The Department of Health and the Welsh Assembly Government have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct an appraisal of interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by the representatives nominated for this appraisal by professional organisations and patient/carer and service user organisations. The Committee has developed preliminary recommendations on the use of interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C.

This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk).

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘ Guide to the technology appraisal process’ (this document is available on the Institute’s website, www.nice.org.uk).

• The Appraisal Committee will meet again to consider the original evidence and this Appraisal Consultation Document in the light of the views of the formal consultees.
• At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
• After considering feedback from the consultation process, the Committee will prepare the Final Appraisal Determination (FAD) and submit it to the Institute.
• Subject to any appeal by consultees, the FAD may be used as the basis for the Institute’s guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:
Closing date for comments: 9 March 2006
Second Appraisal Committee meeting: 21 March 2006

Details of membership of the Appraisal Committee are given in appendix A and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.

Appraisal Committee's preliminary recommendations

Combination therapy comprising peginterferon alfa-2a and ribavirin or peginterferon alfa-2b and ribavirin is recommended, within the licensed indications of these drugs, as an option for the treatment of mild chronic hepatitis C.

Monotherapy with peginterferon alfa-2a or peginterferon alfa-2b is recommended, within the licensed indications of these drugs, as an option for the treatment of mild chronic hepatitis C for people who are unable to tolerate ribavirin, or for whom ribavirin is contraindicated.

The decision as to whether a person with mild chronic hepatitis C should be treated immediately rather than waiting until the disease has reached a moderate stage (‘watchful waiting’) should be made by the person after fully informed consultation with the responsible clinician. Liver biopsy is not required to determine the stage of the disease if treatment is initiated immediately, but may be recommended by the clinician for other reasons or if treatment is delayed.

Treatment with combination therapy should normally last 24 weeks for people with mild chronic hepatitis C associated with genotype 2 or 3 of the hepatitis C virus (HCV).

For people with mild chronic hepatitis C associated with HCV genotype 1, 4, 5 or 6, initial treatment with combination therapy should last for 12 weeks. If the person’s viral load has fallen to less than 1% of the initial level after 12 weeks, treatment should continue for a total of 48 weeks. Treatment should be discontinued in people whose viral load at 12 weeks exceeds 1% of the initial level.

For mild chronic hepatitis C caused by hepatitis C viruses of more than one genotype, any combination of genotypes containing one or more of genotypes 1, 4, 5, or 6 should be treated as in paragraph 1.5.

People with mild chronic hepatitis C who are prescribed peginterferon alfa monotherapy should, regardless of genotype, be tested for viral load at 12 weeks; they should continue treatment for a total of 48 weeks only if viral load has reduced to less than 1% of its initial level.

Second or subsequent courses of treatment are not recommended for people who have been treated with a first course of either combination therapy or monotherapy with peginterferon alfa if they have not had a sustained response (as indicated by reduction in viral load at 12 weeks).

Combination therapy or monotherapy with peginterferon alfa is not recommended for people with mild chronic hepatitis C who are younger than 18 years, or those who have had a liver transplant.

Clinical need and practice

Chronic hepatitis C is a disease of the liver caused by the hepatitis C virus. Generally the virus is transmitted parenterally, but the natural history of the disease is not completely understood. It may be acquired through intravenous drug use or the sharing of needles. Before the viral inactivation programme was implemented in the mid-1980s the virus was spread through blood products; it was spread through blood transfusions before the introduction of screening in 1991. There is also a small risk associated with tattooing, electrolysis, ear piercing and acupuncture. Infection through sexual intercourse may also occur. There is a transmission rate of about 6% from mother to child if the mother is an HCV carrier. Concomitant HIV infection increases the risk of transmission.

People infected with HCV are often asymptomatic, but about 20% will develop acute hepatitis. Some of these people will experience non-specific symptoms including malaise, weakness and anorexia. About 80% of those exposed go on to develop chronic hepatitis. The rate of progression of the disease is slow but variable, taking about 20–50 years. About 30% of those who are infected develop cirrhosis within 20-30 years, and a small percentage of these people are at a high risk of developing hepatocellular carcinoma. A third may never progress to cirrhosis or will not progress for at least 50 years. Some patients with end-stage liver disease or hepatocellular carcinoma may need liver transplantation.

The effectiveness of treatment is related to the genotype of the virus, which affects the ability of the immune system to mount an effective response. Six major genetic types of HCV have been found. Genotype 1 is the most common in the UK, accounting for about 40–50% of cases. Genotypes 2 and 3 contribute another 40–50%; and genotypes 4, 5 and 6 constitute the remainder, about 5%.

Estimates of the number of people infected with HCV in England and Wales vary between 200,000 and 600,000, with recent estimates being towards the top of this range. (In 2005, the Department of Health estimated that only 47,000 people with HCV infection had been diagnosed and only 7000 had been treated.) There is also great variation in prevalence between subgroups of the population: 0.04% in blood donors, 0.4% in people attending antenatal clinics in London, 1% in people attending genito-urinary clinics and up to 50% in intravenous drug users.

Because it is not possible in the short term to directly measure the effectiveness of treatment in reducing progression to cirrhosis and hepatocellular carcinoma, three surrogate markers have been used in trials:

• hepatic histology
• virological loss of HCV-RNA (by quantitative polymerase chain reaction)
• levels of alanine aminotransferase (an enzyme that indicates the presence of liver inflammation).

The previous NICE guidance (NICEtechnology appraisal no. 75) applies only to people with moderate-to-severe chronic hepatitis C, which is defined as histological evidence of significant scarring (fibrosis) and/or significant necrotic inflammation of the liver. For the majority of patients with moderate or severe hepatitis C, the standard treatment is combination therapy with ribivarin and either peginterferon alfa-2a or peginterferon alfa-2b. Monotherapy with peginterferon alfa is used only for people unable to tolerate ribavirin.

In trials, about 75–85% of people with HCV genotype 2 or 3 had a sustained virological response 6 months after finishing a course of treatment with peginterferon alfa and ribavirin. For people with genotype 1 the rate of sustained virological response was about 40–50%, while for the three less common genotypes (4, 5 and 6) the rate appears to be between those for genotype 1 and genotypes 2 and 3.

For people with genotype 2 or 3, the maximum rate of sustained virological response is attained after 24 weeks of treatment. Further treatment does not increase the rate, so treatment beyond 24 weeks is not advised. For people with the other genotypes, it may take longer than 24 weeks to gain a sustained virological response, so the standard treatment length is 48 weeks. However, if no virological response has occurred by 12 weeks of treatment, a sustained response is unlikely to occur. Hence, it is recommended that patients who do not attain a sufficient virological response by 12 weeks should not receive a further 36 weeks of treatment. People infected with genotypes 2 or 3 do not need a test of virological response at 12 weeks, because almost all respond by that time.

Peginterferons are formed by attaching strands of polyethylene glycol (PEG) to the interferon molecules. This slows the rate of absorption and excretion of interferon, reducing the fluctuations in serum concentrations that occur with unmodified interferon. The pegylation process increases the half-life of the interferon molecule in the body: in the case of peginterferon alfa-2b from about 4 hours to about 40 hours, and for peginterferon alfa-2a from 4 hours to between 50 and 130 hours. Accordingly, patients treated with peginterferon alfa need injections only once a week, compared with three times a week for patients treated with non-pegylated interferon. In addition, clinical trials suggest that response rates to interferon among patients with moderate and severe disease are significantly lower than response rates to peginterferon therapy.

2.10

In the past it was the practice to perform a liver biopsy before prescribing interferon alfa or peginterferon alfa, in order to determine whether a person with chronic hepatitis C had reached the moderate or severe stage of the disease. For people with genotype 2 or 3 the requirement for a biopsy before starting peginterferon alfa therapy has been dropped from marketing authorisations.

Standard haematological tests and blood chemistry (that is, full blood count and differential platelet count, liver function tests, uric acid, serum bilirubin and serum creatinine) are necessary for all patients being considered for combination therapy. The HCV genotype with which the patient is infected should be determined for all candidates for combination therapy. Liver biopsy has played a role in helping to determine disease staging, but is no longer considered necessary for people with HCV of genotypes 2 and 3, or if biopsy poses an increased risk. Patients should be seen weekly for the first 4 weeks of treatment and then monthly for 6 months to check for haemolysis and changes in thyroid activity.

Both pegylated and non-pegylated interferon give rise to flu-like symptoms in many patients. Ribavirin leads, in a proportion of cases, to anaemia, pruritus, rash, insomnia and dyspnoea. For full details of side effects and contraindications, see the summary of product characteristics for each drug.

The technologies

Because the technology has not changed from that given in NICE technology appraisal no. 75, its details have been incorporated into section 2 above, with the exception of the current price (which is shown below).

Peginterferon alfa-2a (Pegasys) and ribavirin (Copegus) are manufactured by Roche. For genotypes 2 and 3 the licensed regimen is peginterferon alfa-2a 180 micrograms once per week plus ribavirin 800 mg per dayfor 24 weeks. This course of therapy costs £5,019 (excluding VAT; British National Formulary, 50th edition). For genotypes 1, 4, 5 and 6, the regimen is peginterferon alfa-2a 180 micrograms once per week for at least 24 weeks (low viral load) or for 48 weeks (high viral load) plus ribavirin 1000 mg per day (< 75 kg body weight) or 1200 mg day (> 75 kg) for the same length of time as peginterferon alfa. The cost is £10,963 or £11,889 for 48 weeks depending on body weight. For peginterferon monotherapy, the cost of treatment is £6,339 (for 12 months) for all genotypes.

Peginterferon alfa-2b (ViraferonPeg) and ribavirin (Rebetol) are produced by Schering-Plough. For genotypes 2 and 3 the licensed regimen is peginterferon alfa-2b 180 micrograms once per week plus ribavirin 800 mg per day (< 65 kg body weight) or 1000 mg per day (65–85 kg) or 1200 mg per day (> 85 kg) for 24 weeks. The cost of a course is £6,734 for a person of an average weight of 79 kg (excluding VAT; British National Formulary, 50th edition) . For genotypes 1, 4, 5 and 6, the licensed regimen is peginterferon alfa-2b 180 micrograms once per week for at least 24 weeks (low viral load) or for 48 weeks (high viral load) plus ribavirin 800 mg per day (< 65 kg body weight) or 1000 mg per day (65–85 kg) or 1200 mg per day (> 85 kg) for the same length of time as peginterferon alfa . The cost is £13,468 for a person of average weight. For genotypes 2 and 3 the cost of peginterferon monotherapy is £3,169 (for 6 months), and for other genotypes £6,339 (for 12 months) for other genotypes. For monotherapy, the cost for all genotypes ranges from £3,314 to £9,943, depending on body weight. (British National Formulary, 50th edition). Costs may vary in different settings because of negotiated procurement discounts.

Evidence and interpretation

The Appraisal Committee considered evidence from a number of sources (see appendix B).

Clinical effectiveness

The standard measurement of effectiveness for treatment of chronic hepatitis C is the virological response rate sustained for 6 months (known as the sustained virological response rate). This is defined as the proportion of patients in whom the virus is undetectable in blood samples 6 months after treatment has been completed.

A direct measure of viral activity is viral load, which is the number of copies of the virus in a given quantity of blood. Although a high viral load is likely to mean that the liver deteriorates more quickly than it does under the influence of a low viral load the relationship is not a simple one, and some people live with high viral loads for many years without progressing from mild disease to moderate disease.

A person is classified as having mild or moderate chronic hepatitis C based on the extent of liver damage. Wherever possible, this is determined histologically by biopsy. The main indicator of liver damage is the degree of fibrosis, although the degree of necroinflammation also contributes to the diagnosis.

Five trials of interferon alfa-2b and three trials of peginterferon alfa-2a that included patients with chronic hepatitis C, at least 70% of whom had mild disease, were included in the Assessment Report. All studies included the combination with ribavirin in at least one arm. The comparators in the trials varied. Two of the three peginterferon alfa studies compared longer courses (48 weeks) with shorter courses (24 weeks); the third compared peginterferon alfa-2a with non-pegylated interferon alfa-2a.

No studies compared the strategies of early treatment of mild disease with a strategy of watchful waiting and treatment for those who progress to moderate or severe disease. Because this is the primary comparison of interest in this appraisal, results for the comparator arms in the studies in paragraph 4.1.4 are not reported here.

Peginterferon alfa-2a (Pegasys) plus ribavirin

HCV genotypes 2 and 3

The three trials of peginterferon alfa 2a plus ribavirin in people with genotypes 2 and 3 yielded sustained virological response rates of 72–84% after 24 weeks of treatment and rates of 78–80% after 48 weeks of treatment. For people infected with these genotypes, there was no significant difference between the rates after 24 weeks of treatment or after 48 weeks. These results are consistent with those for studies conducted in people with moderate-to-severe chronic hepatitis C; in the previous appraisal the corresponding rate of sustained virological response in different trials that included people with both mild and moderate-to-severe disease was 79%.

HCV genotype 1

In people infected with genotype 1, peginterferon alfa-2a plus ribavirin yielded sustained virological response rates of 13–42% after 24 weeks of treatment and 40–52% after 48 weeks. In this group, the additional 24 weeks of treatment significantly increased the rate of sustained response.

Peginterferon alfa-2b (ViraferonPeg) plus ribavirin

Although there was no trial of peginterferon alfa-2b combination therapy that met the Assessment Group’s criteria for inclusion of trials of patients with mild chronic hepatitis C, one study included 1,014 (of 1,530) participants who had been documented as having no or minimal fibrosis. In this study, a sustained virological response occurred in 57% of participants with no or minimal fibrosis (that is, with mild disease) who received high-dose peginterferon alfa-2b (1.5 micrograms/kg per week for 48 weeks) plus ribavirin. This compares with a rate of 44% among those who had bridging fibrosis or cirrhosis (that is, moderate-to-severe disease) who received high-dose peginterferon alfa-2b. In people who received low-dose peginterferon alfa-2b (1.5 micrograms/kg per week for 4 weeks, then 0.5 micrograms/kg per week for 48 weeks) plus ribavirin, a sustained virological response rate of 51% was recorded among those with mild disease compared with 43% among those with moderate-to-severe disease. Results by genotype were not reported. The rate of sustained virological response among participants on high-dose peginterferon alfa-2b combination therapy was significantly higher than that of patients on non-pegylated interferon alfa-2b plus ribavirin; however, the rate was not higher among those on the lower dose of peginterferon alfa-2b plus ribavirin.

Monotherapy trials

People who are unable to take ribavirin and are treated with monotherapy with peginterferon alfa or non-pegylated interferon alfa have much lower response rates than people treated with combination therapy. One trial of 159 people compared response rates to three different regimens of peginterferon alfa-2a with one of interferon alfa-2a. Rates of sustained virological response were 3% for interferon alfa-2a and between 10% and 29% for peginterferon alfa-2a, depending on the dose. Altogether, 82% of participants were classified as having mild chronic hepatitis C.

Another trial of 1,219 people compared response rates for three different regimens of peginterferon alfa-2b and one of interferon alfa-2b. Altogether, 83% of participants in this study were classified as having mild disease. Rates of sustained virological response were 12% for those treated with interferon alfa-2b and between 18 and 23% for those treated with peginterferon alfa-2b, depending on the dose.

Summary

Taken as a whole, the evidence for combination therapy and monotherapy, and for pegylated and non-pegylated interferon alfa-2a and pegylated and non-pegylated interferon alfa-2b, suggests that rates of sustained virological response among patients with mild disease are about the same as those among patients with moderate or severe disease. Combination therapy with peginterferon alfa (2a or 2b) and ribavirin results in higher rates of sustained virological response than combination therapy with non-pegylated interferon alfa (2a or 2b). Monotherapy with pegylated interferon alfa 2a or 2b results in higher response rates than monotherapy with non-pegylated interferon alfa.

The most pertinent question is whether it is cost effective to treat immediately people who have mild chronic hepatitis C with peginterferon alfa plus ribavirin or to wait until their disease reaches the moderate stage. If the rate of progression to moderate disease were sufficiently low, it would be better not to subject all people with mild disease to the significant side effects of combination therapy because few would progress to moderate disease or beyond.

The Assessment Report found six studies examining the cost effectiveness of treatment for patients with mild disease. Three of these studies compared interferon combination therapy with no treatment rather than with delayed treatment. These three studies showed that interferon combination therapy was cost effective when compared against standard care (all estimated mean incremental cost-effectiveness ratios [ICERs] were less than £10,000 per quality-adjusted life year [QALY]). Two studies compared early treatment with peginterferon alfa combination therapy against delayed treatment. They showed that for genotypes 2 and 3 early treatment is apparently cost effective when compared with delayed treatment, but the case for early treatment for genotype 1 is less clear.

The model employed in the Roche submission determined the cost effectiveness of peginterferon alfa‑2a plus ribavirin against no treatment. The estimated mean cost per QALY for treating patients with mild disease was £1,000 for genotypes 2 and 3, and £4,000 for genotype 1.

The model employed in the Schering-Plough submission determined the cost effectiveness of peginterferon alfa‑2b plus ribavirin against no treatment. The model is academic-in-confidence. The estimated mean cost per QALY for treating mild chronic hepatitis C was £1,000 for genotypes 2 and 3, and £3,000 for genotype 1.

The model developed by the Assessment Group incorporated seven health states: remission, mild disease, moderate disease, compensated cirrhosis, decompensated cirrhosis, liver cancer and liver transplantation. It used rates of sustained virological response from the manufacturers’ submissions and transition rates between the seven health states from a number of sources. For example, the estimated transition rate from mild to moderate disease as used in the model is 2.5% per year, which was obtained from observational data relating to 373 cases from a routine practice in a hospital in London between 1990 and 2001. Health-state utilities and costs were estimated from the UK mild hepatitis C trial. For comparability with the previous review, benefits were discounted at 1.5% per year and costs at 6%, with a sensitivity analysis at 3.5% for both costs and benefits.

HCV non-1 genotypes

For people with non-1 genotype infection, the base case estimated mean ICER for deferring treatment with peginterferon alfa-2a combination therapy until the disease reaches the moderate-to-severe stage relative to best supportive care (no treatment) is £1,300 per QALY. The corresponding ICER for peginterferon alfa-2b plus ribavirin is £1,400. This analysis confirms that the strategy of treating people with moderate or severe disease is cost effective compared with not treating them.

The estimated mean ICERs for early treatment with peginterferon alfa in combination with ribavirin when compared against deferring treatment until the disease reaches the moderate-to-severe stage in people with non-1 genotype infection are £3,700 for peginterferon alfa-2a and £4,300 for peginterferon alfa-2b. This analysis shows that treatment of mild disease compared with waiting until the patient reaches the moderate stage of the disease is cost effective. These are the key cost-effectiveness estimates for this appraisal.

Further analysis shows that combination therapy with pegylated interferon is cost effective when compared against the corresponding non-pegylated therapy for treating people with mild disease.

HCV genotype 1

For people with genotype 1 infection, the base case estimated mean ICER for watchful waiting followed by treatment with peginterferon alfa-2a combination therapy when the disease reaches the moderate-to-severe stage, relative to best supportive care (no treatment), is £6,900 per QALY. The corresponding ICER for peginterferon alfa-2b plus ribavirin is £4,700. This analysis confirms that the strategy of treating only moderate or severe disease is cost effective compared with not treating the infection.

For people with genotype 1 infection, the estimated mean ICERs for early treatment with peginterferon alfa in combination with ribavirin when compared against deferring treatment until the disease reaches the moderate-to-severe stage are £10,300 for peginterferon alfa-2a and £8,300 for peginterferon alfa-2b. This analysis shows that treating mild disease is cost effective compared with waiting until the patient reaches the moderate stage. These are the key cost-effectiveness estimates for this appraisal.

Further analysis shows that pegylated interferon combination therapy is cost effective against the corresponding non-pegylated therapy for treating people with mild disease.

Monotherapy: all genotypes

In people unable to take ribavirin, monotherapy with peginterferon may be used. The estimated mean ICER for early treatment with peginterferon alfa monotherapy against the same treatment deferred until a later stage is £3,000 per QALY for peginterferon alfa-2a and £2,300 for peginterferon alfa-2b.

Sensitivity analyses

Estimated mean ICERs are even lower using current stopping rules, whereby treatment is stopped at 12 weeks if a 100-fold reduction in viral load has not occurred.

Sensitivity analyses conducted in the Assessment Report do not lead to ICERs of more than £20,000 except when the average age of patients is increased by 15 years.

The Committee reviewed the data on the clinical effectiveness and cost effectiveness of i nterferon alfa (pegylated and non-pegylated) and ribavirin for treating mild chronic hepatitis C. The Committee considered evidence from people who have, or have had, the condition on the nature of the condition and the value placed on the benefits of this treatment, as well as evidence from those who represent them and clinical experts. The Committee was also mindful of the need to take account of the effective use of NHS resources.

The Committee heard from clinical and patient experts that studies show the quality of life of people with mild disease, even in the absence of histological evidence of definitive liver disease, is on average lower than that of people who have had mild disease and who have been cleared of the virus. The experts advised the Committee that such a difference in quality of life is an important contributor to the benefit of early treatment of mild disease.

The Committee also heard from the experts that sustained virological response, when the virus is undetectable 6 months after treatment has finished, is maintained for 10 years in more than 90% of people. Additionally, it is unusual for re-infection with HCV to occur once a sustained virological response has been achieved. These observations were consistent with the assumptions of the cost effectiveness model used in the Assessment Report. The Committee therefore concluded that the model inputs were appropriate in these respects.

The Committee understood that about 3,000 people in England and Wales who are treated each year have a sustained virological response and are effectively cured, but that the number of new cases is greater than the number of people being cured, and that the number of people with the disease is therefore still rising.

The Committee heard that early treatment of people with chronic hepatitis C in the general population could potentially reduce the likelihood of the spread of infection and that this would lead to a better estimate of cost effectiveness than that demonstrated in the models, where the effect of the spread of infection had not been considered.

The Committee considered that although the predicted effectiveness of the treatment of mild disease in a clinical setting was not as high as the average efficacy seen in the clinical trials, this difference was not likely to affect the importance of the therapy or overall cost effectiveness.

The Committee considered estimates used in the models of improvements in quality of life for people receiving treatment for mild disease and whether these improvements were importantly different from the improvements seen in mild and moderate disease. The Committee heard that many people infected with chronic hepatitis C believe that they are stigmatised and discriminated against, which further reduces their quality of life. Clearing the disease is thus associated with improvements that may not be reflected in economic models, and this could lead to an underestimate of the benefits of treatment.

After discussion with the experts and the Assessment Group, the Committee was persuaded that the estimated ICERs for combination therapy or monotherapy with peginterferon alfa for mild disease remained below £26,000 per QALY even if only very small improvements in quality of life (1%) were considered. This was the same for all genotypes. The estimated ICER could be as high as £42,000 per QALY for genotype 1 (the genotype with the highest estimated ICER) only when there was assumed to be no improvement in quality of life when mild disease was cleared. The Committee was not persuaded that this latter scenario was appropriate, and the range of predicted ICERs less than £26,000 per QALY was therefore acceptable.

The Committee discussed the progression rates (from mild to moderate disease). The Committee was told that there is no way of knowing which patients are likely to progress from mild disease to moderate disease, but that progression is somewhat slower for younger patients, for those who have been infected for a shorter time, for females and for different ethnic groups. The committee considered at length the progression rates assumed in the Assessment Report model, and noted that these were from clinical trials of people who presented for treatment. The Committee appreciated that this may represent a small proportion of the total number thought to be infected with HCV and that people who were asymptomatic and had not sought treatment may experience a different rate of progression on average from those who had sought treatment. The Committee accepted that low rates of progression would mean that treating people with mild disease may affect the overall cost effectiveness of early treatment when compared with watchful waiting. The Committee considered that while it may be that among the population of all people with mild disease, low progression rates may exist, it was likely that the progression rates found in clinical studies and used in the cost-effectiveness analysis would be applicable to people with mild disease who present for treatment. The Committee therefore concluded that the estimated ICERs in the clinical setting currently pertaining in England and Wales would not be unacceptably high.

The Committee recognised that if a much higher proportion of people with mild disease were to be diagnosed (for example from a screening programme), the average progression rate of such a group could be so low that it would no longer be optimal to offer early treatment. That is, the Committee considered that the cost effectiveness of treating all people with mild disease identified as a result of a screening programme has yet to be proven, and that the guidance to treat people with mild disease would not necessarily apply to a screened population.

The Committee was persuaded by the experts that the previous guidance (NICE technology appraisal no. 75) on treating people with moderate chronic hepatitis C who continue to use intravenous drugs and/or misuse alcohol and people co-infected with HIV should be extended to members of all such groups who have mild disease.(In the guidance for people with moderate or severe disease, the Committee concluded with respect of those continuing to use intravenous drugs: “ The Committee was prepared to accept that in naturalistic settings, the rate of discontinuation [of treatment] would not be so great as to prevent the treatment being cost effective”. With respect to people who continue consuming alcohol, in the guidance for people with moderate or severe disease , the Committee “considered that continued alcohol consumption was, however, not in itself an absolute contraindication to therapy but should be emphasised as an important factor to be taken into account in advice and information given by the clinical team”.)

The Committee was mindful that the guidance on recommending treatment for mild disease caused by all genotypes would mean that liver biopsy will no longer be required to diagnose the severity of the disease before treatment can be initiated. It was felt that this would increase the uptake of treatment among patients unwilling to undergo this procedure. Additionally, it would reduce the cost of disease management somewhat and also reduce the pain and complications associated with liver biopsy. The Committee heard from a clinical expert that the number of biopsies carried out in people with chronic hepatitis C may not fall a great deal because biopsies would still be recommended for older patients – to determine the extent of liver damage – and for a range of patients – for reasons not directly related to the decision to initiate therapy.

The Committee was mindful that the guidance on recommending treatment for mild disease caused by all genotypes would mean that liver biopsy will no longer be required to diagnose the severity of the disease before treatment can be initiated. It was felt that this would increase the uptake of treatment among patients unwilling to undergo this procedure. Additionally, it would reduce the cost of disease management somewhat and also reduce the pain and complications associated with liver biopsy. The Committee heard from a clinical expert that the number of biopsies carried out in people with chronic hepatitis C may not fall a great deal because biopsies would still be recommended for older patients – to determine the extent of liver damage – and for a range of patients – for reasons not directly related to the decision to initiate therapy.

The Committee decided that the guidance pertaining to moderate or severe disease (NICE technology appraisal no. 75) should be retained unchanged for mild disease with respect to the length of treatment for different genotypes for patients requiring monotherapy for second courses of treatment and for treatment of people under the age of 18 years or who have had a liver transplant.

Proposed recommendations for further research

Research is needed on the quality of life and progression rates among a random sample of people with mild disease, compared with people presenting for treatment. This research might also include retrospective studies of progression among people who have already been diagnosed for reasons other than having symptoms of the disease.

Preliminary views on the resource impact for the NHS

The NICE Costing Unit is currently developing this section. A costing template and report will be available at the time of publication of the final guidance.

Proposals for implementation and audit

This section presents proposals for implementation and audit based on the preliminary recommendations for guidance in section 1.

All clinicians who care for people with chronic hepatitis C should review their practice and policies to take account of the guidance set out in section 1.

Local guidelines, protocols or care pathways that refer to the care of people with chronic hepatitis C should incorporate the guidance.

To measure local compliance with the guidance, the following criteria could be used. Further details on suggestions for audit are presented in appendix C.

A person with mild chronic hepatitis C who is 18 years or older and who has not had a liver transplant is offered the option of treatment with combination therapy comprising peginterferon alfa-2a and ribavirin or peginterferon alfa-2b and ribavirin, within the licensed indications of these drugs.

If a person with mild chronic hepatitis C who is 18 years or older and who has not had a liver transplant is unable to tolerate ribavirin or ribavirin is contraindicated, the person is offered the option of monotherapy with peginterferon alfa-2a or peginterferon alfa-2b, within the licensed indications of these drugs.

A person with mild chronic hepatitis C who is 18 years or older and who has not had a liver transplant makes the decision on immediate treatment with combination therapy or monotherapy or waiting until the disease has reached a moderate stage, after consultation with the responsible clinician.

For a person with mild chronic hepatitis C who is 18 years or older and has not had a liver transplant and who decides to have combination therapy, treatment is carried out as follows.

• If the person is infected with HCV genotype 2 or 3, treatment lasts for 24 weeks.
• If the person is infected with HCV genotype 1, 4, 5 or 6 (or infected with more than one genotype including at least one of genotype 1, 4, 5 or 6), initial treatment is for 12 weeks. If after 12 weeks the viral load has been reduced to less than 1% of its level at the start of treatment, then treatment is continued for 48 weeks. If the viral load at 12 weeks exceeds 1% of its level at the start of treatment, then treatment is discontinued

For a person with mild chronic hepatitis C who is 18 years or older and has not had a liver transplant and who is prescribed peginterferon alfa monotherapy, regardless of genotype, treatment is carried out as follows.

• The person is tested for viral load after 12 weeks. If the viral load has been reduced to less than 1% of its level at the start of treatment, then treatment is continued for 48 weeks.

For a person with mild chronic hepatitis C who has had combination therapy but who has not had a sustained response, a second course of combination therapy is not provided.

Related guidance

NICE has issued the following related technology appraisals.

Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C. NICE technology appraisal no. 75 (January 2004). Available from: www.nice.org.uk/TA075

Proposed date for review of guidance

The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.

The original date proposed for a full review of this topic was November 2006. Given the completion date of this part-review, it is proposed that the guidance on this technology be considered for review in November 2008. The Institute would particularly welcome comment on this proposed date.

David Barnett

Chair, Appraisal Committee

February 2006

The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets twice a month except in December, when there are no meetings. The Committee membership is split into two branches, with the chair, vice chair and a number of other members attending meetings of both branches. Each branch considers its own list of technologies and ongoing topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Jane Adam
Radiologist, St George's Hospital, London

Professor A E Ades
MRC Senior Scientist, MRC Health Services Research Collaboration, Department of Social Medicine, University of Bristol

Dr Tom Aslan
General Practitioner, Stockwell, London

Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester

Mrs Elizabeth Brain
Lay Representative

Dr Richard Cookson
Senior Lecturer in Health Economics, School of Medicine Health Policy and Practice, University of East Anglia

Mrs Fiona Duncan
Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool

Professor Christopher Eccleston
Director Pain Management Unit, University of Bath

Dr Paul Ewings
Statistician, Taunton and Somerset NHS Trust, Taunton

Professor Terry Feest
Professor of Clinical Nephrology, Southmead Hospital

Ms Alison Forbes
Lay Representative, Health Consultant Associate, Eden Insight

Professor John Geddes
Professor of Epidemiological Psychiatry, University of Oxford

Mr John Goulston
Director of Finance, Barts and the London NHS Trust

Mr Adrian Griffin
Health Outcomes Manager, Johnson & Johnson Medical

Ms Linda Hands
Consultant Surgeon, John Radcliffe Hospital

Dr Elizabeth Haxby
Lead Clinician in Clinical Risk Management, Royal Brompton Hospital

Dr Rowan Hillson
Consultant Physician, Diabeticare, The Hillingdon Hospital

Dr Catherine Jackson
Clinical Lecturer in Primary Care Medicine, Alyth Health Centre, Angus

Professor Richard Lilford
Professor of Clinical Epidemiology, Department of Public Health and Epidemiology, University of Birmingham

Dr Simon Mitchell
Consultant Neonatal Paediatrician, St Mary's Hospital, Manchester

Ms Judith Paget
Chief Executive, Caerphilly Local Health Board

Dr Kather