Real prospects for antiviral therapy of chronic hepatitis B (CHB) only started to surface in the 1980s. One earlier agent, the nucleoside analog adenine arabinoside monophosphate,1 had unacceptable neuromyotoxicity. Interferon (IFN) has direct actions on viral replication and indirect actions via immune modulation.2 In the mid-1980s, IFN became the first approved therapy for CHB.3,4 The emergence of human immunodeficiency virus (HIV) infection facilitated the search for effective and safe antiviral agents. Lamivudine, famiclovir and fialuridine were three promising candidates for the treatment of CHB. After clinical assessment, lamivudine was shown to have significant clinical efficacy and a good safety profile.5,6 In 1998, the US Food and Drug Administration registered lamivudine for CHB therapy, another therapeutic milestone. Unfortunately, famiclovir lacks potency and fialuridine causes fatal mitochondrial toxicity, so that clinical trials of these two drugs were abandoned.7,8
Much has been learnt about the virology of hepatitis B virus (HBV) and the natural history of CHB. Hepatitis B e antigen (HBeAg) can be used as a serological marker of active viral replication (see Liaw, this issue of the Journal). Hepatitis B e antigen loss, or seroconversion to anti-HBe, is still being used as the end-point of antiviral therapy, but assay of serum HBV-DNA levels improves the assessment of therapeutic potency. Solution hybridization and signal amplification assays have a lower detection limit of 105−106 virus equivalents/mL, but quantitative polymerase chain reaction (PCR) assays (especially real-time PCR) refine the detection limit down to 100 copies/mL. Accurate measurements of viral levels in the blood have revealed important information on viral dynamics during therapy: the rate of suppression and, more importantly, the rate of elimination of templates for viral replication (cccDNA) in the hepatocytes tend to correlate with better outcomes. The target serum HBV-DNA level may be 104−105 virus equivalents/mL which, in most instances, means that the therapy should be able to reduce serum HBV-DNA by 4–5 log units.
Another revelation from HBV molecular biology is the discovery of HBeAg-negative, anti-HBe-positive CHB.9 Wild-type HBV sometimes undergoes point mutations in CHB patients. The natural history of these ‘precore’ and core promoter HBV mutants is not entirely clear but, at present, therapy is similar to that for wild-type infections and assessment of efficacy data is under close investigation.
Asian people are estimated to account for 75% of the 400 million individuals with chronic HBV infection worldwide.10 In Asian people, HBV is mostly acquired at birth by vertical transmission from CHB mothers or in infancy by close physical contact. In early life, immune tolerance to HBV is the rule, with normal serum alanine aminotransferase (ALT) levels, despite high HBV-DNA levels. Then follows an immunoreactive phase, with fluctuating viral levels and periodic or persistent elevation of serum ALT levels. Up to three-quarters of Asian CHB patients undergo spontaneous HBeAg seroconversion. This is followed by disease quiescence and a good prognosis. The remaining one-quarter of patients have a protracted immune clearance process, eventually resulting in cirrhosis. Without treatment, they will often succumb to complications of cirrhosis or hepatocellular carcinoma. Adults who acquire CHB are more common among non-Asian patients, the routes of infection being parenteral or sexual. They tend to have active liver disease.
Consideration of therapy for CHB must take into account the different stages of liver disease, the intensity of disease activity and genetic variability of the virus and host. Thus, the treatment plan will vary according to the different immune phase and to the viral load, the presence or absence of compensated cirrhosis, acute presentation with liver failure and the prospect of liver transplantation for decompensated cases. Coinfection with hepatitis C virus, hepatitis delta virus and/or HIV may be common in certain high-risk groups; this requires tailored therapy. Few data are available on the management of patients with extrahepatic HBV-related problems, including glomerulonephritis. Patients with CHB who are immunocompromised, for example, those undergoing chemotherapy or organ transplantation, comprise another important subgroup that needs separate management guidelines.
At the beginning of the 21st century, how can we manage our CHB patients in order to benefit most from the recent advances? Are the guidelines likely to be relevant and affordable to all CHB patients in the Asia–Pacific region?