Viral Hepatitis B: Management in Children

Abstract

The natural history of chronic hepatitis B virus (HBV) infection in children varies with age at infection, acquisition, ethnicity, and endemic region. Around the world, most chronic hepatitis B virus (HBV) infection is transmitted perinatally or during early childhood. The risk of chronic infection when acquired in infancy is 90% versus 30% when acquired during the first 5 years of life and <5% in older childhood and adulthood (McMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP, Maynard JE. J Infect Dis 151:599–603, 1985). Loss of hepatitis B e antigen (HBeAg) or seroconversion to anti-HBe can occur spontaneously, and the annual rate differs by age (<2% in children <3 years, 4–5% after age 3), with higher rates during puberty (Chang MH, Sung JL, Lee CY, Chen CJ, Chen JS, Hsu HY et al. J Pediatr 115(3):385–390, 1989; Liaw YF, Chu CM, Lin DY, Sheen IS, Yang CY, Huang MJ. J Med Virol 13(4):385–391, 1984). Children from non-endemic areas are less likely to have been perinatally infected and will often undergo HBeAg seroconversion in the first two to three decades of life (Bortolotti F, Cadrobbi P, Crivellaro C, Guido M, Rugge M, Noventa F et al. Gastroenterology 99:805–810, 1990).

With cessation of active HBV replication, serum alanine aminotransferase (ALT) is normalized, HBeAg is lost with or without development of anti-HBe, and there is improvement in liver histology. Due to persistence of covalently closed circular DNA (cccDNA), the transcriptional template of HBV, in the nucleus of hepatocytes, patients who have undergone HBeAg seroconversion cannot be considered “cured” (Moraleda G, Saptuelli J, Aldrich CE, Averett D, Condreay L, Mason WS. J Virol 71:9392–9399, 1997; Wong DK, Seto WK, Fung J, Ip P, Huang FY, Lai CL et al. Clin Gastroenterol Hepatol 11:1004–1010.el, 2013). These patients are at lifelong risk for reactivation of infection. If patients lose the hepatitis B surface antigen (HBsAg), typically with persistent HBV DNA suppression, this is considered to be an “immunological cure.” This is true whether seroconversion occurs spontaneously or as a result of treatment.

The most serious sequelae of chronic hepatitis B (CHB), cirrhosis and hepatocellular carcinoma (HCC), are not commonly seen during childhood and adolescence. In a study of 292 consecutive HBsAg positive children with elevated ALT levels, 10 patients (3%) had cirrhosis (Bortolotti F, Calzia R, Cadrobbi P, Giacchini R, Ciravegna B, Armigliato M. J Pediatr 108:224–227, 1986). In adults, HCC is thought to be related to the HBV DNA levels, degree of liver injury, and duration of infection. HCC can occur in children who have had HBeAg seroconversion, indicating that risk of HCC may continue even after viral replication is ceased (Livingston SE, Simonetti JP, McMahon BJ, Bulkow LR, Hurlburt KJ, Homan CE et al. J Infect Dis 195:5–11, 2007). Nonetheless, the goal of treatment of HBV in childhood is to decrease the morbidity and mortality of CHB later in life by using the surrogate endpoints of HBeAg seroconversion and ALT normalization.