CME (July 2007)
Monthly Self-Study Series

Management of Chronic Hepatitis B in Children - Part 1

Dr. HUNG Hiu Gong
Specialist in Gastroenterology & Hepatology
MBChB(CUHK), PDipID(HK), MRCP(UK), FHKCP, FHKAM(Medicine)

Introduction

Chronic Hepatitis B (HBV) represents a significant global public health problem. It is estimated that roughly 2 billion people across the world infected with HBV and about 400 million people worldwide are chronic HBV carriers [1]. In Asia (including Hong Kong and Southern China), chronic HBV has a prevalence that ranges from 5-20%, and is among the leading causes of death in those regions. Vertical transmission represents the typical means of infection and generally dictates the worldwide prevalence of chronic HBV infection. Most newborns infected with HBV are unable to clear the infection, where more than 95% of adults with acute infection successfully to do so [2]. Those born with chronic HBV infections have a 15% to 30% lifetime risk of developing complications like hepatitis decompensation, cirrhosis and/or hepatocellular carcinoma (HCC), which ultimately leads to premature death [3-4]. Although vaccination program for HBV have significantly decreased the prevalence of chronic hepatitis B in the infant and adolescents in high endemic area [5], a significant pools of children still needs management and care because of inadequate vaccination policies such as new immigrants, infected before the implementation of vaccination program and the small number of patients that infected despite HBV vaccination.

In this literature review, current concepts about the hepatitis B virus and its interaction with the host immunity, including its natural history will be presented. The efficacy of HBV vaccination, its long term immunogenicity and the public health impact of universal vaccination program will be reviewed. Finally the controversy in treatment of the ¡§immune tolerant patient¡¨ will be discussed.

The Hepatitis B Virus, its life cycle and the host immunity

Hepatitis B virus:

Hepatitis B virus is a prototypic member of the Hepadnaviridae family. HBV has a narrow host range, causing natural infection in man and chimpanzees only. HBV virions are double shelled particles, 40-42 nm in diameter. The virus consists of a capsid surrounded by an envelope (Figure 1).

The lipoprotein envelope contains 3 related forms of surface antigen (pre-S1, Pre-S2 and S). The capsid consists of an assembly of virally encoded core (C) protein encasing the viral nuclei acid and its associated polymerase (P) protein. [6]

Figure 1: Genomes of HBV, adapted from Lee WM. N England J Med 1997; 337:1733-45.

The viral life cycle

The viral replication cycle are schematized in Figure 2. Blood borne virion circulating through the liver attach to the basolateral membranes through specific viral¡Vhost interactions. Pre-S1 protein on the envelope is believed to mediate viral attachment to as yet uncharacterized cellular membrane proteins. Once attached, the virus fuses with membrane protein in a slow temperature dependent reaction. Upon cellular entry, viral core is transported from the cytoplasm towards or into the nucleus while the DNA within the capsid undergoes maturation. The partially double stranded relaxed circular genome in the capsid is converted into a covalently closed; fully double stranded circular DNA (ccc DNA). The maturation of the genome is not dependent on any viral products but requires host machinery to remove covalently bound protein and RNA primers and complete double stranded synthesis. The ccc DNA amplifies viral infection, as it is the template for pregenomic RNA production. It also severs as the template for production of all the RNA species for the production of functional and structural viral protein.

Viral assembly is a complex multi-step reaction in which specific interactions between pregenomic RNA, P protein, host chaperonins and viral core proteins result in capsid formation. Once encapsidation occurs, the pregenomic RNA undergoes reverse transcription with P protein. Reverse transcription occurs within the capsid, which can recycle to the nucleus or bud into the endoplasmic reticulum to acquire the glycoprotein envelope. Enveloped virions are secreted through the constitutive pathway of vascular transport.

Figure 2: The replication cycle of HBV. Adapted from Ganem et al. NEJM 2004:350:1118-1129

Host immunity and HBV infection Individuals who are immunized against recombinant HbsAg prior to exposure to virus develop humoralimmunity, which is largely protective against HBV infection. Universal immunization programs demonstrate success in preventing infection in newborns born to viremic mothers [7]. In the absence of host defense, HBV replication in the liver is not cytotoxic and non cytopathic. Evidence for this includes many HBV carriers are asymptomatic and have minimal liver injury despite extensive and ongoing viral replications [8]. Numerous experiments indicate that the quality of the host immune response dictates clearance versus persistence. Comparisons of cytotoxic T lymphocyte (CTL) responses in patients who clear primary HBV infection to those that don¡¦t demonstrate differences in vigor and breadth of reaction to viral targets [9-10]. Key aspects of the cell-mediated immune response are described and schematized in Figure 3 of Ganem¡¦s paper [6]. In summary, CTL mediated injury is primarily mediated through virus specific CD8+ cells, which are, class I MHC restricted. Besides causing injury, these cells elaborate cytokines, which help neighboring cells to reduce production of viral products. These cytokines act as paracrine non cytopathic mediators to cure hepatocytes of virus. The locally delivered tumor necrosis factor-alpha and interferon¡Vgamma act as major intracellular effectors of the antiviral response after CTL administration. However, how hest cytokines cure hepatocytes of virus is still unclear and need further studies in the future.

Figure 3: Cellular immune response to HBV, adapted from Ganem et al. NEJM 2004:350:1118-1129

Natural history of HBV infection An understanding of the natural history of HBV infection is essential for the proper management of the infection in children. According to literature, three phase of chronic HBV infection have been characterized: the immune tolerance phase, immune clearance phase and the inactive phase [11]. Figure 4 depicts the phases of chronic HBV infection.

Figure 4: Natural course of chronic HBV infection

In the immune tolerant phase, patients have persistent HBV infection without an immune reaction, which is characterized by presence of HbsAg, positive HbeAg antigen and high serum HBV DNA levels (>10^5 copies/ml) but persistently normal ALT levels and minimal histological activity, which implies that there is lack or weak immune response against the infected hepatocytes. The classical immune tolerant patient is a young (<30 years) Asian patient with perinatally acquired HBV infection. According to a Taiwan study, by the age of 15, 85% of babies infected before the implementation of universal vaccination program were still positive for HbsAg and HbeAg antigen [12]. However, it should be noted that tolerance is not permanent as longitudinal follow up studies clearly showed that elevated ALT and acute exacerbations of chronic hepatitis B can be observed in the immune tolerant patient indicating that immune tolerance is a reversible state during the course of chronic HBV infection [13].

During the course of HBV infection, for unknown reasons, patient may enter the second immune clearance phase, which is reflected by high serum HBV DNA levels, elevated ALT levels and increased histological activity, reflecting the host immune mediated lysis of infected hepatocytes. The degree of ALT elevation typically correlates with liver disease activity. Patients in this phase may have either HbeAg positive or negative chronic hepatitis B. For those infected vertically, this phase is characterized by frequent fl are up of hepatitis resulted in worsening of liver disease. Prospective studies from Taiwan and Hong Kong showed that those infected vertically, a prolonged immunoclearance phase was observed [14-15]. Seroconversion from HbeAg to anti-Hbe occurs spontaneously in 50-70% of patients with elevated ALT levels and marks the end of the immune clearance phase and the beginning of the inactive HbeAg carrier state. The transition to inactivity is typically accompanied by ALT normalization and serum HBV DNA <10^4 copies/ml. The inactive carrier state may last for lifetime, but a proportion of patients may undergo subsequent spontaneous reactivation with raise of ALT levels and reappearance of high levels of HBV DNA with or without HbeAg seroconversion [11].

During the natural course of HBV infection, those born with chronic HBV infections have a 15% to 30% lifetime risk of developing complications like hepatitis decompensation, cirrhosis and/or hepatocellular carcinoma (HCC), which ultimately leads to premature death [3-4]. Individuals with chronic HBV infection also face an increased risk of developing HCC, especially if they have developed cirrhosis [16]. A recent Taiwan study by Chen et al showed that the risk of HCC increases as serum HBV DNA levels increased [17]. So, in conclusion, although HBV infection is a relatively benign disease in children, but complications still occur in adult life. Thus form the rationale for prevention and treatment.

Self-Assessment Questions
(Please indicate true or false to the following questions.)

  1. In Asia, chronic HBV has a prevalence that ranges from 5-20% and is among the leading causes of death in those regions.

  2. Hepatitis B virus is a RNA virus.

  3. The natural history of HBV infection can be divided into 3 phases: immune tolerance, immune clearance and inactive carrier.

  4. In the immune tolerance phase, HBV replication in the liver is not cytotoxic and non cytopathic.

  5. In the immune tolerance phase, patients have high ALT levels and low DNA levels.

  6. In the immune clearance phase, patients have high ALT levels and high DNA levels.

  7. The inactive carrier state will last for life without reactivation.

  8. The risk of HCC increases as serum HBV DNA levels increased.

  9. The life time risk of serious complications like cirrhosis and HCC in a HBV infected patient is around 15-30%.

  10. The cccDNA is the template for viral messenger RNA transcription.

References:

  1. Lee WM. Hepatitis B virus infection. N England J Med 1997; 337:1733-45.

  2. CDC. Incidence of acute hepatitis B-United States, 1990-2002. MMWR.2004; 52:1252-1254.

  3. Realdi G, Fattovich G, Hadziyannis S, et al. Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicentre study. J Hepatol. 1994; 21:656-666.

  4. De Jongh FE, Janseen HL, de Man RA et al. Survival and prognostic indicators in hepatitis B surface antigen positive cirrhosis of the liver. Gastroenterology 1992; 103: 1630-1635.

  5. Chang MH, Chen CJ, Lai MS et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N England J Med 1997; 336:1855-1859.

  6. Don Ganem and Alfred M. Hepatitis B virus infection-Natural History and Clinical Consequences. N England J Med 2004; 350:1118-1129.

  7. Lee CF, Gong Yan, Jesper Brok et al. Effect of hepatitis B immunization in newborn infants of mothers positive for hepatitis B surface antigen: systemic review and meta-analysis. BMJ 2006; 332:328-336.

  8. De Franchis R, Meucci G, Vecchi M, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med 1993; 118:191-194.

  9. Maini MK, Boni C, Lee CK et al. The role of virus specific CD8+ cells in viral control and liver damage during persistent hepatitis B infection. J Exp Med 2000; 191:1269-1280.

  10. Thimme R, Wieland S, Steiger C et al. CD8 (+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B infection. J Virol 2003; 77(1): 68-76.

  11. Lok AS, Heathcote, EJ, Hoofnagle JH. Management of hepatitis B 2000-summary of a workshop. Gastroenterology 2001; 120:1828-1853.

  12. Chang MH. Natural history of hepatitis B virus infection in children. J Gastroenterol Hepatol 2000; 15: E 16-19.

  13. Lok AS, Lai CL. Acute exacerbations in Chinese patients with chronic HBV infection. J Hepatol 1990; 10:29-34.

  14. Liaw YF, Tai DI, Chu CM et al. The development of cirrhosis in patients with chronic hepatitis B: a prospective study. Hepatology 1988; 8:493-496.

  15. Yuen MF, Lai CL. Natural history of chronic hepatitis B virus infection. J Gastroenterol Hepatol 2000; 15:E20-24.

  16. Lok AS, McMahon B. Chronic Hepatitis B: Update of recommendations. Hepatology. 2004; 39:857-861.

  17. Chen CJ, Yang HI, Su J et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006 Jan 4,295(1):65-73.