Burden of chronic hepatitis B (CHB)
Worldwide more than 350 million people are chronically infected with hepatitis B virus (HBV) and at increased risk of death from cirrhosis of the liver and hepatocellular carcinoma (HCC) .
Chronic hepatitis B is characterized by elevated serum aminotransferase (ALT) levels, high or fluctuating levels of serum HBV-DNA and active liver disease on biopsy . Persistently elevated serum HBV-DNA levels are associated with increased long-term risk of cirrhosis, HCC and liver failure [3–5].
Persons with CHB may have hepatitis B e antigen (HBeAg) or antibodies to HBeAg (anti-HBe) in their sera. HBeAg seroconversion is associated with clearance of HBeAg from serum and with the appearance of anti-HBe. In persons who are HBeAg-positive, spontaneous HBeAg seroconversion can occur, often accompanied by a transient elevation in ALT levels. After HBeAg seroconversion, most persons have persistently normal ALT levels and suppressed levels of HBV-DNA, usually <103 copies/mL. However, almost 20% of patients have active liver disease following spontaneous HBeAg-seroconversion, due to the development of mutations in the precore stop codon or core promoter region. HBeAg-negative, anti-HBe-positive type CHB is now recognized as an important and increasingly prevalent form of CHB, often associated with certain HBV genotypes (B, C and D but not A or G) . More than 95% of HBV infections in Asia-Pacific countries are HBV genotypes B or C, explaining the high prevalence of HBeAg-negative CHB in this region.
Chronic hepatitis B remains an important public health problem in Singapore. Although the incidence of HBV infection is decreasing, as a result of the compulsory vaccination of babies born to infected mothers, nevertheless, between 160 000 and 230 000 Singaporeans were chronically infected as of 2001 . The annual healthcare costs for the year 2003 of managing CHB, compensated cirrhosis (CC), decompensated cirrhosis (DCC) and HCC, were estimated by Li et al., 2004 . Direct healthcare costs were classified in terms of outpatient consultations, inpatient admissions, antiviral drug treatment, other medications, laboratory tests, imaging and procedures. Lost income and lost productivity from illness will be additional indirect costs of CHB for the population. The annual cost of treatment increases dramatically as the disease progresses from CC to DCC or HCC respectively (Fig. 1).
Asian-Pacific guidelines for the management of CHB
The Asia-Pacific consensus guidelines (2005)  on the management of CHB state: ‘… sustained viral suppression is the key to the reduction or prevention of hepatic injury and disease progression. Therefore, the primary goal of treatment for CHB is to eliminate or permanently suppress HBV. The ultimate long-term goal of therapy is to prevent hepatic decompensation, to reduce or prevent progression to cirrhosis and/or HCC, and to prolong survival’.
Current treatment options
Conventional interferon-α has been used in the treatment of CHB for many years. Treatment is administered by subcutaneous injection, at a dosage of 5–10 MU three times a week for 4–6 months. Predictors of a nonresponse to interferon-α include Asian ethnicity, childhood infection, HBeAg-negative CHB, high serum HBV-DNA levels and low serum ALT levels .
Pegylated interferon α-2a is administered by subcutaneous injection (180 μg) once-weekly for 48 weeks. Although pegylated interferon has more antiviral efficacy than conventional interferon, the side-effect profile appears to be similar for both formulations .
For most patients with CHB, sustained viral suppression is only attainable through long-term nucleos(t)ide analogue therapy, as short-course therapies (4–12 months) only achieve sustained responses in a minority of patients .
The disadvantage of long-term antiviral monotherapy is the emergence of virological breakthrough secondary to the selection of drug resistant mutants . If resistance develops in patients with compensated liver disease, an alternative antiviral drug should be used to control the disease. The patient can either have a second drug added or can be switched to another drug with the option of a 1- or 2-month overlap. If resistance emerges in patients with advanced liver disease, a second drug should be added to continued ongoing therapy with the first drug .
Lamivudine was the first nucleoside analogue to be licensed by the FDA for use in the chronic treatment of HBV infection in 1998. It is well tolerated and results in HBV suppression, ALT normalization and reduction of hepatic inflammation, although resistant strains emerge when lamivudine is used long term .
Adefovir dipivoxil is a new CHB antiviral treatment option that is well tolerated and long-term therapy results in incremental increase in rate of viral suppression below the level of detection, ALT normalization and histological improvement. In comparison with lamivudine, resistance to adefovir is delayed and less frequent .
Mechanisms of resistance to lamivudine and adefovir have distinct structural differences, and mutations conferring cross-resistance to both drugs have not been reported .
Economic evaluation of CHB treatments
A new treatment is usually regarded as cost-effective when it provides improved outcomes at an acceptable increased cost. Cost-utility is a form of cost-effectiveness analysis that involves the estimation of incremental cost per quality adjusted life year (QALY). QALYs take into consideration quality of life as well as quantity of life . The ‘Q’ in QALY is a utility weight with values from 0 to 1. Death has a utility value of 0 and perfect health has a utility value of 1. Cost per QALY potentially allows for comparison between the cost-effectiveness of treatments in different disease areas with very different clinical outcome measures. This can facilitate healthcare resource allocation decisions .
The decision rule that payers apply to judging whether a new healthcare intervention is cost-effective is often not stated explicitly. However, US health economists generally agree that if an intervention can save 1 year of life for less than US$ 50 000, it is cost-effective. Moreover, the UK National Institute for Clinical Excellence recently stated that the cost-effectiveness threshold is between £20 000 and £30 000 (approximately US$ 36 000–54 000) . As US$ 1 = approximately S$ 1.6, therefore a cost-effective threshold of $50 000 is equivalent to approximately S$ 80 000 in Singapore. However, adjusting for differences in purchasing power parity (PPP) based Gross National Income (GNI) per capita (2001) provides a cost-effectiveness threshold in Singapore of approximately S$ 53 000 ($80 000 × US$ 22 850/US$ 34 280) .
The purpose of this study was to establish the economic evaluation of short-duration treatments of CHB and long-duration antiviral treatments for up to 5 years. The context for the economic evaluation was the Singapore healthcare system and the healthcare needs of the CHB patient, in which only direct costs were included. As a result, indirect costs, such as lost productivity, from time off work due to illness or premature death were excluded.