andimblitar: in my mind: GANCICLOVIR TREATMENT FOR NEONATAL HEPATITIS CYTOMEGALOVIRUS

The necessity of treatment in neonatal Cytomegalovirus (CMV) hepatitis is still controversial, as spontaneous recovery in most cases unless severe systemic disease occurs.^{1 2} However, an increasing number of studies indicate the necessity of treatment, especially in cases with symptoms of acute or chronic cholestatic hepatitis or proven histopathological findings.^2-4

Currently, there are four antivirals available that are active agains CMV: ganciclovir, valganciclovir, foscarnet and cidofofir. At this time, none have approved indication for use in children.⁵ Although ganciclovir treatment reported to be effective in CMV in adults, there is insufficient research in children.^6-8

Ganciclovir, a synthetic acyclic nucleotide analog of guanine, is phosphorilated to a triphosphate within the cell and act as an inhibitor of viral DNA synthesis.^{7 9} Ganciclovir is a nucleoside analogue of guanosine, a homologue of acyclovir, and the first antiviral drug to be effective in the treatment of CMV diseases in humans.^{6 7 9 10}

Ganciclovir cause bone marrow suppression, teratogen and carcinogen, associated with gonad atrophy and decreased spermatogenesis. Although there are limited data regarding the dose, pharmacokinetics, safety, and adverse events, ganciclovir have been the best studied in the infant.

The intravenous administration of ganciclovir (5 mg/kg in one hour) results in a peak serum concentration 8.3 µg/mL. The plasma half life is 2.9 hours, and the systemic clearance rate is 3.6 ml/kg/minute. Twelve hours after infusion, the serum concentration is below 0.5 µg/mL. A typical regimen of 7.5 to 10 mg/kg/day of ganciclovir given intravenously in two divided doses results in a peak serum concentration were 0.7 µg/mL when a simultaneous measured serum concentration was 2.2 µg/ml, 3.5 hours after intravenous administration of a dose 2.5 mg/kg. The fraction of the dose that enter the cerebrospinal fluid is not know.⁶

Children with non-cholestatic type would not relapse or become chronic liver diseases and showed a decrease GGT, SGOT, SGPT and bilirubin levels after 1 year of observation.^{4 11} Ganciclovir clinically proven reduce jaundice and hepatosplenomegaly after two weeks of treatment and absent in second months in both babies.

The efficacy of this treatment is controversial.¹ All of the patients (100%) in the non-cholestatic hepatitis group and three of four cases (75%) in the cholestatic hepatitis group treated with ganciclovir had recovery from acute CMV hepatitis. This result suggested that ganciclovir could be effective in the acute phase of severe and persistent CMV hepatitis whether associated with cholestasis or not.⁴

Ten papers were included in meta analysis showed that the ganciclovir therapy increased the improvement rate (91.4% vs 34.0%; p<0.01) and led CMV infection indexes to become negative in more patients (87.6% vs 15.3%; p<0.01) and decreased incidence of hearing disturbance (4.7% vs 37.2%; p<0.01) as compared with the non-ganciclovir therapy control group.¹²

Until the certain indication of ganciclovir treatment for neonatal CMV hepatitis is well defined, every patient should be evaluate individually and treatment should be given to those with progressive disease who did not response to supportive treatment. Multicenter randomized investigations in a large study group are necessary to determine the indication for ganciclovir treatment for neonatal CMV hepatitis.

REFERENCES

1. Vancikova Z, Kucerova T, Pelikan L, Zikmundova L, Priglova M. Perinatal cytomegalovirus hepatitis: to treat or not to treat with ganciclovir. J Paediatr Child Health 2004;40(8):444-8.

2. Rosenthal P. Neonatal hepatitis and congenital infection. In: Suchy F, Sokol R, Balistreri, editors. Liver diseases in children. 13th ed. Canbrige: Canbrige University Press, 2007:232-46.

3. Fernandez-Ruiz M, Munoz-Codoceo C, Lopez-Medrano F, Fare-Garcia R, Carbonell-Porras A, Garfia-Castillo C, et al. Cytomegalovirus myopericarditis and hepatitis in an immunocompetent adult: successful treatment with oral valganciclovir. Intern Med 2008;47(22):1963-6.

4. Tezer H, Secmeer G, Kara A, Ceyhan M, Cengiz AB, Devrim I, et al. Cytomegalovirus hepatitis and ganciclovir treatment in immunocompetent children. Turk J Pediatr 2008;50(3):228-34.

5. Marshall BC, Koch WC. Antivirals for cytomegalovirus infection in neonates and infants: focus on pharmacokinetics, formulations, dosing, and adverse events. Paediatr Drugs 2009;11(5):309-21.

6. Crumpacker CS. Ganciclovir. N Engl J Med 1996;335(10):721-9.

7. Leung AK, Sauve RS, Davies HD. BARU Congenital cytomegalovirus infection. J Natl Med Assoc 2003;95(3):213-8.

8. Ozkan TB, Mistik R, Dikici B, Nazlioglu HO. Antiviral therapy in neonatal cholestatic cytomegalovirus hepatitis. BMC Gastroenterol 2007;7:9.

9. Stehel E, Sanchez P. Cytomegalovirus infection in fetus and neonate. NeoReview 2005;6(1):38-45.

10. Revello MG, Gerna G. Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant. Clin Microbiol Rev 2002;15(4):680-715.

11. Nigro G, Scholz H, Bartmann U. Ganciclovir therapy for symptomatic congenital cytomegalovirus infection in infants: a two-regimen experience. J Pediatr 1994;124(2):318-22.