Aim

The aim of this systematic review and economic evaluation was to assess the clinical effectiveness and cost-effectiveness of adefovir dipivoxil (ADV) and pegylated interferon alfa-2a (PEG) for the treatment of adults with chronic hepatitis B (CHB) infection. This independent assessment was used by the National Institute for Health and Clinical Excellence (NICE) to issue guidance to the health service in England and Wales on treatment for patients with CHB.

Epidemiology and background

Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV). Key routes of transmission include injecting drug use, sexual contact and from mother to child (particularly in South-east Asia).

Acute infection is largely asymptomatic, and is cleared by 95% of adults. Chronic disease results from an inadequate immune response to the primary infection, allowing continued viral replication and presence of the surface antigen (HBsAg). Those who develop chronic disease may remain asymptomatic for some time before developing symptoms of liver disease. Patients with CHB may be HBeAg positive or HBeAg negative, depending on the presence or absence of the e antigen.

There are approximately 156,000 people in England and Wales infected with CHB [180,000 (0.3%) in the UK], with around 7000 new cases every year (mostly from immigration of established HBV carriers). Intravenous drug use remains the single greatest risk factor for UK acquired acute HBV infection, with maternal transmission responsible for many of the chronic cases.

Methods

Electronic databases were searched from 1995-6 to April 2005 for studies of clinical effectiveness, cost-effectiveness, quality of life, resource use/costs and epidemiology/natural history. For the clinical effectiveness review, randomised controlled trials (RCTs) were included that compared PEG and ADV with currently licensed treatments for CHB, including non-pegylated ('standard') interferon alfa (IFN), lamivudine (LAM), and best supportive care. Short-term outcomes were biochemical, histological and virological response to treatment, drug resistance and adverse effects. The trials were reviewed in a narrative synthesis but meta-analysis was not undertaken owing to heterogeneity in the interventions and comparators evaluated.

A model was developed to estimate the cost-effectiveness (cost-utility) of PEG and of ADV compared with IFN, LAM and best supportive care in a UK cohort of adults with CHB. The perspective of the cost-effectiveness analysis was that of the NHS and personal social services.

A Markov state transition model was constructed, informed by a systematic search of the literature to identify source material on the natural history, epidemiology and treatment of CHB. In the state transition model, patients with CHB may remain in that state, may move on to more progressive stages of liver disease (such as cirrhosis or hepatocellular carcinoma) or may clear the disease spontaneously/move into remission. A cohort of treated and untreated patients pass through the eight disease states of the model at different rates:

• CHB
• HBeAg seroconversion/remission
• HBsAg seroconversion
• compensated cirrhosis
• decompensated cirrhosis
• hepatocellular carcinoma
• liver transplant
• death.

The model has a lifetime horizon and a cycle length of 1 year, with a half-cycle correction applied. For treated patients, clinical effectiveness results [HBeAg seroconversion rates and alanine aminotransferase (ALT) normalisation rates] were taken from the Phase II/III RCTs identified in our systematic review. Transition probabilities for untreated patients were taken from the published literature.

The baseline cohort comprised individuals with a median age of 31 years (HBeAg-positive CHB) and 40 years (HBeAg-negative CHB). About 70% of HBeAg-positive and 90% of HBeAg-negative patients are male. All have CHB, but have not progressed to cirrhosis.

To estimate changes in health-related quality of life (HRQoL) published age-specific quality of life weights for both CHB and chronic hepatitis C were taken from the literature. Resource and health state costs for assessment, investigation, treatment and monitoring were derived from the literature and from discussions with clinical colleagues and supplied by an English NHS Hospitals Trust. Costs are discounted at 6% and health outcomes at 1.5%.

Interventions were evaluated against their closest comparator (for PEG this is IFN, and for ADV this is LAM). In addition, the cost-effectiveness of sequential treatment scenarios was modelled. The results of these comparisons were reported in terms of the incremental gain in quality-adjusted-life years (QALYs) and the incremental costs determined in the cohort analysis.

Results

Conclusions

ADV and PEG-2a are associated with significant improvements in a number of biochemical, virological and histological outcomes in both HBeAg-positive and -negative patients. For a small proportion of patients this is associated with resolution of infection. For another proportion it leads to remission and a reduced risk of progressing to cirrhosis, hepatocellular carcinoma, liver transplant and death. For others who do not respond or who relapse, retreatment with another agent is necessary.

The results of our cost-effectiveness analysis demonstrate that incremental costs per QALY for a range of comparisons were between £5994 and £16,569 and within the range considered by NHS decision-makers to represent good value for money. When subjected to sensitivity analysis, most costs per QALY estimates remained under £30,000.

Recommendations for further research

Further RCT evidence of the effectiveness of anti-viral treatment is required, particularly for subgroups of patients with different genotypes, patients with cirrhosis, patients from different ethnic groups, patients with co-infections (e.g. HIV, HCV) and co-morbidities, liver transplant patients and children and adolescents.

Further published evidence is awaited on:

• the effectiveness of ADV in combination with LAM in treatment-naïve patients
• the long-term effectiveness of ADV
• the effectiveness of PEG in LAM non-responders and in interferon alfa non-responders
• long-term follow-up of PEG treatment
• HRQoL.

Publication

• Shepherd J, Jones J, Takeda A, Davidson P, Price A. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation. Health Technol Assess 2006;10(28). [PubMed: 16904047]

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