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Family Practice Advance Access originally published online on June 23, 2006
Family Practice 2006 23(4):393-406; doi:10.1093/fampra/cml032
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© Crown Copyright 2006. Reproduced with the permission of the Controller of Her Majesty's Stationery Office

Case finding for hepatitis C in primary care: a cost utility analysis

Joanna Thompson Coona, Emanuela Castelnuovoa, Martin Pitta, Matthew Crampd, Uwe Siebertb,c and Ken Steina

a Peninsula Technology Assessment Group (PenTAG), Peninsula Medical School, Universities of Plymouth and Exeter Noy Scott House, Barrack Road, Exeter, EX2 5DW, UK
b Institute for Technology Assessment, Massachusetts General Hospital, Harvard Medical School Boston, MA, USA
c Department of Public Health, Medical Decision Making and HTA, University of Health Sciences, Medical Informatics and Technology Hall i.T, Austria
d Hepatology Department, Derriford Hospital, and Peninsula Medical School Plymouth, UK

Correspondence to Joanna Thompson Coon, Peninsula Technology Assessment Group (PenTAG), Peninsula Medical School, Universities of Plymouth and Exeter, Noy Scott House, Barrack Road, Exeter EX2 5DW, UK; Email: Joanna.Thompson-Coon{at}pentag.nhs.uk.

Received 9 January 2006; Accepted 23 May 2006.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding body
 Competing interests
 References
 
Background. Hepatitis C is an important public health problem. The need for more intensified action to identify those infected with the virus has been recognized. Primary care is an important setting for case finding.

Objectives. To estimate the cost utility of case finding for hepatitis C in primary care, specifically amongst former injecting drug users (IDUs).

Methods. A Markov model was developed to investigate the impact of case finding and treatment on progression of hepatitis C (HCV) in a hypothetical cohort of 1000 former IDUs. Comparison was made with a similar cohort in which no systematic case finding was implemented but spontaneous presentation for testing was allowed. Two scenarios were explored. The testing protocol utilized ELISA and PCR tests. Those eligible for treatment received combination therapy with pegylated interferon and ribavirin. Parameter estimates were obtained from literature searches and experts in the field.

Results. Few estimates of the uptake of HCV testing in primary care are available. Cost utility was estimated at around £16 000/QALY for both scenarios. At a willingness to pay of £30 000/QALY, there is approximately a 75% probability that the initiatives would be cost-effective. Choices regarding the utility data, discounting and the rates of spontaneous/re-presentation outside of a case-finding programme appear to be important areas of uncertainty in this model.

Conclusion. Case finding for HCV in primary care is likely to be considered cost-effective but substantial uncertainties remain. Further research is needed on different approaches to case finding in primary care.

Keywords. Case finding, cost–benefit analysis, hepatitis C, intravenous substance abuse, primary health care.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding body
 Competing interests
 References
 
Hepatitis C is a blood borne virus causing slowly progressive chronic liver disease. Chronic hepatitis C infection is an important public health problem. Estimates based on studies in low-risk populations suggest that 0.4% of the population (200 000 individuals) of England and Wales may be chronically infected.1 Other estimates suggest that the number may be between 300 000 and 600 000.2 Only a fraction of these cases have been diagnosed; the total number of diagnoses reported to the Communicable Disease Surveillance Centre between 1992 and 2003 was ~39 000.3

Contact with blood and blood products represents the primary route for virus transmission. Sharing of injecting paraphernalia amongst injecting drug users (IDUs) is currently the most common route of infection. Even a short ‘injecting career’ can be a significant risk factor for virus transmission. The prevalence of chronic infection amongst former IDUs in contact with drug services is ~40%, though some regional variation (33–57%) has been shown.4

Approximately 80% of individuals infected with the hepatitis C virus have no symptoms at the time of exposure and ~85% will develop chronic infection. Disease progression is slow and patients may be asymptomatic for many years. Many people with chronic hepatitis C are therefore unaware of their condition.

The Royal College of Physicians of Edinburgh Consensus Statement on Hepatitis C recommended in 2004 that ‘a high priority for case finding should be given to former IDUs, especially those over 40, who are likely to have a stage of disease which would benefit from treatment.’ The Chief Medical Officer recently identified hepatitis C as needing ‘intensified action’ to improve prevention, diagnosis and treatment. This resulted in the publication of the ‘Hepatitis C Action Plan for England’ in 2004. The aims of which are to improve surveillance and research, increase awareness of hepatitis C and thereby reduce undiagnosed infections, to ensure that high quality services for assessment and treatment are co-ordinated and accessible to patients and to intensify prevention efforts to reduce the spread of the disease in high risk populations. More recently the All Party Parliamentary Group on Hepatology has urged the Government to revise the Action Plan calling for greater investment to deal with the virus and a pro-active testing programme targeted on risk groups.

Primary care provides an obvious potential setting for finding undiagnosed cases of hepatitis C, particularly those who may have been experimental, recreational or opportunistic IDUs in the past. However, the potential impact of case finding and the value for money such activities may represent for the NHS is unknown. We therefore developed a decision-analytic model to investigate the impact of case finding and treatment on progression of hepatitis C (HCV) disease in the primary care setting. We were able to find few examples of case finding in general practice in published or unpublished literature5 (Eleanor Anderson, personal communication, February 2005). We therefore examined two possible but theoretical case-finding approaches: (i) an offer of testing to all those within a target age group (‘population’) and (ii) offering testing to those known to be at highest risk of having contracted hepatitis C (‘targeted’).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding body
 Competing interests
 References
 
A decision-analytic Markov model was developed to investigate the impact of systematic case finding in primary care on treatment and progression of HCV disease. A systematic case-finding strategy was modelled after which individuals were allowed to re-present for testing at a later date. This was compared with a non-case-finding arm in which individuals were permitted to spontaneously present for testing. At the start of the model, individuals are assumed to have an average age of 37 years [based on data from the Trent HCV Study Cohort Database (William Irving, personal communication, October 2004)]. We used a lifelong time horizon and direct costs were assessed from a UK NHS perspective. Costs (base year 2004) and benefits [Quality-Adjusted Life Years (QALYs)] were discounted at 6 and 1.5%, respectively.

The model has four components:

  1. Case-finding strategies. We were able to locate few published examples of case finding for HCV in general practices in the UK. We therefore developed two possible approaches to case finding following discussion with experts in the field. Simple proportions embedded in a decision tree were used to estimate uptake of initial ELISA testing and HCV prevalence. The first case-finding strategy (‘population’) is based on an unpublished example of a case-finding initiative conducted in an area of high deprivation in Scotland, identified through contact with experts (Eleanor Anderson, personal communication, February 2005). In this study, counselling on HCV and ELISA testing was offered to all patients aged 30–54 years attending a general practice for a non-urgent appointment. Fifty percent of the target population (584/1165) attended the practice during the 6-month study period and ELISA tests were performed in 10% (n = 117) of the population. Fifteen patients (12.5% of those tested) had positive ELISA results. In this strategy, we have assumed that the risk factors for acquiring HCV are explained to all patients within the target age range (30–54 years) attending for a non-urgent appointment. An appointment with a nurse counsellor is made available for people who consider testing. The second case-finding strategy (‘targeted’) considers testing people already known to be at increased risk. In effect, this means that all patients with a history of current or former injecting drug use would be identified from patient records using a combination of clinical history and treatment codes. A letter from the patient’s GP would be sent to each patient along with an information leaflet describing the risk factors for contracting HCV and treatment possibilities. Interested patients would be invited to make an appointment with a nurse counsellor for further discussion of testing. Parameters used in both strategies are shown in Table 1.
  2. Testing and diagnosis. A diagnostic decision tree represents the pathway from the point of identifying people for testing through to the offer of treatment with antiviral combination therapy and/or alcohol harm reduction advice. The analysis combines the performance of ELISA and reverse transcription PCR testing with information on acceptance of ELISA, PCR, biopsy and treatment, eligibility for biopsy and treatment and adverse events using a decision tree (Figures 1 and 2). Parameters for this part of the model are shown in Table 1.
  3. Treatment. Treatment decisions are based on evidence from randomized clinical trials. In eligible cases, treatment is with pegylated interferon at standard doses combined with ribavirin. We assumed that all eligible patients are offered treatment and, in those that accept, treatment is for 48 weeks. Patients with genotype 2 or 3 or cirrhosis proceed directly to treatment without biopsy. For individuals with genotypes 1 or 4 treatment is based on histology. Individuals with moderate or severe disease are offered treatment, those with mild disease are observed. Reduction in alcohol consumption is advised for all tested cases. Parameter data for treatment are shown in Tables 2 and 3. Quality of life (utility) values associated with treatment are shown in Table 5.
  4. Long-term consequences. Using a Markov model, the long-term consequences of HCV infection are calculated for people who refuse any step of the management pathway, those who are not identified for testing through case finding and those who do not present spontaneously. Data regarding the long-term consequences of HCV are shown in Tables 3 and 4. Utility values associated with the various health states are shown in Table 5. Progression to cirrhosis was estimated from a meta-analysis of epidemiological studies.6


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  		TABLE 1 Testing and diagnosis—model parameters

 

Figure 1
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  		FIGURE 1 Testing and diagnosis—model schema. ELISA, enzyme-linked immunoassay; PCR, reverse transcription polymerase chain reaction; *this will also include some people with false positive result on PCR

 

Figure 2
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  		FIGURE 2 Results—testing, diagnosis and initiation of treatment—‘targeted approach’

 

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  		TABLE 2 Treatment—parameters

 

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  		TABLE 3 Treatment—costs

 

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  		TABLE 4 Long-term consequences—model parameters

 

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  		TABLE 5 Treatment and long-term consequences—utilities

 
In the Markov model, disease progression is represented as transitions between the key health states (mild hepatitis, moderate or severe hepatitis, cirrhosis, decompensated cirrhosis, liver transplant and death) at fixed time intervals (cycles) (Figure 3). The cycle length is 3 months. Total costs and health outcomes are estimated over the total lifetime of individuals attaching costs and quality of life weights to the amount of time spent in each state. The cost-effectiveness of case finding is then calculated as the difference in total cost between the two cohorts relative to the difference in quality-adjusted life years gained.


Figure 3
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  		FIGURE 3 Long-term consequences—model schema

 
Parameter estimates were obtained from literature searches carried out on a range of electronic databases [Medline (OVID 1996–2004), Embase (1980–2004), Cochrane Library (2004 Issue 4), DARE (October 2004), NHS EED (October 2004) and the HTA database (October 2004)], and through contact with researchers and clinicians in the field. Further details of the search strategies are available from the authors. Searches were not limited by methodological features. The extent to which non-English language papers add to the accuracy of parameter estimates is unclear and as we were endeavouring to identify parameter estimates that would be applicable to a UK situation; articles published in languages other than English were excluded. Values included in the model were chosen on the basis of the methodological quality of the study, publication date (favouring more recent studies), relevance to the UK and the appropriateness and sample size of the population.

Uncertainty in the analysis was explored using probabilistic sensitivity analysis. Details of the distributions used are shown in Tables 6GoGoGo–10.


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  		TABLE 6 Probabilistic distributions used of population characteristics in the model

 

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  		TABLE 7 Probabilistic distributions used for cost data in the model

 

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  		TABLE 8 Probabilistic distributions used for utility data in the model

 

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  		TABLE 9 Probabilistic distributions for natural history data used in the model

 

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  		TABLE 10 Probabilistic data for testing algorithm used in the model

 
The model used in this paper was developed as part of a national health technology assessment commissioned by the NHS R&D HTA Programme (http://www.hta.ac.uk/project.asp?PjtId=1457) in which the effectiveness and cost-effectiveness of a generic approach to case finding were considered. As part of this project, extensive one-way sensitivity analyses were performed to explore the inherent uncertainty in the model.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding body
 Competing interests
 References
 
Testing diagnosis and initiation of treatment

  1. ‘Population’ strategy This approach to case finding has limited success in identifying individuals who complete the diagnostic process and receive treatment. Low rates of acceptance for ELISA and PCR tests lead to many individuals remaining undiagnosed. In a cohort of 10 000 individuals, 1200 have been exposed to the virus. The case-finding initiative results in the successful identification of 4 cases of which 13 individuals subsequently receive antiviral therapy.
  2. ‘Targeted’ strategy Results for the targeted approach to case finding are illustrated in Figure 3.

Direct comparisons between the two possible case-finding strategies are not appropriate due to the difference in the size of the population affected.

Longer term consequences

  1. ‘Population’ strategy In a cohort of 10 000 individuals, over a 30-year period, re-presentation for testing of individuals who have previously refused the offer of a test results in the identification of further 720 individuals, 550 of whom receive antiviral therapy. In the non-case-finding scenario 660 individuals spontaneously present for testing and 450 receive treatment. Case-finding results in the aversion of 9 cases of decompensated cirrhosis, 4 cases of hepatocellular carcinoma (HCC) and 7 deaths due to HCV per 10 000 individuals tested.
  2. ‘Targeted’ strategy In a cohort of 10 000 individuals, as a result of re-presentation for testing, only 490 individuals remain undiagnosed in the case-finding arm after 30 years. Despite spontaneous presentation for testing in the non-case-finding scenario, the lack of a case-finding initiative means that 1510 people remain undiagnosed after 30 years. Thirty five cases of decompensated cirrhosis, 16 cases of HCC and 29 deaths due to HCV are averted as a result of the case-finding initiative.

Cost utility
The cost utility results are shown in Table 11.

  1. ‘Population’ strategy The discounted incremental cost per patient was £170 with an associated gain in quality-adjusted life years of 0.011 QALYs (approximately four quality-adjusted life days). The resulting incremental cost-effectiveness ratio (ICER) is £15 493 per QALY.
  2. ‘Targeted’ strategy The discounted incremental cost per patient was higher for the ‘targeted’ strategy at £758, but was associated with a greater gain in benefits of 0.046 QALYs (~17 days) producing an ICER of £16 493 per QALY.


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  		TABLE 11 Cost utility analysis: discounted and undiscounted results for the ‘population’ and ‘targeted’ approach to case finding (results are presented per patient)

 
One-way sensitivity analyses
Extensive exploration of the results highlighted the importance of the quality of life (utility) data in the model. Four factors had an important impact: (i) the decrement in quality of life experienced at presentation, (ii) the decrement in quality of life experienced during treatment, (iii) the improvements in quality of life reported following sustained viral response and (iv) the improvements in quality of life due to the avoidance of the long-term consequences of HCV infection.

Changes in discount rates for costs and benefits also have a large impact on the results. Using a discount rate of 3.5% for both costs and benefits, produces an ICER of approximately £35 000/QALY for the ‘population’ strategy and £33 000/QALY for the ‘targeted’ strategy, indicating that case finding would be less likely to be considered cost-effective under these conditions.

Rates of spontaneous and re-presentation of individuals for testing outside of the case-finding strategy also have an impact on the results of the model. As the rates of spontaneous and re-presentation increase, the effect of the case-finding strategy is swamped by the large numbers of individuals who are identified anyway. As a consequence the difference between the two arms of the model, in terms of both costs and benefits decreases. For the ‘targeted’ strategy, if the rate of presentation outside of the case-finding initiative is set to 2.5% per year in both scenarios of the model (i.e. case finding and non-case finding), the ICER rises to approximately £23 000/QALY. With a presentation rate of 7.5% per year the ICER for active case finding increases to approximately £65 000/QALY.

Probabilistic sensitivity analysis
The probabilistic sensitivity analysis shows that if commissioners consider £30 000 per QALY an acceptable return on investment, there is a 73% probability that a population-based strategy approach to case finding for HCV in general practice would be considered cost-effective. For the ‘targeted’ strategy to case finding, the corresponding figure is 77%. The cost-effectiveness planes are shown in Figure 4 and the cost-effectiveness acceptability curves in Figure 5.


Figure 4
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  		FIGURE 4 Results—cost-effectiveness plane

 

Figure 5
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  		FIGURE 5 Results—Cost-effectiveness acceptability curves

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding body
 Competing interests
 References
 
Summary of main findings
Using a modelling approach based on the best available data we have demonstrated that case-finding strategies within general practice are likely to be effective in terms of identifying and successfully treating additional individuals. Moderate numbers of cases of advanced liver disease, HCC and deaths would be prevented through systematic case finding. The cost utility analysis shows that case finding is likely to cost more but to result in additional benefits, at a level which is likely to be considered cost-effective, although substantial uncertainties remain. The analysis of the ‘population’ strategy to case finding based on the only currently available data on case finding in general practice suggests a cost per QALY of about £15 000. The ICER for the approach designed to target those most at risk of contracting HCV disease is estimated at around £16 000 per QALY.

Choices regarding the quality of life (utility) data, discounting rates and the rates of spontaneous/re-presentation outside of a case-finding programme appear to be important areas of uncertainty in our model.

Strengths and limitations of this study
This is the first model of case finding for hepatitis C to consider the identification of potential individuals for testing in general practice and it highlights the paucity of reported data on acceptance of testing and subsequent treatment. We have included a more extensive analysis of uncertainty than the earlier models, including probabilistic sensitivity analysis. Two approaches to case finding have been suggested to identify not only the ‘stereotypical’ former IDU but also those who may have been recreational users many years earlier.

However, there are several limitations. Firstly, we have not modelled treatment of people who are currently injecting drugs. It is likely that some of the individuals tested as part of the case-finding initiative will be current injectors. Currently, individuals who continue to inject drugs are considered ineligible for antiviral therapy. Resources used to identify these individuals will therefore not be rewarded with the associated benefits of antiviral therapy. Hence, the inclusion of current injectors in the testing programme would tend to decrease the probability that case finding would be cost-effective. The size of this effect is not clear as the proportion of current injectors volunteering for HCV testing is unknown and is likely to vary between settings.

Secondly, although we attempted to use setting-specific data for the testing and treatment pathways, we found a striking lack of available evidence. This has limited our ability to model the cost-effectiveness of case finding or to consider the impact of case finding in different population subgroups. For example, alcohol use may interact with adherence and eligibility as may time since cessation of injecting behaviour. There is currently insufficient data to explore these important aspects of case finding. However, because combination therapy is clearly cost-effective, a relatively large amount can be spent on identifying patients for testing (£160/patient tested for the ‘population’ approach) and the case-finding initiative will still be considered cost-effective at the £30 000/QALY level.

Comparison with existing literature
There appear to be very few studies of case finding for HCV in general practice in the UK available in the literature. Earlier reviews of cost-effectiveness studies found that studies from other health systems are unlikely to be informative for the UK given differences in disease patterns, clinical practice and health service organization.7,8

Implications for future research or clinical practice
There are several areas in which further research could improve the model estimates; (i) Pilot studies of case-finding strategies within general practice, together with the reporting of uptake and adherence at the various stages of the testing and treatment pathways; (ii) Improved estimates of the number and type of IDUs within the community and the incidence of relapse into injecting behaviour; (iii) Research into the quality of life in chronic HCV disease, combination therapy or counselling to achieve behavioural modification, and viral clearance in former IDUs and (iv) Studies on the effectiveness and cost-effectiveness of conventional and complementary treatment options such as low dose pegylated interferon or dietary interventions, in terms of improving viral clearance and slowing disease progression.

Case finding for HCV disease is already supported by national and international guidelines. This report adds weight to these policies by demonstrating that case-finding strategies within general practice are likely to be considered cost-effective. However, estimates are not so low that all approaches can be expected to represent good value for money.

In conclusion, we estimate that case finding for HCV disease in general practice is likely to be cost-effective, although substantial uncertainties remain. The results add further cautious support to national and international guidelines. Further empirical research to inform the nature of the most effective and cost-effective strategies for case finding within primary care should be given priority.


   Funding body
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding body
Competing interests
 References
 
This work is part of a larger project that was commissioned by the NHS R&D HTA Programme (Project reference number 04/40/01). The work was carried out between October 2004 and May 2005.


   Competing interests
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding body
 Competing interests
References
 
KS received an unrestricted grant from Schering Plough (UK) to carry out work on the cost-effectiveness of combination therapy for hepatitis C in 2000. MC sits on hepatitis C advisory boards for both Schering Plough and Roche. He has received unrestricted educational grants from Roche and Schering Plough to support research and service development. He has been awarded an NHS R&D grant looking at IDUs who do not have hepatitis C virus infection. US has received an HTA grant from the German Agency of Health Technology Assessment at the German Institute for Medical Documentation and Information/German Federal Ministry of Health and Social Security and unrestricted research grants from ESSEX Pharma GmbH, Munich, Germany (German subsidiary of Schering Plough Inc, Kenilworth, MJ, USA). Joanna Thompson Coon received a grant from the Hepatitis C Trust to conduct a systematic review of complementary and alternative therapies for the treatment of chronic hepatitis C.


   Acknowledgments
 
We gratefully acknowledge the help of the following: Jo Perry for help with project management and preparation of the manuscript, Professor Howard Thomas and Mr Richard Grieve for providing data from the NHS HTA RCT and cost-effectiveness model of combination therapy for mild hepatitis C, Professor William Irving for providing unpublished data from the Trent Hepatitis C Cohort Database and the Expert Advisory Group involved in the national health technology assessment project (Dr Eleanor Anderson, Specialist Registrar in Public Health Medicine, Lanarkshire; Professor John Campbell, Professor of General Practice, Exeter; Professor Graham Foster, Professor of Hepatology, London; Dr Matthew Hickman, Senior Lecturer in Epidemiology, London; Dr Sharon Hutchinson, Epidemiologist, Glasgow; Professor William Irving, Professor of Virology, Nottingham; Dr Janice Main, Reader in Infectious Diseases, London; Dr David Mutimer, Consultant Hepatologist, Birmingham; Dr Nicholas Pugh, Consultant in Communicable Disease Control, Walsall).

The views and opinions expressed there in are those of the authors and do not necessarily reflect those of the Department of Health.


   Notes
 
Thomson Coon J, Castelnuovo E, Pitt M, Cramp M, Siebert U and Stein K. Case finding for hepatitis C in primary care: a cost utility analysis. Family Practice 2006; 23: 393–406.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding body
 Competing interests
 References
 
1 Department of Health. (2002) Hepatitis C Strategy for England.

2 Consensus Conference on Hepatitis C. Royal college of Physicians of Edinburgh Consensus Statement. (2004) J Viral Hepat 11:Suppl 1, 2–4.[Web of Science][Medline]

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4 Health Protection Agency. Supplementary data tables of the Unlinked Anonymous Survey of Injecting Drug Users in contact with services: data to the end of 2003. (2004) Department of Health.

5 Thompson J. (2002) Audit improves access to care for drug users with hepatitis C. Guidelines in Practice 5:39–52.

6 Freeman AJ, Dore GJ, Law MG, et al. (2001) Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology 34:809–816.[CrossRef][Web of Science][Medline]

7 Stein K, Dalziel K, Walker A, et al. (2002) Screening for hepatitis C among injecting drug users and in genitourinary medicine clinics: systematic reviews of effectiveness, modelling study and national survey of current practice. Health Technol Assess 6:1–122.[Medline]

8 Sculpher M, Pang FS, Manca A, et al. (2004) Generalisability in economic evaluation studies in healthcare: a review and case studies. Health Technol Assess 8:.

9 Bird SM, Goldberg DJ, Hutchinson SJ. (2001) Projecting severe sequelae of injection-related hepatitis C virus epidemic in the UK. Part 1: Critical hepatitis C and injector data. J Epidemiol Biostat 6:243–265.[CrossRef][Medline]

10 Mohsen AH and Group TH. (2001) Trent HCV Study Group. The epidemiology of hepatitis C in a UK health regional population of 5.12 million. Gut 48:707–713.[Abstract/Free Full Text]

11 Colin C, Lanoir D, Touzet S, Meyaud-Kraemer L, Bailly F, Trepo C. (2001) Sensitivity and specificity of third-generation hepatitis C virus antibody detection assays: an analysis of the literature. J Viral Hepat 8:87–95.[CrossRef][Web of Science][Medline]

12 Serfaty M, Lawrie A, Smith B, et al. (1997) Risk factors and medical follow-up of drug users tested for hepatitis C—can the risk of transmission be reduced? Drug Alcohol Rev 16:339–347.[CrossRef][Web of Science][Medline]

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15 Wright M, Grieve R, Roberts J, Main J, Thomas H. on behalf of the UK mild hepatitic C trial investigators. (2005) Health Benefits of anti-viral therapy for mild chronic hepatitis C. 95/24/03.

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18 Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J. (2004) Pegylated interferon alpha-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation. Health Technol Assess 8:1–140.[Medline]

19 Beich A, Thorsen T, Rollnick S. (2003) Screening in brief intervention trials targeting excessive drinkers in general practice: a systematic review and meta-analysis. BMJ 327:536–543.[Abstract/Free Full Text]

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