Health Technology Assessment 2006; Vol 10: number 28
Executive SummaryView/Download full monograph in Adobe Acrobat format (930 kbytes)
J Shepherd,* J Jones, A Takeda, P Davidson and A Price
Southampton Health Technology Assessments Centre, UK
* Corresponding author
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.
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.
Electronic databases were searched from 19956 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 (costutility) 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:
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.
A total of 1086 references to clinical effectiveness studies were identified. After screening, seven fully published RCTs and one systematic review met the inclusion criteria. Four of the RCTs evaluated the effectiveness of ADV and three reported results for PEG. In addition, a conference abstract was reviewed which reported interim results from an on-going Phase II RCT of ADV in combination with LAM. The published trials were of good quality, although details of randomisation and allocation of concealment were poorly reported.
Only one fully published economic evaluation was identified, reporting a US cost-effectiveness study of ADV as salvage therapy for CHB with LAM resistance. A Markov model was used to estimate cost-effectiveness of interferon alfa (612 months), LAM and LAM followed by ADV when resistance occurs. ADV generated the most (undiscounted) life-years, but at highest costs, with an incremental cost-effectiveness ratio (ICER) of US$14,204 per life-year gained.
In addition to this study, six cost-effectiveness studies of existing treatments for CHB were identified, published between 1995 and 2002. There was little published literature on HRQoL in CHB.
From a model developed for this study by the authors, the incremental cost per QALY estimates (baseline cohort of all patients) were:
Incremental cost per QALY estimates (HBeAg-positive patients only) were:
Incremental cost per QALY estimates (HBeAg-negative patients only) were:
For the sequential treatment strategies, incremental cost per QALY estimates ranged from £3604 (IFN followed by LAM versus IFN alone) to £11,402 (IFN followed by LAM with adefovir salvage versus IFN followed by LAM). Separating these results out for patients with HBeAg-positive and -negative disease reveals different patterns in the cost-effectiveness of these sequential treatment strategies. In all of these cases, the ICERs are well within the range that would conventionally be regarded as being cost-effective.
Deterministic sensitivity analysis showed that:
The probabilistic sensitivity analysis found that:
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.
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:
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).
The research findings from the NHS R&D Health Technology Assessment (HTA) Programme directly influence key decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC) who rely on HTA outputs to help raise standards of care. HTA findings also help to improve the quality of the service in the NHS indirectly in that they form a key component of the ‘National Knowledge Service’ that is being developed to improve the evidence of clinical practice throughout the NHS.
The HTA Programme was set up in 1993. Its role is to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and provide care in the NHS. ‘Health technologies’ are broadly defined to include all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care, rather than settings of care.
The HTA Programme commissions research only on topics where it has identified key gaps in the evidence needed by the NHS. Suggestions for topics are actively sought from people working in the NHS, the public, service-users groups and professional bodies such as Royal Colleges and NHS Trusts.
Research suggestions are carefully considered by panels of independent experts (including service users) whose advice results in a ranked list of recommended research priorities. The HTA Programme then commissions the research team best suited to undertake the work, in the manner most appropriate to find the relevant answers. Some projects may take only months, others need several years to answer the research questions adequately. They may involve synthesising existing evidence or conducting a trial to produce new evidence where none currently exists.
Additionally, through its Technology Assessment Report (TAR) call-off contract, the HTA Programme is able to commission bespoke reports, principally for NICE, but also for other policy customers, such as a National Clinical Director. TARs bring together evidence on key aspects of the use of specific technologies and usually have to be completed within a short time period.
Criteria for inclusion in the HTA monograph series
Reports are published in the HTA monograph series if (1) they have resulted from work commissioned for the HTA Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.
Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.
The research reported in this monograph was commissioned and funded by the HTA Programme on behalf of NICE as project number 03/59/01. The protocol was agreed in December 2004. The assessment report began editorial review in October 2005 and was accepted for publication in November 2005. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.
The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme, NICE or the Department of Health.
Editor-in-Chief: Professor Tom Walley
Series Editors: Dr Aileen Clarke, Dr Peter Davidson, Dr Chris Hyde, Dr John Powell, Dr Rob Riemsma and Dr Ken Stein
Managing Editors: Sally Bailey and Sarah Llewellyn Lloyd
© 2006 Crown Copyright Top ^