The H epatitis B virus (H B V ) is a w ell-characterised virus that can also cause chronic liver disease. Like HCV, the virus itse lf is not directly cytopathic, liver injury appears to be a consequence o f the im m une response to HBV and there is a low rate o f spontaneous viral clearance once chronic infection is established.
HBV is as a partially double stranded DNA virus w here there is asym m etry in the length o f strands [EASL international consensus conference on H epatitis B, 2003]. There are 4 potential genes depending on the strategic placem ent o f the open reading frames. T he S gene alone or in com bination with the pre-S l and pre-S2 genes produce the surface antigen or outer protein coat, consisting o f large, m iddle and m ajor surface proteins. The C gene alone produces the nucleocapsid or core antigen that fom is the inner protein coat that interacts with HBV DNA. T he C gene in com bination w ith the pre-C gene encode for the envelope protein that once produced is excreted into the serum and undergoes renal degradation. T he P gene produces D N A polym erase-reverse transcriptase responsible for replication. T he X gene product acts as a transcriptional trans-activator o f viral and cellular prom oter elem ents such as the T N F -a gene.
1.3.7.2 C linical virology o f H B V infection
The clinical spectrum o f disease in HBV is dependent on the relative im pact o f the three distinct im m unological phases o f infection that in turn is dependent on the age o f acquisition. T he im m une tolerant phase signifies a lack o f im m unogenicity w hereby the host im m une response is quiescent, there are high circulating HBV DNA levels and near norm al histology. T he im m une clearance phase signifies im m une reactivity with
seroconversion from H B eA g, declining HBV D N A and fluctuating A LT levels. The residual phase is a non-replicative state w ith low concentrations o f HBV DNA and norm al A LT levels.
Perinatal acquisition o f H BV results in chronic infection in up to 90% , as is seen in endem ic areas such as SE A sia and sub-Saharan Africa. T he individual rem ains in the im m une tolerant phase usually until the fourth decade o f infection w hen the immune
clearance phase begins, with the onset o f significant liver injury. The duration o f this phase is highly variable. The outcom e serologically is either viral clearance w ith loss o f H BsA g or HBeAg seroconversion resulting in a chronic carrier state or a H B eA g negative chronic HBV infection due to the generation o f dom inant m utants. T his HBeAg negative chronic hepatitis is associated w ith m ore rapid histological progression, m ore treatm ent failure and a worse outcome.
In adults w ho acquire HBV the pattern o f infection differs radically. A cute infection results in viral clearance in up to 95% o f adults infected. In those chronically infected, the im mune tolerant phase is alm ost non-existent and progress to im m une clearance m ore rapid.
Typically 30% will live as chronic carriers and 70% with chronic active hepatitis. A pproxim ately 8 to 20 % o f HBeAg positive individuals will develop cirrhosis over a 5 year period. Risk factors for disease progression include severity o f fibrosis and or
necroinflam m ation at diagnosis, recurrent episodes o f severe acute exacerbations, older age and persistent viral replication. HBV is a risk factor for the developm ent o f HCC, w here the prevalence o f HCC is increased in areas o f endem ic HBV infection from 2 per 100,000 per year in the USA, N Europe and A ustralia com pared to >50 p er 100,000 per year in SE Asia and sub-Saharan.
1.3.7.3 Im m unopathogenesis o f HBV infection
In acute infection, the im mediate host defence is propagated by the non-virus-specitlc antiviral effects o f NK and NK-T cells. The virus-specific defence m echanism s include both a hum oral and cellular im mune response that is triggered both by the presentation o f the HBV antigen com plexed with the HLA antigens to the T-cell receptor and by the interaction o f the co-stim ulatory m olecules on the surface o f the A P C ’s w ith T-cell
receptors. T he humoral response directed against HBsAg is crucial to neutralise circulating HBV particles and prevent infection o f new hepatocytes. H ow ever, elim ination o f
intracellular HBV is caused by both the cytolytic activity o f class II restricted H B V -specific C TL and by the suppression o f viral gene expression and replication by soluble factors, including IFN-y and T N F -a. Peripheral blood CD4 and CDS m ediated responses to HBV antigens are stronger in acute infection than in viraem ic subjects w ith chronic infection. In these subjects, peripheral blood CD4 and CDS cells appear hypo-responsive to HBV antigen stim ulation and H B V -specific C T L 's are present in the liver but at low frequencies. In com parison, in subjects chronically infected w ith suppressed viral replication, the CTL responses in vitro appear efficient.
1.3.7.4 Im m unogenetics o f HBV infection
B ecause o f the inherent role o f the M HC is the cellular response to HBV several studies have exam ined the im m unogenetics o f this infection. In the G am bia, the largest study to
date exam ined for this association in both aduhs and children chronically infected com pared w ith those w ith resolved infection and healthy carriers [Thursz et al, 1995]. An association with H LA D R B l *1302 and resolved infection w as docum ented in children (relative risk (RR) 0.53) and confirm ed in adults (RR 0.24). T he class I antigen HLA- Cw*01 appears to be associated w ith chronic infection in children only (RR 9.82). H ow ever, the serological typing m ethods and the sm aller adult population m ay have underestim ated potential associations. T he association betw een HLA D R B l *1302 and resolved infection has also been identified in A m erican (Thio et al, 2003) and Germ an (H ohler et al, 1997) populations. An association with H LA D rl3 was docum ented in a K orean population, but typing to the allelic level was not perform ed (Ahn et al, 2000). O ther studies have associated chronic infection w ith H LA D r 9 in C hinese and Korean populations (A hn et al, 2000, M eng et al, 2003) or D Q A l *0501 in A m erican (Thio et al,
1999) and C hinese (Jiang et al, 2003) populations. Hence, the association w ith HLA D R B l *1302 appears conserved over several racial groups. F urther studies identifying this binding epitope m ay hold great potential in understanding viral elim ination and even vaccine developm ent for those w ho fail to m ount a response against current vaccines. Data on the association betw een HBV and the T N F -a gene polym orphism s are limited. To date the TN F 308.A polypm orphism has been associated w ith spontaneous resolution in a K orean population (Kim et al, 2003) and the 238.A polym orphism w'ith chronic infection in a G erm an population (H ohler et al, 1998).