes mellitus has been found rarely in adults4 but it has not been reported in children. Pulmonary fibrosis and respiratory problems reported in adults receiving very large doses of interferon α have not been identified in children.
Given the difficulties of the treatment, its only moderate success rate, and the limited definition of success, it is reasonable to ask whether this treatment is worth the trouble, especially for children. The analysis reported by Bortolotti and colleagues (see page 715) suggests that the major effect of interferon α treatment may be only to speed up a natural history which would take place anyway. Thus the natural history of chronic hepatitis B in childhood is critical to assessing the value of this treatment. A small study from Italy predating interferon α treatment in children highlights the issue somewhat differently.5 Thirty six children with chronic hepatitis B diagnosed aged 1–9 years (mean 4.3) were followed for 10–18 years (mean 12.6). Initially most were HBeAg positive; four were anti-HBe positive and six had neither marker. At the end of follow up, all patients were spontaneously anti-HBe positive. Follow up liver biopsies showed that six had cirrhosis (progressing from severe chronic active hepatitis in four), 11 had fibrosis, three had moderately severe chronic active hepatitis, and seven had chronic persistent hepatitis. Recurrent, ineffective immune mediated assaults on HBV probably lead to chronic liver damage and cirrhosis; using a drug therapy to effect HBeAg seroconversion and viral inactivation earlymay therefore be beneficial.
Although natural history studies have indicated that lack of ongoing HBV replication is associated with improved outcome,6whether treatment induced HBeAg seroconversion (indicating the end of extensive viral replication) confers an improved prognosis should be confirmed. Using HBeAg seroconversion as the primary end point for successful treatment seems to be a compromise: what the patient really wants is to get rid of the HBV infection entirely. Data from several large clinical trials of interferon α treatment for adults with chronic hepatitis B are now available. The results are mixed. In a German study of 103 patients treated compared with 53 untreated patients, both overall survival and survival without development of hepatic complications were significantly greater in patients who became negative for HBeAg after treatment; adverse outcomes in treated patients occurred only in non-responders.7 A study of male patients (17–55 years) from Taiwan suggested that successful treatment with interferon α conferred long term benefit based on approximately 10 years of follow up.8 The cumulative survival rate was significantly higher in the treated group. HCC occurred in only one treated patient who had reverted to being positive for HBeAg and in four untreated patients who remained HBeAg positive.
Other studies reserve judgment on the long term outcome in adults. In a review of several randomised controlled trials in Europe, 58 of 210 treated patients (28%) responded to interferon α with loss of HBV DNA and HBeAg and improved serum ALT and all but 14% remained the same at the end of follow up (approximately five years); 22 of 98 untreated controls (22%) responded spontaneously and all but 9% maintained this response. In these patients cirrhosis and/or HCC developed in both treated and untreated patients, with no discernible difference between the two groups. The authors could not establish a beneficial long term effect from treatment induced HBeAg seroconversion on the basis of these data.9 Another study from southern Italy showed that individuals with chronic hepatitis B had a higher mortality rate than the general population and that young patients without cirrhosis whose ALT normalised over prolonged follow up had the best prognosis. In this large but heterogeneous cohort, interferon α treatment appeared beneficial but the authors could not conclude that it prolonged survival, mainly because of the study's design limitations.10 Thus data from adult studies are not really conclusive, even though they point toward long term benefit. Whether these data can be translated to the paediatric age group may also be questioned.
An important picture emerges from both short term and long term studies: the rate of HBsAg to anti-HBs seroconversion may be enhanced by interferon α treatment. The original report that 13 of 20 (65%) adult patients with sustained responses to interferon α eventually lost HBsAg, expressed anti-HBs, and became HBV DNA negative by PCR seemed optimistic.11 A separate report supported these findings: 23% of successfully treated adults cleared HBsAg compared with 10% of untreated patients with spontaneous response.12 In the Düsseldorf study, 19% of patients with a sustained response cleared HBsAg compared with none of the untreated controls. The five year probability of HBsAg loss was 11.6% after successful treatment.7 In the combined European trials, 34% of those with a sustained response after treatment compared with 20% of untreated patients with a spontaneous response lost HBsAg.9 HBsAg seroconversion occurred even if cirrhosis was present. In a large study of adults with chronic hepatitis B and cirrhosis the five year probability of HBsAg loss was 16% in those successfully treated and only 4% in untreated cirrhotic patients.13 On a cautionary note, there may be ethnic or racial variation: studies from the Orient reported no loss of HBsAg over prolonged follow up.8 14
This observation extends to children with chronic hepatitis B. In the randomised controlled trial already discussed, loss of HBsAg was observed within the time constraints of the study: seven of 70 treated children (or 39% of sustained responders to treatment) compared with one of 74 untreated children (or 12% of spontaneous responders) lost HBsAg.2 In an untreated group of children with chronic hepatitis B followed over approximately 13 years, eight of 117 (7%) lost HBsAg spontaneously.15 Indeed, enhanced rates of clearance of HBsAg in children responding to interferon α were also found in the paediatric cohorts reported here. HBV clearance may be a treatment outcome surpassing the natural history of chronic hepatitis B.
In summary, interferon α can be used successfully to treat selected children over two years old who have chronic hepatitis B. Children with moderately elevated serum ALT and comparatively low viral load are most likely to respond with HBeAg seroconversion. These are the same children most likely to experience spontaneous HBeAg seroconversion. Further observations are still needed to determine whether artificially speeding up the natural history of chronic hepatitis B is worthwhile. It is possible that the development of cirrhosis—and consequently HCC—will be avoided. Moreover, successful treatment may lead to complete loss of HBV infection, a highly desirable outcome.
See article on page 715