The Department of Health and the Welsh Assembly Government have asked the National Institute for Clinical Excellence (NICE or the Institute) to conduct an appraisal of interferon alpha (pegylated and non-pegylated) and ribavirin in the treatment of 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 alpha (pegylated and non-pegylated) and ribavirin in the treatment of 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).

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 on the Institute's website).

• 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: Monday 1 September 2003
Second Appraisal Committee meeting: Wednesday 10 September 2003

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.

Combination therapy with pegylated interferon alpha and ribavirin, at usual doses and as described in 1.1.1 and 1.1.2, is recommended for the treatment of people over the age of 18 years with moderate to severe chronic hepatitis C (CHC), defined as histological evidence of significant scarring (fibrosis) and/or significant necrotic inflammation.

People who have not previously been treated with interferon alpha (standard or pegylated, as monotherapy or in combination therapy), those who have received standard interferon alpha monotherapy or combination therapy and cleared the virus at the end of therapy but have subsequently relapsed, and those who have been treated previously with standard interferon alpha therapy (whether in combination with ribavirin or not) and who did not respond to it, should be treated as follows.

• People infected with hepatitis C virus (HCV) of genotype 2 or 3, treat for 24 weeks.
• People infected with HCV of genotype 1, 4, 5 or 6, after 12 weeks of treatment, test for circulating viral RNA using PCR. Where the viral load has been reduced to less than 1% of its level at the start of treatment (a fall of at least 2 log₁₀ units, see Section 4.1.2.7), continue treatment for a total of 48 weeks. Where PCR shows that the viral load exceeds 1% of its level at the start of treatment, do not continue treatment.
  

People satisfying the conditions in 1.1.1 but for whom ribavirin is contraindicated or is not tolerated should be treated with pegylated interferon alpha monotherapy. Regardless of genotype, individuals should be tested for viral load at 12 weeks, and if the viral load has reduced to less than 1% of its level at the start of treatment, treatment should be continued for a total of 48 weeks.

People who have been treated with pegylated interferon alpha combination therapy and whose hepatitis C was not responding at the end of treatment should not be treated a second time.

There is insufficient evidence to support making recommendations on the use of combination therapy using pegylated or standard interferon alpha for people younger than 18 years of age.

There is also insufficient evidence to support making recommendations on the use of combination therapy after liver transplantation. Treatment of CHC recurrence after liver transplantation (whether or not the person had been treated with interferon alpha therapy at any time prior to transplantation) should be considered as experimental and carried out only in the context of a clinical trial.

Treatment for CHC should be provided by specialist physicians with access to supportive services. Care for people with HCV should include the following.

• Careful monitoring of side effects, by both self-report and laboratory tests, on a regular and consistent basis.
• Individualised care that provides time for discussion and support during and after therapy, including informed decision-making.
• Collaboration with services catering for HIV (if co-infection is an issue), addiction (if drug or alcohol abuse is) and oncology or transplantation.
• Centralised management, preferably via a clinical nurse specialist and a physician with clinical expertise in the management of CHC and access to diagnostics, including virology and pathology as indicated.

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. Before the introduction of screening in 1991 it was spread through blood transfusions. Before the viral inactivation programme in the mid-1980s it was also spread through blood products. It can be acquired through intravenous drug use and the sharing of needles. There is a small risk associated with tattooing, electrolysis, ear piercing and acupuncture. Infection through sexual intercourse can also occur. There is a transmission rate of about 6% from mother to child if the mother is an HCV carrier. Concomitant HIV infection is thought to increase the risk of transmission.

People are often asymptomatic after exposure to the virus, but about 20% will develop acute hepatitis: some of these will experience malaise, weakness and anorexia. Up to 85% of those exposed do not clear the virus and go on to develop CHC. Progression of the disease occurs over 20-50 years. About 20-30% of those initially infected develop cirrhosis within 20 years and a small percentage of these are at high risk of developing hepatocellular carcinoma. One third may never progress to cirrhosis or will not progress for at least 50 years. Some people with end-stage liver disease or hepatocellular carcinoma may require liver transplantation.

The ease with which the virus can be cleared is partly related to its genotype, because the immune system responds differently to the different genotypes. Six major genetic types of HCV have been found, of differential virulence. Genotype 1 (G1) is the most common in the UK, and is found in about 40-50% of cases. Genotypes 2 and 3 (G2/3) contribute another 40-50%, and genotypes 4, 5 and 6 constitute the remainder of about 5%.

Many individuals with HCV infection do not display symptoms. However, non-specific symptoms including fatigue, irritability, nausea, muscle ache, anorexia, abdominal discomfort and right upper quadrant pain have been reported even in the absence of secondary pathology. If cirrhosis develops, people may have severe symptoms and complications.

Estimates of prevalence for hepatitis C in England and Wales vary considerably. The extant NICE guidance (see Section 8.1) puts the figure between 200,000 and 400,000, while the Assessment Report suggests between 50,000 and 500,000. There is also great variation in prevalence between certain 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.

About two-thirds of people with HCV infection are men, mainly because there are far more men with haemophilia and more men are injecting drug users.

Because it is not possible to measure directly the effectiveness of treatment in reducing progression to cirrhosis and hepatocellular carcinoma in the short term, three surrogate markers have been used in trials: hepatic histology; virological loss of HCV-RNA (by quantitative polymerase chain reaction, PCR); and levels of alanine aminotransferase (ALT, an enzyme that indicates liver inflammation).

The primary aims of treatment for people with CHC are to achieve acceptable ALT levels and to clear HCV (defined as undetectable HCV-RNA in the serum), with both sustained for at least 6 months after treatment cessation, in order to improve quality of life for patients and reduce the risk of cirrhosis and hepatocellular carcinoma.

The diagnosis of hepatitis C causes considerable anxiety to people. It is generally accepted that all people diagnosed with the condition should receive adequate counselling from a health carer with knowledge and experience in the field.

Interferon alpha, used as monotherapy or in combination with ribavirin, is the only licensed treatment for CHC. The precise antiviral mode of action of interferon is unknown. However, it appears to alter host-cell metabolism. It is available in the UK in two forms, interferon alpha 2a (Roferon A) and interferon alpha 2b (Viraferon).

Treatment with monotherapy is for either 24 or 48 weeks, depending on the genotype of the virus. For monotherapy, more than half of those who clear the virus after treatment relapse within 6 months of stopping treatment, but for those who remain clear after 6 months, it appears that about 90% remain clear after 6 years. Thus, for this group, treatment may arguably be called a cure. Treatment with standard interferon alpha is usually at the dose of 3 million units three times per week by subcutaneous injection. Injections may be administered by clinical staff or by the patient after adequate training. People who respond usually do so within 12-16 weeks, but some have to continue with this dose of interferon alpha for 48 weeks.

Many, although not all, people find interferon alpha therapy very hard to tolerate. After each injection, they may suffer influenza-like symptoms, and up to half of all treated people suffer from fatigue, headaches, pyrexia (fever), myalgia (aches and pains), insomnia and/or nausea. About a quarter suffer hair loss, arthralgia (pain in the joints), rigors, irritability, pruritis (itching), depression, dermatitis and/or decreased appetite. There are significant problems of dropout and non-compliance with treatment as a result. Dropout rates of 7-14% have occurred. Figures on compliance are more difficult to quantify.

In the late 1990s, combination treatment of standard interferon alpha and ribavirin commenced, following trials that showed that although ribavirin alone showed no activity against HCV, the effect of the combination of ribavirin with interferon alpha was much enhanced compared with that of interferon alpha alone. Since the introduction of combination therapy, monotherapy is used only for people unable to tolerate ribavirin.

Ribavirin (Copegus; Rebetol) is a nucleoside analogue with a broad spectrum of antiviral activity against RNA viruses. It is currently licensed for use in combination with interferon alpha 2a and/or interferon alpha 2b for treatment of CHC in:

• adult patients with histologically proven, previously untreated CHC, without liver decompensation, who are positive for serum HCV-RNA and who have fibrosis or high inflammatory activity
• adult patients with CHC who have previously responded (with normalisation of ALT at the end of treatment) to interferon alpha but subsequently relapsed.
  

Ribavirin is administered orally, usually in divided doses (200 mg per capsule). The dosage varies according to the patient's weight. In conjunction with interferon alpha 2a, people weighing less than 75 kg take 1000 mg per day and people weighing more than 75 kg take 1200 mg. In conjunction with interferon alpha 2b, the dose is 800 mg for those weighing less than 65 kg, 1000 mg for those weighing 65-85 kg and 1200 mg for those heavier than 85 kg. Regular monitoring of full blood count to detect haemolytic anaemia is needed in order to judge whether to reduce or cease ribavirin treatment.

Ribavirin is contraindicated in pregnancy and breastfeeding, in severe debilitating medical conditions (particularly of the heart, blood, kidneys and liver), and in the presence of autoimmune diseases or severe psychiatric conditions. It may also cause haemolytic anaemia, for which close monitoring is required, and a reduction in dose or cessation of treatment may be necessary.

Adverse effects related to combination therapy are similar in type and frequency to those of interferon alpha monotherapy and include influenza-like symptoms (fatigue, headache, fever), decreases in haematological parameters (neutrophil count, white blood cell, platelet), gastrointestinal complaints (anorexia, nausea), dermatological symptoms (alopecia) and psychiatric disturbances (depression, anxiety). The trials indicate that discontinuation of treatment is more frequent (10-20%) for combination therapy than for monotherapy. For combination therapy, haematological events were the most common reason for either study withdrawal or dose reduction.

The following factors affect the efficacy of treatment.

• Genotype of the virus is the most important determinant of efficacy of treatment.
• The higher the viral load, the lower the proportion of people with HCV who have a sustained virological response (other things being equal). This is the second most important determinant of efficacy of treatment.
• Younger people fare better than older people. This may be because HCV has been infecting older people for longer, but it appears to be an independent factor beyond that.
• Fibrosis and cirrhosis of the liver act as markers for the damage done by the virus. The greater the damage, the less likely it is that the body can rid itself of the virus.
• The higher the pretreatment ALT, the lower the probability of treatment success.
• Studies in the USA have shown that black people had poorer response to treatment than white people, but there is no evidence of the impact of ethnicity in a UK setting.
• Women respond somewhat better to treatment than do men.
  

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

The standard measurement of effectiveness of treatment of CHC is the virological response rate sustained for 6 months, called the SVR. SVR has been shown to be a good surrogate for biopsy and ALT results taken from the same people at the same time.

Pegylated combination therapy versus standard combination therapy

Pegylated monotherapy versus standard monotherapy

Many people with haemophilia were infected by blood products, in most cases by HCV G1. Many cases of G1 did not respond to monotherapy, or relapsed within 6 months. Small studies showed that a small but significant proportion of these relapsers and non-responders respond to pegylated combination therapy.

Other patient subgroups: HIV comorbidity

It is common for people with CHC to be co-infected with HIV, because of their common transmission routes. Several patient submissions, one manufacturer and the Assessment Report examined this set of circumstances.

In people infected with both viruses, the rate of progression of CHC is much faster.

Several small trials have been conducted, all involving interferon alpha 2b, which show that the therapies work in the same fashion as for those who do not have HIV infection, except that the SVRs are of the order of 30% lower (for example, 35% instead of 50%).

There is no evidence that interferon alpha interacts with drugs taken for HIV, but there is evidence that ribavirin could do so when taken with pegylated interferon, and may prove toxic. Additional care is called for when monitoring such people.

Other patient subgroups: injecting drug users

There is a need to distinguish between current injecting drug users and those on methadone or other substitution drug therapies. The former have high rates of discontinuation in trials and relatively high rates of psychiatric comorbidities, and thus do not achieve high success rates with interferon therapy. The latter, in a study of 47 people with CHC on methadone treatment against 47 matched pairs with CHC not on methadone, showed that the SVR for those on methadone treatment was 63% compared with 78% for those in the control group (p = 0.15).

Other patient subgroups: people with heavy alcohol consumption

Heavy alcohol consumption (more than 7 units per week in this context) not only increases liver damage for those infected with HCV, but also adversely affects its treatment.

Other patient subgroups: liver transplants

People with HCV who require a liver transplant will usually develop the disease in the new liver. Limited data on six people showed that four people responded to pegylated combination therapy with interferon alpha 2b.

Other patient subgroups: age, sex and ethnicity

Some differences have been observed in the success of treatment between people of different ages, between men and women, and between people of different ethnicity. These differences are relatively small compared with those resulting from viral genotype or viral load.

Other patient subgroups: mild CHC

Trials in people with mild disease have not yet reported, and this appraisal focuses on the treatment of moderate or severe CHC.

Cost effectiveness

Pegylated combination therapy versus standard combination therapy. The Assessment Report shows that pegylated combination therapy is a very cost effective intervention. For G2/3, only the first 24 weeks of treatment are cost effective. For G1+ , 48-week treatment is cost effective (See Table 1).

Pegylated combination vs standard combination

£11,000

Pegylated combination vs standard combination

4-6

£9,000

Pegylated combination vs standard combination

Not 1

24

£1,100

Pegylated combination (24 weeks) vs pegylated combination (48 weeks)

Not 1

24 weeks vs 48

£69,000* compared with 24 week treatment

Pegylated combination (24 weeks) vs pegylated combination (48 weeks)

1

24 weeks vs 48

£15,000* compared with 24 week treatment

For monotherapy, all treatments are for 48 weeks (see Table 2).

Pegylated monotherapy vs standard monotherapy

Pegylated monotherapy vs standard monotherapy

2 and 3

£7,000

Pegylated monotherapy vs standard monotherapy

4-6

£2,000

Consideration of the evidence

The Committee reviewed the evidence available on the clinical and cost effectiveness of treatment with interferon alpha and ribavirin in chronic hepatitis C, having considered evidence on the nature of the condition and the value placed by users on the benefits of interferon alpha and ribavirin from people with HCV, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources.

The Committee considered that pegylated interferon alpha combination therapy was both clinically and cost effective compared with standard interferon alpha combination therapy; in addition, that pegylated interferon alpha monotherapy was both clinically and cost effective compared with standard interferon alpha monotherapy. Pegylated interferon alpha therapy should therefore supersede treatment using standard interferon alpha for all people. Combination therapy should also be used rather than monotherapy, except for people for whom ribavirin is contraindicated or cannot be tolerated.

The Committee further considered the clinical and cost effectiveness of pegylated interferon alpha 2a versus pegylated interferon alpha 2b. Although it was aware that the two drugs were administered differently, and had somewhat different pharmacokinetics it considered, with expert evidence received, that the clinical effectiveness of the two products was essentially comparable. In particular, in the absence of any head-to-head trials, the Committee considered that the evidence did not generally favour one of these products over another. The Committee accepted that clinicians wished to have both products available in order to target different groups of people under particular clinical circumstances.

The Committee understood that the responsiveness to therapy (as measured by SVR) was directly related to HCV genotype. Thus on the basis of the evidence reviewed it concluded that HCV G2 and 3 should be treated in a similar fashion and should be considered differently from genotypes 4, 5 and 6, which should be treated as for G1. Thus, for combination therapy, people with G2/3 should receive 24 weeks' treatment while those with all other genotypes who have demonstrated a sufficient initial response should receive 48 weeks' treatment.

For combination therapy, the Committee discussed the requirement for testing for viral load at 12 weeks after the initiation of treatment as a means of assessing response. For G2/3, the number of non-respondents at this stage was such a small proportion that testing them to exclude further treatment was not considered cost effective. For all other genotypes, because the proportion of non-responders was much higher than for G2/3, the viral load response at 12 weeks is important to inform the need for treatment up to 48 weeks.

The Committee considered the use of pegylated interferon alpha for combination therapy in groups of people with HCV infection that were not represented in the pivotal clinical trials. This included haemophiliacs and people co-infected with HIV. The Committee concluded that, based on the evidence available, there was no reason to make any different provision for these groups than in the general guidance. It did, however, note that there might be occasions where ribavirin may interact with medication for HIV, necessitating either a change in the latter or a switch to pegylated interferon alpha monotherapy.

The Committee heard that although injecting drug users with HCV might seek treatment less frequently, on average, than other people with HCV, those who did had similar compliance rates to other people with HCV. Furthermore, the evidence provided by the experts persuaded the Committee that current information indicated that HCV re-infection rates for those on interferon therapy were low in those who continue to use intravenous drugs.

The Committee found the case of people with HCV who continue to drink alcohol to be more problematic. It heard that continued alcohol consumption even at relatively low levels of intake (compared with recommended maximum levels for the general population) might be harmful in people with HCV-induced liver disease. This is because of the effect of alcohol on the progression of liver disease and also because alcohol reduces the efficacy of interferon as therapy for HCV. 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 the counselling by the clinical team.

For people unable to take ribavirin the Committee decided that pegylated interferon alpha monotherapy should be the treatment of choice, because it is both clinically and cost effective compared with standard interferon alpha monotherapy, despite lower clearance rates of the virus than for combination therapy. All people on pegylated interferon alpha monotherapy should receive treatment for 48 weeks, regardless of genotype, because it was noted that there is currently no evidence for the effectiveness of a shorter period (24 weeks) of treatment. The requirement for 12 weeks' viral load testing was also considered for this group, and it was concluded that it should apply to people with every HCV genotype. Although there was no direct evidence of the cost-effectiveness for this recommendation, it could reasonably be assumed that viral testing at 12 weeks would be at least as cost effective as in combination therapy, and there was no evidence to support G2/3 being treated any differently from other genotypes. The provisos for combination therapy in Section 4.3.3, and Sections 4.3.5 to 4.3.9, also apply to treatment with monotherapy.

The Committee considered the treatment of people classified on the basis of liver biopsy as having mild chronic HCV. It was aware that there were two trials of people with mild disease that would be shortly be reporting. The correct and cost effective management of this group was considered very important and although people with mild disease represent a small subgroup of the current RCT evidence base, it was decided that waiting for the current specific trials to report would provide a more robust basis on which to provide guidance to the NHS.

The Committee discussed the question of the need for liver biopsy at some length. It concluded that, because the basis for the extant guidance (see Section 8.1) required the definition of the extent of liver disease, the requirement for biopsy before deciding on appropriate therapy should remain. It was persuaded that alternative non-invasive tests of liver function could not currently be relied upon to act as appropriate surrogates for direct histological examination. However, it considered that in due course the result of the trials in mild disease might affect this requirement. The Committee believed that there were grounds for making exceptions for people with haemophilia and risk of bleeding, and for those with extra-hepatic symptoms sufficient to merit treatment.

For people who have had a course of standard interferon alpha monotherapy or combination therapy but who did not show a response at the end of treatment (that is, the amount of virus circulating in the blood failed to fall below 1% of its pretreatment level), re-treatment with pegylated interferon alpha combination therapy will result in a response in a small proportion of cases. The Committee decided, after hearing from the experts and from viewing cost effectiveness analysis (supplied by the Assessment Group between the meeting and the release of the ACD), that re-treatment with pegylated interferon alpha combination therapy is recommended for anyone previously treated with standard interferon alpha, whether as monotherapy or in combination.

The Committee considered that the effective delivery of the guidance in Section 1 would be critically dependent on the context and structure of the care environment for people with HCV. Thus, it concluded that the decision to undertake therapy should only be initiated by a physician with specialist knowledge of the treatment of HCV. Additionally it is important that a clinical team including specialist nurses and counselling staff is available for lifestyle advice to facilitate the informed decision of the individual to undertake treatment and to help him or her successfully complete the course of therapy.

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