Nucleot(s)ide analogues are making milestones in the treatment of chronic hepatitis B (CHB) as safe oral therapy. FDA approved lamivudine in adult patients in 1998, adefovir dipivoxil in 2002, and entecavir in March 2005. Lamivudine is effective in viral suppression, ALT normalization, and improvement in histology in both HBeAg positive and HBeAg negative / HBV DNA positive patients. HBeAg seroconversion rates correlate directly with pretreatment ALT levels at 18-30% after one year of therapy. Hepatitis flares may occur if lamivudine is stopped before HBeAg seroconversion. Lamivudine resistant YMDD mutants emerge at a rate of 15-20% per year of therapy; often associated with the rebound viraemia, relapse of hepatitis or even hepatic decompensation. Durability of response off lamivudine therapy is not satisfactory and may be dependent on duration of therapy post-seroconversion. Lamivudine is well tolerated with few serious adverse events, even in patients with decompensated cirrhosis. Long term therapy in viraemic patients with advanced fibrosis or cirrhosis delays clinical progression. Adefovir dipivoxil is an oral prodrug of adefovir. 10 mg daily is effective in suppressing both wild-type HBV and YMDD mutants, normalising ALT and improving histology. Adefovir dipivoxil has been shown to be well tolerated in longterm therapy. Renal toxicity reported in higher dosages is rarely seen except among patients with creatinine clearance less than 50 ml/min. Adefovir resistance may emerge and the overall rate is much lower than lamivudine, reaching 18% after 4 years of therapy. Adefovir-resistant mutants (rt N236T) are susceptible to lamivudine and entecavir. Little data is available for durability of response off therapy. Entecavir is an oral nucleoside analogue with a recommended dosage of 0.5 mg daily for nucleoside-naive patients, and 1 mg daily for lamivudine-refractory patients. It is a potent antiviral and may also reduced intrahepatitic cccDNA. Entecavir resistance so far has only been detected in lamivudine resistant patients in the one-year studies. Patient counseling is very important to decide on the choice among available therapeutic options. The assessment of the risks/benefits of each option should be carefully explained to individual patient.
The association of hepatitis B virus (HBV) infection and liver cancer is well documented in epidemiological study. Patients with chronic hepatitis B have increased risk of hepatocelluar carcinoma (HCC), in particular those with active liver disease and cirrhosis. The incidence of HCC increases with age and is more common among male patients. The introduction of universal HBV vaccination program for the newborn in endemic regions has started to show beneficial impact. Taiwan introduced this program two decades ago and the incidence of liver cancer among infants and young children have declined significantly. The carcinogenic events leading to HCC are under intense research. A number of hypotheses have been proposed. HBV is not directly hepatotoxic but its interaction with the host immune system creates opportunity for HBV DNA integration into the host genome. One of the main foci of research is the HBX-encoded X protein. Its integration and protein expression impose alteration in cell proliferation cycle and apoptosis process. Many other factors may be involved including viral-induced alterations in p53 and telemerase, HBV genotypes, co-infection with HCV or delta agents, patient's lifestyle such as smoking, alcohol excesses, and genetic factors of the host patient. The processes of necroinflammation, cell proliferation and fibrosis facilitate the initial carcinogenic development. HCC surveillance with tumor markers such as alpha-foetal protein, decarboxylated prothrombin, in conjunction with imaging techniques has identified early small HCC that is amenable to curative therapy. Viral load has been correlated with increase risk of HCC. The available anti-viral agents have demonstrated clinical benefit among those with maintained and sustained response. Interferon and lamivudine therapy have demonstrated reduction of HCC among responders. However, they only constitute a minority proportion of treated patients. The mainstay of prevention should lie in prevention of HBV infection and early effective therapy of chronic hepatitis B infection.
Of the estimated 50 million new cases of hepatitis B virus (HBV) infection diagnosed annually, 5-10% of adults and up to 90% of infants will become chronically infected, 75% of these in Asia where hepatitis B is the leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). In Indonesia, 4.6% of the population was positive for HBsAg in 1994 and of these, 21% were positive for HBeAg and 73% for anti-HBe; 44% and 45% of Indonesian patients with cirrhosis and HCC, respectively, were HBsAg positive. In the Philippines, there appear to be two types of age-specific HBsAg prevalence, suggesting different modes of transmission. In Thailand, 8-10% of males and 6-8% of females are HBsAg positive, with HBsAg also found in 30% of patients with cirrhosis and 50-75% of those with HCC. In Taiwan, 75-80% of patients with chronic liver disease are HBsAg positive, and HBsAg is found in 34% and 72% of patients with cirrhosis and HCC, respectively. In China, 73% of patients with chronic hepatitis and 78% and 71% of those with cirrhosis and HCC, respectively, are HBsAg positive. In Singapore, the prevalence of HBsAg has dropped since the introduction of HBV vaccination and the HBsAg seroprevalence of unvaccinated individuals over 5 years of age is 4.5%. In Malaysia, 5.24% of healthy volunteers, with a mean age of 34 years, were positive for HBsAg in 1997. In the highly endemic countries in Asia, the majority of infections are contracted postnatally or perinatally. Three phases of chronic HBV infection are recognized: phase 1 patients are HBeAg positive with high levels of virus in the serum and minimal hepatic inflammation; phase 2 patients have intermittent or continuous hepatitis of varying degrees of severity; phase 3 is the inactive phase during which viral concentrations are low and there is minimal inflammatory activity in the liver. In general, patients who clear HBeAg have a better prognosis than patients who remain HBeAg-positive for prolonged periods of time. The outcome after anti-HBe seroconversion depends on the degree of pre-existing liver damage and any subsequent HBV reactivation. Without pre-existing cirrhosis, there may be only slight fibrosis or mild chronic hepatitis, but with pre-existing cirrhosis, further complications may ensue. HBsAg-negative chronic hepatitis B is a phase of chronic HBV infection during which a mutation arises resulting in the inability of the virus to produce HBeAg. Such patients tend to have more severe liver disease and run a more rapidly progressive course. The annual probability of developing cirrhosis varies from 0.1 to 1.0% depending on the duration of HBV replication, the severity of disease and the presence of concomitant infections or drugs. The annual incidence of hepatic decompensation in HBV-related cirrhosis varies from 2 to 10% and in these patients the 5-year survival rate drops dramatically to 14-35%. The annual risk of developing HCC in patients with cirrhosis varies between 1 and 6%; the overall reported annual detection rate of HCC in surveillance studies, which included individuals with chronic hepatitis B and cirrhosis, is 0.8-4.1%. Chronic hepatitis B is not a static disease and the natural history of the disease is affected by both viral and host factors. The prognosis is poor with decompensated cirrhosis and effective treatment options are limited. Prevention of HBV infection thorough vaccination is still, therefore, the best strategy for decreasing the incidence of hepatitis B-associated cirrhosis and HCC.