TREATMENT OF PEDIATRIC CHRONIC HEPATITIS B AND HEPATITS C

hepatitis B

hepatitis C

VIRAL HEPATITIS

Chronic hepatitis B may lead ultimately to cirrhosis and liver cancer. Eradication of viral replication (HBe antigen) is likely to stop the evolution of the liver damage, although some HBe Ag negative patients may reactivate the inflammatory process with viral replication ( pre-core mutants). The healthy carrier state is therefore no more to be considered as a guarantee to future complete recovery ⁽⁴⁵⁾.

Iinterferon alpha, given at a dosage of 5 megaunits per square meter body surface area, three times weekly for six months, interferon increased the rate of loss of the HBe ag from 11 to 28% at one year and 33% at 18 months in a large multicenter trial . HBs Ag loss reached 10% after one year of treatment versus 1% in controls and histology improved.⁽⁴⁶⁾. A similar response rate had been found previously in other national trials ^47,48. Low viral DNA, young age and female sex are indicative of favourable response. Ethnic origin, contrarily to previous suggestions, does not influence the response rate. Controversies remain upon the prognostic value of basal transaminases.

Nucleoside analogues are emerging as alternative treatments, in particular Lamivudine : this drugs is able to inhibit completely viral replication to undetectable levels within four weeks of treatment in more than 90% of the patients ⁽⁴⁹⁾. Pharmakokinetic studies have already been performed in children and a multicenter efficacy trial showed that 23 % of children after one year had virological response (HBe Ag & HBV DNA neg ), versu 13% of controls. In patients with basal transaminases > 2 x ULN, response reached 34% versus 16% in controls (Sokal &al; EASL Prague 2001). In adults treated with a daily dosis of 100 mg, the HBe Ag to antibody seroconversion , after 52 weeks of therapy reached 16% , while serum HBV DNA decreased by 98%. Transaminases normalized in 72% of the patients and progression to fibrosis was reduced ⁵⁰. The main question with nucleoside analogues remains to determine how long the patients should be kept under treatment, since systematic relapse of viral replication post treatment is observed in patients who have not reached HBe AG-AB seroconversion. Parents should therefore be clearly aware that prolonged treatment for several years will probably be necessary , at least as long as HBV DNA remains negative without seroconversion. In case of positive DNA under treatment, a YMDD mutant virus should be suspected. Emergence of Lamivudine YMDD mutants is observed in 19% of pediatric patients after one year (Sokal& al; EASL Prague 2001), resulting in disease reactivation( ^49,50) . There is so far no evidence that the YMDD mutant causes more severe liver disease ^{(50), and it is not clear whether treatment should be continued or stopped in presence of a YMDD mutant in a child.}

Adefovir is currently being investigated in children. Long tyerm efficacy study is running.

Hepatitis C treatment with interferon alone remains controversed , and long term response -i.e. normalization of serum transaminases and negative serum HCV RNA- in children as in adults have been disappointing, reaching at maximum 15 to 25%. Combined interferon and Ribavirin treatment are currently being used in adults, but the latter drug is so far not released for children ^(51,52). This combination may be most useful in patients with high levels of viremia, but may not help patients who previously did not respond to interferon. Prolonged treatments with higher dosages of interferon may achieve better results ^(52,53). Although there is no sufficient evidence of efficacy to recommend systematic treatment of children , treatment remains an option particularly in children with low levels of viremia (<10 ^{to the 5} viral copies /ml). Genotype 1 B is by far the most common, and is less favourable for response than genotypes 2 or 3. Most children have absence of fibrosis on liver biopsy, and a relatively short disease evolution, both criteria being favourable for response in adults. Early normalisation of transaminases and negativation of HCV RNA during treatment (within two months) are predictive of favourable response and should encourage to prolong treatment up to one year. On the contrary, lack of such result after three months means non response and treatment should be interrupted ^(53,54). Treatment is not recommended before two years of age, and up to 12% of children infected perinatally may spontaneously clear the virus during this period ⁽⁵⁵⁾.
Additional benefits may be obtained by the use of pegylated interferon : Tolerance is improved better, with a unique weekly injection. Results in adults have recently been published (Table).

BENEFITS of PEGYLATED INTERFERON VERSUS INTERFERON

BENEFITS OF PEGYLATED INTERFERON+RIBAVIRIN ACCORDING TO GENOTYPES

FRIED & al .

Tolerance of interferon is poor in children, and may be improved by the use of PEG interferon. In children with chronic hepatitis B, interferon was shown to impair growth velocity during treatment , with catch up growth after treatment discontinuation. . Combination of Peg interferon and Ribavirin in pediatric pilot studies brings a 61% sustained virological response. An international trial is currently running in St Luc using pegylated intereron and Ribavirin to compare response in pediatric age group with adults. The hypothesis is that children will response probably better than adults in view of the favourable response criteria in this age group.

.............................. Ref Wirth & al

Finally, recent studies using Peg alpha 2a+ Riba show that sustained repsonse rate is identical ina dults with normal or elevated transaminase, with a 52 % response for all genotypes and a 40% respons ein genotype I (Zeuzem, AASLD 2003). In genotype III a sustained 72% response rate is obtained after 24 w of treatment.

recent references

Interferon & Ribavirin in oncologic patients: Interferon-alpha and ribavirin in treating children and young adults with chronic hepatitis C after malignancy.
Hepatitis B & C: review :Update on prevention and treatment of viral hepatitis in children
Hepatitis C : review : Transmission, natural history, and treatment of hepatitis C virus infection in the pediatric population
Wirth & al Hepatology. 2002 Nov;36(5):1280-4 ; Use of interferon + Riba in children