Ta75 hepatitis c - pegylated interferons, ribavirin and alfa interferon: guidance

NHS
National Institute for
Clinical Excellence
Interferon alfa (pegylated
and non-pegylated) and
ribavirin for the treatment
of chronic hepatitis C
This guidance is a review and extension of Technology Appraisal Guidance No. 14 issued in October 2000.
Technology Appraisal 75
January 2004
Technology Appraisal Guidance 75
Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment for chronic hepatitis C
Issue date: January 2004
Review date: November 2006
This document, which contains the Institute's full guidance for this appraisal, is available from theNICE website (www.nice.org.uk/TA075guidance).
An abridged version of this guidance (a 'quick reference guide') is also available from the NICEwebsite (www.nice.org.uk/TA075quickrefguide). Printed copies of the quick reference guide can beobtained from the NHS Response Line: telephone 0870 1555 455 and quote reference number N0427.
Information for the Public is available from the NICE website or from the NHS Response Line (quotereference number N0428 for a version in English and N0429 for a version in English and Welsh). The quick reference guide has been distributed to the following: • Primary care trust (PCT) chief executives• Local health board (LHB) chief executives• NHS trust chief executive in England and Wales• Strategic health authority chief executives in England and Wales• Medical and nursing directors in England and Wales• Clinical governance leads in NHS Trusts in England and Wales• Audit leads in NHS Trusts in England and Wales• NHS trust, PCT and LHB libraries in England and Wales• Patient advice and liaison co-ordinators in England• Consultant hepatologists and gastroenterologists in England and Wales• Consultants in infectious diseases• Consultants in genito-urinary medicine in England and Wales• Senior pharmacists and pharmaceutical advisors in England and Wales• NHS Director Wales• Chief Executive of the NHS in England• Chief medical, nursing and pharmaceutical officers in England and Wales• Medical Director & Head of NHS Quality – Welsh Assembly Government• Commission for Health Improvement• NHS Clinical Governance Support Team• Patient advocacy groups• Representative bodies for health services, professional organisations and statutory bodies, and the This guidance is written in the following context:
This guidance represents the view of the Institute, which was arrived at after careful consideration
of the available evidence. Health professionals are expected to take it fully into account when
exercising their clinical judgement. This guidance does not, however, override the individual
responsibility of health professionals to make appropriate decisions in the circumstances of the
individual patient, in consultation with the patient and/or guardian or carer.
National Institute for
Clinical Excellence
MidCity Place71 High HolbornLondonWC1V 6NA ISBN: 1-84257-507-4Published by the National Institute for Clinical ExcellenceJanuary 2004Typeset by Icon Design, Eton National Institute for Clinical Excellence. January 2004 All rights reserved. This material may be freely reproducedfor educational and not for profit purposes within the NHS. No reproduction by or for commercial organisations is permitted without the express written permission of the Institute.
Contents
Guidance
Clinical need and practice
The technology
Evidence and interpretation
Recommendations for further research
Implications for the NHS
Implementation and audit
Related guidance
Review of guidance
Appendix A:
Appendix B:
Appendix C:
This guidance is a review and extension of Technology AppraisalGuidance No. 14 issued in October 2000.
The Institute reviews each piece of guidance it issues. The reviewand re-appraisal has resulted in an extension to the guidance: • combination therapy with pegylated interferon alfa and ribavirin is recommended for the treatment of people aged 18years and over with moderate to severe chronic hepatitis C.
Guidance
Combination therapy with peginterferon alfa and ribavirin isrecommended within its licensed indications for thetreatment of people aged 18 years and over with moderateto severe chronic hepatitis C (CHC), defined as histologicalevidence of significant scarring (fibrosis) and/or significantnecrotic inflammation.
People with moderate to severe CHC are suitable fortreatment if they have: • not previously been treated with interferon alfa or • been treated previously with interferon alfa (as monotherapy or in combination therapy), and/or • previously received peginterferon alfa monotherapy only and responded at the end of treatment but subsequentlyrelapsed, or did not respond at the end of treatment.
People currently being treated with interferon alfa, either ascombination therapy or monotherapy, may be switched tothe corresponding therapy with peginterferon alfa.
Treatment for the groups identified in Sections 1.1 and 1.2should be as follows.
• People infected with hepatitis C virus (HCV) of genotype 2 and/or 3 should be treated for 24 weeks. • For people infected with HCV of genotype 1, 4, 5 or 6, initial treatment should be for 12 weeks. Only peopleshowing, at 12 weeks, a reduction in viral load to less than1% of its level at the start of treatment (at least a 2-logreduction, see Section 4.1.2.5) should continue treatmentuntil 48 weeks. For people in whom viral load at 12 weeksexceeds 1% of its level at the start of treatment,treatment should be discontinued.
• People infected with more than one genotype that includes one or more of genotypes 1, 4, 5, or 6 should betreated as for genotype 1. People satisfying the conditions in Sections 1.1 and 1.2 butfor whom ribavirin is contraindicated or is not toleratedshould be treated with peginterferon alfa monotherapy.
Regardless of genotype, individuals should be tested for viralload at 12 weeks, and if the viral load has reduced to lessthan 1% of its level at the start of treatment, treatmentshould be continued for a total of 48 weeks. If viral load hasnot fallen to this extent, treatment should stop at 12 weeks. People for whom liver biopsy poses a substantial risk (such asthose with haemophilia, or those who have experienced anadverse event after undergoing a previous liver biopsy), andpeople with symptoms of extra-hepatic HCV infectionsufficient to impair quality of life, may be treated on clinicalgrounds without prior histological classification.
There is insufficient evidence to recommend combinationtherapy using peginterferon alfa or interferon alfa in peoplewho: • have previously been treated with combination therapy • are younger than 18 years of age, and/or • have had a liver transplantation. Treatment of CHC recurrence after liver transplantation (whether or not theperson had been treated with interferon alfa orpeginterferon alfa therapy at any time beforetransplantation) should be considered as experimentaland carried out only in the context of a clinical trial.
Clinical need and practice
Chronic hepatitis C (CHC) is a disease of the liver caused bythe hepatitis C virus (HCV). Generally, the virus is transmittedby blood-to-blood contact. Before the introduction ofscreening in 1991 it was also spread through bloodtransfusions. Before the viral inactivation programme in themid-1980s it was also spread through blood products. HCVcan be acquired by people who inject drugs through thesharing of needles. There is a small risk of infectionassociated with tattooing, electrolysis, body piercing andacupuncture. Infection through sexual intercourse can alsooccur. There is a transmission rate of about 6% from motherto child if the mother is an HCV carrier. Concomitant HIVinfection 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 themwill experience malaise, weakness and anorexia. Up to 85%of those exposed do not clear the virus and go on to developCHC. Progression of the disease occurs over 20–50 years.
About 5–30% of people initially infected will developcirrhosis within 20 years and a small percentage of these areat high risk of developing hepatocellular carcinoma. One-third may never progress to cirrhosis or will not progress forat least 50 years. Some people with end-stage liver disease orhepatocellular carcinoma may require liver transplantation.
Six major genetic types of HCV have been identified.
Genotype 1 (G1) is the most common in the UK, and is foundin about 40–50% of cases. Genotypes 2 and 3 (G2/3)contribute another 40–50%, and genotypes 4, 5 and 6constitute the remainder of about 5%. Response totreatment varies between different genotypes. G1 isrelatively more common among people infected throughblood products, and G2/3 is relatively more common amongpeople who inject themselves with illicit drugs.
Many individuals with HCV infection do not displaysymptoms. However, non-specific symptoms, such as fatigue,irritability, nausea, muscle ache, anorexia, abdominaldiscomfort and pain in the upper right quadrant, have beenreported even in the absence of secondary pathology. Ifcirrhosis develops, people may have severe symptoms andcomplications.
Estimates of prevalence for hepatitis C in England and Walesvary considerably. The extant NICE guidance (see Section 8.1)puts the figure between 200,000 and 400,000, whereas theAssessment Report suggests between 50,000 and 500,000.
There is also great variation in prevalence between certainsubgroups of the population: 0.04% in blood donors, 0.4%in people attending antenatal clinics (in London), 1% inpeople attending genito-urinary clinics and up to 50% ininjecting drug users.
About two-thirds of people with HCV infection are men,mainly because more men inject themselves with illicit drugs,but also because there are far more men than women withhaemophilia.
Because it is not possible to measure directly theeffectiveness of treatment in reducing progression tocirrhosis and hepatocellular carcinoma in the short term,three surrogate markers have been used in trials: hepatichistology; virological loss of HCV-RNA (measured by thepolymerase chain reaction, PCR); and levels of alanineaminotransferase (ALT, an enzyme that indicates liverinflammation).
The primary aim of treatment for people with CHC is to clearHCV (defined as undetectable HCV-RNA in the serum) for atleast 6 months after treatment cessation, in order to improvequality of life for patients and reduce the risk of cirrhosisand hepatocellular carcinoma. The diagnosis of hepatitis C causes considerable anxiety topeople. It is generally accepted, though without formal trialevidence, that all people diagnosed with the conditionshould receive adequate advice and information from ahealthcare professional with knowledge and experience inthe field.
The current standard treatment for moderate and severechronic HCV infection is combination treatment withinterferon alfa and ribavirin, except for people who cannottolerate ribavirin, when interferon alfa monotherapy is used(Section 8.1 references the NICE guidance that is replaced bythis guidance). The precise antiviral mode of action ofinterferon alfa is unknown. However, it appears to alter host-cell metabolism. It is available in the UK in two forms,interferon alfa-2a (Roferon A, Roche) and interferon alfa-2b(Viraferon, Schering-Plough).
Interferon alfa is eliminated from the body rapidly, having aplasma half-life of only about 4 hours. To maintaineffectiveness against HCV, doses must be administered byinjection on a minimum of 3 days a week.
The duration of monotherapy treatment is 48 weeks. Formonotherapy, more than half of people who clear the virusafter treatment relapse within 6 months of treatmentcessation, but for those who remain clear after 6 months,about 90% remain so after 6 years. Thus, for this group,treatment may be called a cure. The dosage for interferonalfa treatment is usually 3 million units three times per weekby subcutaneous injection. Injections are administered byclinical staff or by the patient after adequate training. Peoplewho respond usually do so within 12–16 weeks. Those whorespond continue with this dose of interferon alfa for 48 weeks.
Many, but not all, people find interferon alfa therapy veryhard to tolerate. After each injection, they may sufferinfluenza-like symptoms, and up to one-half of all peopletreated suffer from fatigue, headaches, pyrexia (fever),myalgia (aches and pains), insomnia and/or nausea. Aboutone-quarter suffer hair loss, arthralgia (pain in the joints),rigors, irritability, pruritus (itching), depression, dermatitisand/or decreased appetite. There are significant problems ofdropout and non-adherence with treatment as a result.
Dropout rates of 7–14% have occurred. Figures on adherenceare more difficult to quantify.
In the late 1990s, combination treatment of interferon alfaand ribavirin commenced, following trials that showed that,although ribavirin alone showed no activity against HCV, theeffect of the combination of ribavirin with interferon alfawas much enhanced compared with that of interferon alfaalone. Since the introduction of combination therapy,monotherapy is used only for people unable to tolerateribavirin.
Ribavirin (Copegus, Roche; Rebetol, Schering-Plough) is anucleoside analogue with a broad spectrum of antiviralactivity against RNA viruses. It is licensed for use incombination with interferon alfa-2a or interferon alfa-2b fortreatment of CHC in: • adult patients with histologically proven, previously untreated CHC, without liver decompensation, who arepositive for serum HCV-RNA and who have fibrosis or highinflammatory activity • adult patients with CHC who have previously responded (with normalisation of ALT at the end of treatment) tointerferon alfa but subsequently relapsed.
Ribavirin is administered orally, usually in divided doses (200 mg per capsule or tablet). The dosage varies accordingto the patient’s weight. Regular monitoring of full bloodcount to detect haemolytic anaemia is needed in order tojudge whether to reduce or cease ribavirin treatment.
Ribavirin is contraindicated in pregnancy and breastfeeding,in severe debilitating medical conditions (particularly of theheart, blood, kidneys and liver), in haemoglobinopathies andin the presence of autoimmune diseases or severe psychiatricconditions. It may also cause haemolytic anaemia, for whichclose monitoring is required and a reduction in dose orcessation of treatment may be necessary.
Adverse effects related to combination therapy are similar intype and frequency to those of interferon alfa monotherapyand include influenza-like symptoms (fatigue, headache andfever), decreases in haematological parameters (neutrophil,white blood cell and platelet counts), gastrointestinalcomplaints (anorexia and nausea), dermatological symptoms(alopecia) and psychiatric disturbances (depression andanxiety). The trials indicate that discontinuation of treatmentis more frequent (10–20%) for combination therapy than formonotherapy. Studies of combination therapy show thathaematological events were the most common reason foreither study withdrawal or dose reduction.
Standard treatment with interferon alfa combinationtherapy is either for 24 weeks (for people with G2/3) or for48 weeks (for people with G1). Treatment with interferon alfa monotherapy or combinationtherapy is not licensed for people younger than 18 years ofage.
The following factors affect the efficacy of treatment.
• Genotype of the virus. This is the most important determinant of efficacy of treatment.
• High viral load. The higher the viral load, the lower the proportion of people with HCV who have a sustainedvirological response (SVR), all other things being equal.
High viral load is the second most important determinantof efficacy of treatment.
• Age. Younger people fare better than older people. This may be because older people tend to have been infectedfor longer, although there appears to be an independentfactor beyond that.
• The period between infection and treatment. Longer delays appear to adversely affect the efficacy of treatment.
• Weight. People who weigh more than the average have a lower response rate to treatment than those who weighless than the average, when the dosages of interferon alfa(and ribavirin for combination therapy) are fixed.
• Fibrosis and cirrhosis of the liver (which 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 pre-treatment ALT level. The higher the pre-treatment ALT level, the lower the probability of treatment success.
• Racial group. Studies in the USA have shown that black people had a poorer response to treatment than whitepeople, but there is no evidence of the impact of ethnicityin a UK setting.
• Gender. Women respond somewhat better than men to fixed doses (though evidence suggests that this may bedue to women’s lower average weight, and hence to theeffective dose per kilogram).
Because HCV and HIV share common routes of transmission,many people with HIV are also infected with HCV. In thesepeople, hepatitis C is a leading cause of death. It appearsthat HIV is associated with an acceleration of liver diseasecaused by HCV. Treatment of co-infected people iscomplicated by the possibility of adverse drug interactions,particularly with ribavirin. Studies show that treatment ofpeople co-infected with HIV and HCV with interferon alfacombination therapy results in worthwhile (if somewhatlower) clearance rates of HCV than in people with HCV butnot HIV. This is likely to be attributable to higherdiscontinuation rates and problems of drug interactions. A 4-week cycle of interferon alfa at 3 million units threetimes a week costs around £200. Ribavirin for the sameperiod costs from about £350 to £500. (All prices exclude VAT,British National Formulary 45th edition.) Therefore, 24 weeksof combination therapy of interferon alfa plus ribavirin willcost around £4000 (excluding monitoring costs). The cost of treatment depends on which of interferon alfa-2a orinterferon alfa-2b is used, and on weight, because theaccompanying ribavirin dose is differentially weight-related.
The value of triple therapy (combination therapy of interferonalfa and ribavirin plus amantadine) has to be fully assessed.
The technology
Two product licences for a new form of interferon alfa,pegylated interferon alfa (called peginterferon alfa), have nowbeen granted, both for use as monotherapy and forcombination therapy with ribavirin in adults with hepatitis C.
The pegylated form of interferon alfa contains an essentiallyinert ‘tail’, the function of which is to slow down the rate atwhich the body eliminates the molecule, enabling dosing to beless frequent. Of the two forms of pegylated interferon,peginterferon alfa-2a has a 40 kD branched chain polyethyleneglycol molecule attached to the interferon with a stable bond.
Peginterferon alfa-2b has a linear 12 kD polyethylene glycolchain that is attached via an unstable bond that breaks downin solution, releasing interferon alfa-2b. Ribavirin doses for combination therapy are as follows. Inconjunction with peginterferon alfa-2a (as for interferon alfa-2a), people who have HCV genotype 1 or 4 (and usuallythose who have genotype 5 or 6) and who weigh less than 75kg take 1000 mg daily of ribavirin in divided doses. Peoplewho weigh more than 75 kg take 1200 mg ribavirin daily individed doses. For people with HCV genotype 2 or 3 (and lessusually those who have genotype 5 or 6) the dose of ribavirinis 800 mg daily in divided doses. In conjunction withpeginterferon alfa-2b (as for interferon alfa-2b) and regardlessof genotype, people who weigh less than 65 kg take 800 mgof ribavirin daily in divided doses, people who weigh 65–85 kgtake 1000 mg daily in divided doses, and people who weighmore than 85 kg take 1200 mg daily in divided doses.
Peginterferon alfa has a much longer plasma half-life (50–130 hours for peginterferon alfa-2a and about 40 hoursfor peginterferon alfa-2b) than interferon alfa. It thereforeneeds to be injected only once per week, and the aggregatedose per month can be lower than for interferon, reducingmost side effects. However, data show a higher incidence ofneutropenia and thrombocytopenia for peginterferon alfa aseither monotherapy or combination therapy than for thecorresponding treatment regimen with interferon alfa. Theseadverse events may be managed by dose reduction. For people who are considered for peginterferon alfacombination therapy, standard haematological tests andblood chemistry (full blood count and differential plateletcount, liver function tests, uric acid, serum bilirubin, serumcreatinine, and electrolyte concentrations) are necessary forall people before initiating therapy. The HCV genotype is alsodetermined and baseline viral load established. Liver biopsy isundertaken, if there are no increased risks, in order to assessliver scarring and necro-inflammation according to anaccepted severity scale. This is important in determining theneed for treatment for people with significant fibrosis andnecro-inflammation. People are seen weekly for 4 weeks, andthen monthly during treatment, to check for side effects suchas haemolysis, neutropenia, thyroid changes, depression andretinopathy.
Both peginterferon alfa-2a and alfa-2b are administeredonce a week by subcutaneous injection. The dose forpeginterferon alfa-2a is 180 µg for either monotherapy orcombination therapy. The dose for peginterferon alfa-2b is1.5 µg per kg body weight (combination therapy), and either0.5 µg or 1.0 µg per kg body weight (monotherapy).
Substituting peginterferon alfa for interferon alfa increasesthe 4-week cost of the interferon component from about£200 to about £550. Thus, a 24-week course of combinationtherapy with peginterferon alfa will cost about £6000. Formonotherapy, the 24-week costs for interferon alfa andpeginterferon alfa are about £1200 and £3200, respectively.
The cost of a 48-week course is double that of a 24-weekcourse. (All prices exclude VAT, British National Formulary45th edition.) Costs may vary in different settings because ofnegotiated procurement discounts.
In pregnant or breastfeeding women, treatment withpeginterferon alfa is contraindicated. Treatment withribavirin is also contraindicated for these groups. For fulldetails of side effects and contraindications of peginterferonalfa and of ribavirin, see the Summary of ProductCharacteristics.
Evidence and interpretation
The Appraisal Committee (Appendix A) considered evidence from anumber of sources (see Appendix B).
Clinical effectiveness
The standard measurement of effectiveness of treatment ofCHC is the virological response rate sustained for 6 months,called the SVR. SVR has been shown to closely reflect biopsyand ALT results taken from the same people at the sametime.
Peginterferon alfa combination therapy versus interferon
alfa combination therapy
4.1.2.1 The effectiveness of peginterferon alfa and ribavirin combination therapy, compared with interferon alfa andribavirin combination therapy, for patients being treatedwith interferon alfa or peginterferon alfa for the first timehas been investigated in two randomised controlled trials(RCTs) lasting 48 weeks. One trial used ribavirin andpeginterferon alfa-2a (n = 1121) and the other used ribavirinand peginterferon alfa-2b (n = 1530). The results werebroadly similar. For the first trial, peginterferon alfa-2a incombination with ribavirin yielded an SVR of 56% versus44% for interferon alfa-2b in combination (95% confidenceinterval [CI] on the difference of 12 percentage points is 5 to 19 percentage points). In the second trial, the intention-to-treat analysis (which included patients taking ribavirin atlower than the licensed dose) of peginterferon alfa-2b incombination with ribavirin, the SVR was 54% versus 47% forinterferon alfa-2b in combination (95% CI on the differenceof 7 percentage points is 0.4 to 12.7 percentage points). Inthis arm of the study, all patients received 800 mg ofribavirin with 1.5 µg per kg body weight of peginterferonalfa-2b. The effect of ribavirin dose adjusted according tobody weight was analysed in a subset of 188 of thesepatients. In this sub-population, the SVR for peginterferonalfa-2b in combination was 61% versus 47% for interferonalfa-2b in combination (95% CI on the difference of 14percentage points is 5 to 22 percentage points). The licencefor peginterferon alfa-2b combination therapy is based onthis weight-adjusted ribavirin dosage. The Assessment Reportrecognises that the treatments with peginterferon alfa-2aand alfa-2b (both in combination with ribavirin) may bedifferent and that there are differences between the trial populations. However, it shows that, if the results of thetrials of these two treatments are pooled, peginterferon alfa combination therapy yields an SVR of 56% on anintention-to-treat basis, whereas the interferon alfacombination yields an SVR of 47% on the same basis. Thedifference (9 percentage points) has a 95% CI from 5 to 13percentage points. A second trial of peginterferon alfa-2acombination therapy has so far been reported in abstractform only. It extends the knowledge gained from the firsttrial by comparing different doses of ribavirin and lengths oftreatment. Broadly, it confirms the results of the first trialusing peginterferon alfa-2a. (Further results are currentlycommercial-in-confidence.) 4.1.2.2 The SVR in each of the two fully reported trials varied with both the baseline viral load and the genotype of the HCV.
When there were more than 2 million copies of the virus ineach millilitre of a patient’s blood, the SVR was significantlylower than when there were fewer than 2 million copies.
This was true for both arms of both of the trials.
4.1.2.3 SVRs for patients infected with HCV G1 are much lower than those for G2/3, whereas SVRs for genotypes 4, 5 and 6 (whenthey are known) appear to be between those of the moreprevalent genotypes. For G1, SVRs for peginterferon alfa-2acombination therapy were 46%, compared with 36% forinterferon alfa-2a combination therapy. When peginterferonalfa-2b combination therapy and interferon alfa-2bcombination therapy were compared, the SVR values were42% and 33%, respectively, on an intention-to-treat basis. Ona weight-based ribavirin dosage, they were 48% and 34%,respectively. For G2/3, the SVR for peginterferon alfa-2acombination therapy was 76%, compared with 61% for theinterferon alfa-2a therapy. When the peginterferon alfa-2band interferon alfa-2b combination therapies werecompared, the SVR values were 82% and 79%, respectively,on an intention-to-treat basis. On a weight-based ribavirindosage, they were 88% and 80%, respectively. 4.1.2.4 Patients infected with HCV G2/3 respond to combination treatment with peginterferon alfa-2a in 95% of cases ormore, and in about 80% of cases the response is sustained 6 months after treatment has finished. These rates areachieved after 24 weeks of treatment and are not increasedby prolonging treatment for a further 24 weeks. For G1,however, the SVR after 48 weeks of treatment is much higherthan that for 24 weeks of treatment, even though it is of theorder of only 40–50%. This pattern follows that ofcombination therapy with interferon alfa-2a and interferonalfa-2b.
4.1.2.5 After 12 weeks of treatment, the viral load in people who eventually have an SVR after 24 or 48 weeks’ treatment isgenerally reduced by a factor of 100 or more. That is, forevery 1000 copies of the virus in the blood at the beginningof treatment, there would be 10 or fewer copies at the endof 12 weeks’ treatment. This is known as a 2-log reduction.
4.1.2.6 For patients infected with HCV G2/3, more than 99% will respond with a 2-log reduction at 12 weeks. About 80% willeventually have an SVR. Of the very small number of patientsnot responding at 12 weeks, very few (perhaps less than0.5% of the group that started treatment) have an SVR. Forgenotypes 1, 4, 5 and 6 (together called G1+), only 70–80%have a 2-log reduction at 12 weeks and, of these, about 60%(40–50% of the total group) have an SVR. Of the 20–30%that are non-responders at 12 weeks, few (perhaps 0.5% ofthose originally treated) go on to have an SVR.
4.1.2.7 Data from a subgroup of people with cirrhosis or bridging fibrosis and G2/3 in a recent trial of peginterferon alfa-2a,details of which are still confidential until its full publication,suggest that treatment beyond 24 weeks does not result inan increase in the SVR.
Peginterferon alfa monotherapy versus interferon alfa
monotherapy
4.1.3.1 The Assessment Report found four RCTs that compared peginterferon alfa monotherapy with interferon alfamonotherapy. Three of these trials, involving about 960people, were conducted with peginterferon alfa-2a, and onetrial, involving more than 1200 people, was conducted withpeginterferon alfa-2b. SVRs were much lower than forcombination therapy. Peginterferon alfa-2a yielded a 36%pooled response, compared with 14% for interferon alfa-2a,whereas the SVR values for peginterferon alfa-2b versusinterferon alfa-2b were 23% and 12%, respectively. Differentdoses of peginterferon alfa were used in three of the fourtrials, which occurred at different stages of drugdevelopment. All trials were 48 weeks in duration; hence theshorter treatment possibility for G2/3 was not tested.
Re-treatment of non-responders
4.1.4.1 The Assessment Report found 10 RCTs, involving some 860 people, that compared interferon alfa combination therapywith interferon alfa monotherapy for the re-treatment ofnon-responders to interferon alfa monotherapy. Of those re-treated with monotherapy, only 7 out of 413 had avirological response at the end of the trial, whereas forcombination therapy, 53 out of 449 had such a response. Forstudies including both failure to respond and relapses fromprevious monotherapy, there were 16 responses out of 323for monotherapy, compared with 75 out of 330 forcombination therapy. The differences between the successrates for monotherapy compared with combination therapyare marked, although the percentage of successes when re-treating people failing to respond to monotherapy withcombination therapy is only of the order of 10%.
4.1.4.2 Data for re-treatment with peginterferon alfa combination therapy for people previously treated with interferon alfamonotherapy or combination therapy is still tentative. Adherence
4.1.5.1 Three studies (one published and one unpublished study of peginterferon alfa combination therapy, and one study ofpeginterferon alfa monotherapy) have retrospectivelyexamined satisfactory adherence, defined as adhering to thedesignated dosing pattern at least 80% of the time. Allstudies show that SVR is significantly higher among peoplewith G1 who show satisfactory adherence. For people withG2/3, one of the three studies also shows that SVR issignificantly higher among those with satisfactory adherence. Other patient subgroups: haemophilia
4.1.6.1 Many people with haemophilia were infected by blood products, in most cases by HCV G1. Many cases of G1 did notrespond to monotherapy, or relapsed within 6 months. Smallstudies showed that a small but significant proportion ofthese relapses and treatment failures responded topeginterferon alfa combination therapy.
4.1.7 Other patient subgroups: HIV comorbidity
4.1.7.1 It is not unusual for people with HCV to be co-infected with HIV, because of their common transmission routes. Severalpatient submissions, one manufacturer and the AssessmentReport examined this set of circumstances.
4.1.7.2 In people infected with both viruses, the rate of progression 4.1.7.3 Several small trials have been conducted, all involving interferon alfa-2b, which show that the SVRs are of theorder of 30% lower (for example, 35% instead of 50%) forpeople co-infected with HIV than for those without HIV.
4.1.7.4 There is no evidence that interferon alfa interacts with drugs taken for HIV, but there is evidence that ribavirin could do sowhen taken with peginterferon alfa, and may prove toxic.
Additional care is called for when monitoring peoplereceiving medication for HIV co-infection.
Other patient subgroups: injecting drug users
4.1.8.1 Current injecting drug users can have high rates of discontinuation in trials, and thus do not achieve successrates in trials with interferon alfa therapy as high as thoseobtained by other participants. However, there is evidencethat where adherence is achieved, success rates are notsignificantly different. Other patient subgroups: people with continued alcohol
consumption
4.1.9.1 Alcohol consumption of more than 7 units per week not only increases liver damage for those infected with HCV, but alsoadversely affects its treatment.
Other patient subgroups: liver transplants
4.1.10.1 People with CHC who require a liver transplant usually develop the disease in the new liver. Very limited data (sixpeople) showed that four people responded topeginterferon alfa-2b combination therapy.
Other patient subgroups: age, gender and ethnicity
4.1.11.1 Some differences have been observed in the success of treatment between people of different ages, between menand women, and between people of different ethnicity.
These differences are relatively small compared with thoseresulting from viral genotype or viral load.
Other patient subgroups: mild CHC and acute hepatitis C
4.1.12.1 Trials in people with mild disease have not yet reported.
Treatment of mild CHC is outside of the scope of thisappraisal.
4.1.12.2 Acute infection is not covered by this appraisal. One trial has shown better clearance if HCV infection is treatedimmediately after onset, but it may not be possible togeneralise its results to most people infected with HCV.
Cost effectiveness
Peginterferon alfa combination therapy versus interferon
alfa combination therapy
4.2.1.1 The Assessment Report shows that peginterferon alfa combination therapy is a very cost effective interventioncompared with interferon alfa combination therapy. ForG2/3, given the very high sustained success rates at 24 weeks,treatment is cost effective at 24 weeks but not thereafter.
For G1, 48-week treatment is cost effective compared withstopping therapy after 24 weeks. See Table 1. Table 1: Cost effectiveness of combination therapy for different HCV
genotypes
Comparison
Genotype
Treatment Estimated
length incremental
(weeks)
cost/QALY
combination vs interferon alfa combination Notes on Table 1: The estimated incremental cost/QALY figures were obtained fromthe Assessment Report using a modelling approach. Rows (1) and (3): use data from the pivotal trials of peginterferon/interferon alfa-2aand of alfa-2b. The estimates differ because they are based on (a) different trialsand (b) different doses of ribavirin. Row (2): Uses data from the pivotal trial of peginterferon/interferon alfa-2b.
Rows (4) and (5): use data from an unpublished trial of peginterferon/interferonalfa-2a submitted in confidence by the manufacturer, for different doses ofribavirin. The genotype ‘not 1’ essentially refers to genotypes 2 and 3, as thenumbers of those in genotypes 4, 5 and 6 were small.
4.2.1.2 In the Assessment Report, the estimates of incremental cost effectiveness ratios by viral genotype differ depending on thetype of peginterferon alfa or interferon alfa and the dose ofribavirin. For G1, the estimated cost per quality-adjusted lifeyear (QALY) gained of peginterferon alfa combinationtherapy compared with the corresponding interferon alfacombination therapy for 48 weeks’ treatment ranges from£4000 to £11,000. For G2/3, the corresponding figures are£7000 to £38,000. 4.2.1.3 For monotherapy, all treatments are for 48 weeks (see Table 2).
Table 2: Cost effectiveness of monotherapy for different HCV
genotypes
Comparison
Genotype
Estimated
incremental
cost/QALY
monotherapy vs interferon alfa monotherapy monotherapy vs interferon alfa monotherapy monotherapy vs interferon alfa monotherapy Note on Table 2: The estimated incremental costs per QALY gained were obtainedfrom the Assessment Report, based on a modelling approach using SVRs taken froma meta-analysis. 4.2.1.4 The manufacturers’ models are similar in structure to that of the Assessment Report, and the estimates of costeffectiveness derived from them show even lower costs perQALY. In one instance, this can be explained in part by thelonger time horizon (expected lifetime, as opposed to 30years).
4.2.1.5 The Assessment Report shows that testing viral load at 12 weeks for G1+ and stopping treatment for people who donot exhibit a 2-log reduction in viral load is cost effectivecompared with continuing treatment. Some 20–30% ofpeople infected with G1+ do not respond at 12 weeks, and of these, less than 2% will eventually have an SVR. The cost per QALY gained from continuing treatment for the non-responders at 12 weeks is estimated to be £227,000. This isnot the case for G2/3; there are very few non-responders at12 weeks.
4.2.1.6 The cost effectiveness of treating with peginterferon combination therapy non-responders to interferonmonotherapy has been estimated to be £3000 per QALY againstno treatment. For non-responders to interferon combinationtherapy, it is £9000 per QALY against no treatment.
Consideration of the evidence
The Committee reviewed the evidence available on theclinical and cost effectiveness of treatment with interferonalfa and peginterferon alfa and ribavirin in CHC, havingconsidered evidence on the nature of the condition and thevalue placed by users on the benefits of interferon andpeginterferon alfa and ribavirin from people with CHC, those who represent them, and clinical experts. It was alsomindful of the need to take account of the effective use ofNHS resources.
The Committee considered that peginterferon alfacombination therapy was both clinically and cost effectivecompared with interferon alfa combination therapy.
Additionally, peginterferon alfa monotherapy was bothclinically and cost effective compared with interferon alfamonotherapy. The Committee concluded that peginterferonalfa therapy should therefore supersede treatment usinginterferon alfa for all people unless particular side-effectconsiderations (neutropenia and thrombocytopenia risk)favour interferon alfa (without pegylation). The Committeealso concluded that combination therapy should be usedrather than monotherapy, except for people for whomribavirin is contraindicated or cannot be tolerated.
The Committee gave careful consideration to the differentialefficacy of treatment for patients infected with the differentHCV genotypes. On the basis of the evidence reviewed, theCommittee concluded that patients infected with HCV G2/3should be considered differently from those with G1, andgenotypes 4, 5 and 6 should be treated as for G1. Forcombination therapy, people with G2/3 should receive 24 weeks’ treatment, whereas people with all othergenotypes who have demonstrated a sufficient initialresponse should receive 48 weeks’ treatment.
For combination therapy, the Committee discussed therequirement for testing for viral load at 12 weeks after theinitiation of treatment as a means of assessing response. ForG2/3, the number of non-respondents at this stage was sucha small proportion that testing them to exclude furthertreatment was not considered cost effective. For all othergenotypes, because the proportion of non-responders wasmuch higher than for G2/3, the viral load response at 12 weeks is important to inform the need for treatment upto 48 weeks.
The Committee further considered the clinical and costeffectiveness of peginterferon alfa-2a versus peginterferonalfa-2b. Although it was aware that the two drugs haddifferent dosage regimens and pharmacokinetic profiles, itconsidered that, in the absence of any head-to-head trialsand on the basis of expert opinion received, the evidencewas insufficient to recommend one of these products overthe other. The Committee concluded that it would beimportant for clinicians to have the choice of either productin order to target different groups of people underparticular clinical circumstances. The Committee, in thiscontext, gave consideration to genotypes 2 and 3. TheCommittee noted that the SVRs for peginterferon alfa-2awere 15 percentage points above those for interferon alfa-2b, whereas for peginterferon alfa-2b, the SVRs were only 3percentage points above those for interferon alfa-2b.
However, the Committee considered the response of theformer control group to be relatively low, whereas that ofthe latter control group was relatively high. It also notedthat, when the weight-related dosage of ribavirin (on whichthe peginterferon alfa-2b licence is based) was considered,the relative efficacy of peginterferon alfa-2b compared withinterferon alfa-2b was more marked. The Committeetherefore considered that the apparent differences inresponse between the two forms of peginterferon for G2/3should not result in a differential recommendation. The Committee considered the use of peginterferon alfa forcombination therapy in groups of people with HCV infectionthat were not represented in the pivotal clinical trials. Theseincluded people with haemophilia and people co-infectedwith HIV. The Committee concluded that, based on theevidence available, there was no reason to make anydifferent provision for these groups. It did, however, notethat there might be occasions where ribavirin may interactwith medication for HIV, necessitating either a change in thelatter or a switch to peginterferon alfa monotherapy.
For combination therapy, the Committee considered thedifferences in treatment efficacy for people of different age,gender and ethnicity, and decided that, where sufficientevidence existed, the efficacy differences were not greatenough to give rise to a different recommendation for anyof these subgroups. The Committee heard that, although injecting drug userswith HCV might, on average, seek treatment less frequentlythan other people with HCV, those who do seek treatmenthave similar adherence rates to other people with HCV.
Furthermore, the evidence provided by the expertspersuaded the Committee that current information indicatedthat HCV re-infection rates for people on interferon orpeginterferon therapy were low in those who continue toinject illicit drugs. Thus, although rates of discontinuation ofinjecting drug users in trials have been high, the Committeewas prepared to accept that in naturalistic settings, the rateof discontinuation would not be so great as to prevent thetreatment being cost effective. The Committee heard that continued alcohol consumptioneven at levels of intake much lower than the recommendedmaximum levels for the general population might beharmful for people with CHC-induced liver disease. This isbecause of the effect of alcohol on the progression of liverdisease and also because alcohol reduces the efficacy ofpeginterferon/interferon alfa as therapy for CHC. TheCommittee considered that continued alcohol consumptionwas, however, not in itself an absolute contraindication totherapy but should be emphasised as an important factor tobe taken into account in advice and information given by theclinical team.
The Committee carefully considered the situation of peoplewho had already been treated with peginterferon orinterferon alfa. Evidence shows that for those treated withinterferon alfa monotherapy who had either not responded,or had responded but then relapsed, further treatment withcombination therapy (with either peginterferon or interferonalfa) will be cost effective, although not as cost effective asfor people not previously treated. The Assessment Groupproduced a further modelling analysis which assumed thatre-treatment with peginterferon alfa combination, for thosewho had already undergone interferon alfa combinationtherapy, would yield an SVR equal to the difference betweenthe SVRs of the two therapies. This analysis suggested that itcould be cost effective to re-treat those previously treatedwith interferon alfa combination therapy who had relapsed or who had not responded. The Committee, after alsoreceiving expert clinical advice on this matter andrecognising the great uncertainty surrounding theseestimates, decided that these groups of people should besuitable for treatment. The Committee reached the sameconclusion for the few, if any, people previously treatedwithout sustained virological response with peginterferonalfa monotherapy. However, it decided that there was noclinical or modelling evidence, or expert opinion, to supportre-treatment of people who had previously been treatedwith peginterferon alfa combination therapy.
For people unable to take ribavirin, the Committee decidedthat peginterferon alfa monotherapy should be thetreatment of choice, because it is both clinically and costeffective compared with interferon alfa monotherapy,despite lower clearance rates of the virus than forcombination therapy. All people taking peginterferon alfamonotherapy should receive treatment for 48 weeks,regardless of genotype, because it was noted that there iscurrently no evidence for the effectiveness of a shorterperiod (24 weeks) of treatment. The requirement for 12 weeks’ viral load testing was also considered for thisgroup, and it was concluded that it should apply to peoplewith every HCV genotype. Although there was no directevidence of the cost effectiveness for this recommendation,it could reasonably be assumed that viral testing at 12 weekswould be at least as cost effective as in combination therapy,and there was no evidence to support G2/3 being treatedany differently from other genotypes. The provisos forcombination therapy in Section 4.3.3 (except for the 24-weektreatment for G2/3), and Sections 4.3.5 to 4.3.9, also apply totreatment with monotherapy.
The Committee considered the treatment of people classifiedon the basis of liver biopsy as having mild chronic CHC. It wasaware that there were two trials of people with mild diseasethat would shortly be reporting. The correct and cost-effective management of this group was considered veryimportant and, although people with mild disease representa small subgroup of the current RCT evidence base, it wasdecided that waiting for the current specific trials to reportwould provide a more robust basis on which to provideguidance to the NHS. The Committee discussed the question of the need for liverbiopsy at some length. It concluded that, because the basisfor the original guidance (see Section 8.1) required thedefinition of the extent of liver disease, the requirement forbiopsy before deciding on appropriate therapy shouldremain. It was persuaded that alternative non-invasive testsof liver function could not currently be relied upon to act asappropriate surrogates for direct histological examination.
However, the Committee considered that, in due course, theresult of the trials in mild disease might affect thisrequirement. The Committee believed that there weregrounds for making exceptions for people with haemophiliaand risk of bleeding or with a previous adverse reaction toliver biopsy, and for those with extra-hepatic symptomssufficient to merit treatment.
The Committee considered that the effective delivery of theguidance in Section 1 would be critically dependent on theexistence of a properly structured clinical environment forpeople with CHC. Thus, it concluded that the decision toundertake therapy should only be initiated by a physicianwith specialist knowledge of the treatment of CHC.
Additionally it is important that a clinical team includingspecialist nurses is available for lifestyle advice to facilitatethe informed decision of the individual to undertaketreatment and to help him or her successfully complete thecourse of therapy.
Recommendations for further research
Current trials involving peginterferon alfa for people withmoderate or severe chronic CHC are reported in Appendix 11of the Assessment Report. These consist of one trial of atriple therapy, five trials of combination therapy, two ofmonotherapy, five of co-infected populations and one toassess the long-term SVR in children. Trials for people withmild chronic CHC are also near completion. In addition, arandomised controlled trial of combination therapy involvingpegylated interferon alfa-2a versus alfa-2b is being planned.
A well-constructed trial of peginterferon alfa combinationtherapy versus other therapies involving interferon alfa isneeded in children with chronic CHC.
Implications for the NHS
The total budgetary impact of combination therapy dependson a number of factors: prevalence, proportion of peoplediagnosed, proportion of the people diagnosed who attendfor assessment, and the proportion considered suitable fortreatment, as well as the proportions who actually take uptherapy and complete it. It also depends on whetherpeginterferon alfa combination treatment is being comparedwith interferon alfa combination therapy, peginterferon alfaor interferon alfa monotherapy, or no treatment.
Currently, only about 2000 people in England and Wales eachyear are being treated for HCV infection with some form ofinterferon or peginterferon alfa therapy. On the basis that allthese people will eventually receive peginterferon alfacombination therapy, that the numbers being treated do notchange with time, and that peginterferon alfa combinationtherapy costs about £3200 more per patient than interferonalfa combination therapy, the additional drug expenditurewould be up to £6.4 million per year. However, it is likelyfirst, that the number of people able to benefit fromtreatment (injecting drug users and people who have had analcohol problem) will be increased as a consequence of thisguidance, and second, that the number of people seekingtreatment will increase as education about the conditionincreases and as people become aware of improvements intreatment. This would significantly increase drugexpenditure.
Testing people with G1+ infection at 12 weeks and endingtreatment for those who are not responding to therapywould cut the additional costs by about 16%, or about £1 million.
There will also be a re-treatment cost for non-responders toprevious therapy. The numbers of people involved are notknown with any degree of certainty. The followingassumptions have been made: • 1000 people have not had an SVR to monotherapy and have not subsequently been treated with a combinationtherapy • 250 are still alive and would wish to undertake • half of the people with G1+ respond after 12 weeks and are treated for 48 weeks at a cost of £12,000 each • the other half of the people with G1+ are treated for • the people with G2/3 are treated for 24 weeks at a cost of • the number of people who have been treated with previous interferon combination therapy but who haveeither not responded or have relapsed is 2000, of whom75% (1500) are G1+ and 25% (500) are G2/3 • 1000 of the G1+ and 400 of the G2/3 seek re-treatment • 25% of the G1+ group respond after 12 weeks and are treated for 48 weeks at a cost of £12,000 each; the 75%that does not respond are treated for 16 weeks • the G2/3 group is treated for 24 weeks at a cost of £6000 The drug cost, compared with no interferon treatment,would be approximately £1.8 million for people who havehad previous monotherapy treatment and a further £8.4million for people who have had previous combinationtherapy treatment. This is likely to be spread over about 2 years, equating to £5.1 million per year. The total increaseddrug cost for the next 2 years would therefore be about£10.5 million per year. Should people seeking re-treatmentdelay further treatment, the costs per year would be lowerthan £10.5 million per year, but would be spread over alonger time period.
This estimation procedure ignores other costs, such as thecost of testing for genotype and viral load, but also ignoresthe additional potential treatment offsets down the line.
Implementation and audit
Treatment for CHC should be provided by physicians who areexpert and experienced in the diagnosis and management ofviral hepatitis, and a clinical nurse specialist for hepatitis withaccess to supportive services including an accredited virologylaboratory, a liver pathologist and a radiology department,consistent with Department of Health (2002) Hepatitis CStrategy for England. London: Department of Health.
All clinicians who care for people with CHC should reviewtheir current practice and policies to take account of theguidance set out in Section 1.
Local guidelines, protocols or care pathways that refer to thecare of people with CHC should incorporate the guidance.
To measure compliance locally with the guidance, thefollowing criteria could be used. Further details onsuggestions for audit are presented in Appendix C.
An individual with moderate to severe CHC who is aged 18 years or older (except a woman who is pregnant orbreastfeeding) is treated with peginterferon alfa andribavirin combination therapy within licensed indications ifhe or she meets any one of the following.
7.4.1.1 The individual has not previously been treated with interferon alfa or peginterferon alfa.
7.4.1.2 The individual has been treated previously or is currently being treated with interferon alfa as monotherapy orcombination therapy.
7.4.1.3 The individual has been previously treated with peginterferon alfa monotherapy only, and either respondedat the end of treatment but subsequently relapsed, or wasnot responding at the end of treatment.
For an individual who meets the criteria in Section 7.4.1,treatment is carried out as follows.
7.4.2.1 If the individual is infected with HCV of genotypes 2 and/or 3, 7.4.2.2 If the individual is infected with HCV of genotypes 1, 4, 5 or 6, (or infected with more than one genotype including at least one of genotypes 1, 4, 5 or 6), initial treatment is for 12 weeks. If the viral load has been reduced to less than 1% of its level at the start of treatment, treatment iscontinued for 48 weeks. If the viral load exceeds 1% of itslevel at the start of treatment, treatment is discontinued.
An individual with moderate to severe CHC who is aged 18 years or older (except a woman who is pregnant orbreastfeeding) for whom ribavirin is contraindicated or is nottolerated is treated with peginterferon alfa monotherapy.
The individual is tested for viral load at 12 weeks oftreatment. If the viral load has reduced to less than 1% of its level at the start of treatment, treatment continues for atotal of 48 weeks. If the viral load has not fallen to less than1% of its level at the start of treatment, treatment isstopped at 12 weeks.
Before treatment is given, an individual has a liver biopsy todetermine if the individual has moderate or severe CHC,except if the individual meets one of the following. 7.4.4.1 Liver biopsy poses a substantial risk to the individual. 7.4.4.2 The individual has symptoms of extra-hepatic HCV infection sufficient to impair quality of life.
Related guidance
This guidance is a review of and an extension to: National Institute for Clinical Excellence (2000) Guidance onthe use of ribavirin and interferon alpha for hepatitis C. NICE Technology Appraisal No. 14. London: National Institutefor Clinical Excellence. Available from: www.nice.org.uk Review of guidance
The use of this technology for mild CHC (and any consequentchanges that this may have on this guidance) will beconsidered after the publication of the results of the tworelevant clinical trials, and at the earliest in August 2004. The full guidance will be reviewed in November 2006. A version of this guidance written for people with chronichepatitis C, and the public, is available from the Institute'swebsite (www.nice.org.uk) and from the NHS Response Line(telephone 0870 1555 455 and quote reference number N0428 for a version in English only and N0429 for a version in Englishand Welsh).
Appendix A
Appraisal Committee members and NICE project
team
A. Appraisal Committee members
NOTE 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 thetechnology to be appraised. If it is considered there is a conflict ofinterest, the member is excluded from participating further in thatappraisal. The minutes of each Appraisal Committee meeting, which includethe names of the members who attended and their declarations ofinterests, are posted on the NICE website.
Dr Jane Adam
Dr Peter Barry
Dr Sunil Angris
General Practitioner,
Professor John Brazier
Dr Darren Ashcroft
Professor John Cairns
Professor Mike Campbell
Professor David Barnett (Chair)
Dr Mark Chakravarty
Professor Andrew Stevens
(Vice-Chair)
Professor Mary Watkins
Dr Peter I Clark
Clatterbridge Centre forOncology, Wirral, Merseyside Dr Norman Waugh
Department of Public Health,
Dr Mike Davies
Consultant Physician, UniversityDepartment of Medicine &Metabolism, Manchester RoyalInfirmary Professor Jack Dowie
Health Economist, London
School of Hygiene
Dr Paul Ewings
Statistician, Taunton & Somerset
NHS Trust, Taunton
Ms Sally Gooch
Director of Nursing, Mid-Essex
Hospital Services NHS Trust,
Chelmsford
Professor Robert Kerwin
Professor of Psychiatry and
Clinical Pharmacology, Institute
of Psychiatry, London
Dr Stephen Saltissi
Consultant Cardiologist, Royal
Liverpool University Hospital
Mr Miles Scott
Chief Executive, Harrogate
Health Care NHS Trust
B. NICE Project Team
Each appraisal of a technology is assigned to a Health TechnologyAnalyst and a Technology Appraisal Project Manager within theInstitute.
Dr Alastair Fischer
Nina Pinwill (up to August 2003)
and Dr Sarah Cumbers
(from August 2003)
Project Managers,
NICE project team
Appendix B
Sources of evidence considered by the Committee
The following documentation and opinions were made available tothe Committee: The Assessment Report for this appraisal was prepared bythe Southampton Health Technology Assessment Centre(SHTAC), Wessex Institute for Health Research andDevelopment, University of Southampton I Shepherd J, Brodin H, Cave C, et al, Pegylated interferon alpha 2a and 2b in combination with ribavirin in thetreatment of chronic hepatitis C: a systematic review, 29 May 2003 The following organisations accepted the invitation toparticipate in this appraisal. They were invited to makesubmissions and comment on the draft scope, AssessmentReport and Appraisal Consultation Document (ACD).
Consultee organisations are provided with the opportunityto appeal against the Final Appraisal Determination.
• Roche Products Ltd • Schering-Plough Ltd II Professional/specialist and patient/carer groups: • Action on Hepatitis C• Association of Nurses in Substance Abuse• British Association for Study of the Liver• British Liver Trust• British Society of Gastroenterology• Department of Health and the Welsh Assembly • Haemophilia Society• Hepatitis C Trust• Hepatitis Nurse Specialist Forum• Mainliners• Royal College of General Practitioners• Royal College of Pathologists• Royal College of Physicians• Royal Pharmaceutical Society• Terrence Higgins Trust • UK Haemophilia Centre Doctors' Organisation III Commentator organisations (without the right of appeal): • National Hepatitis C Resource Centre• NHS Quality Improvement Scotland The following individuals were selected from clinical expertand patient advocate nominations from theprofessional/specialist and patient/carer groups. Theyparticipated in the Appraisal Committee discussions andprovided evidence to inform the Appraisal Committee’sdeliberations. They gave their expert personal view oninterferon alfa (pegylated and non-peglyated) and ribavirinin the treatment of chronic hepatitis C by attending theinitial Committee discussion and/or providing writtenevidence to the Committee. They were invited to commenton the ACD.
• Dr Has Dasani, Physician for Haemophilia Centre, • Dr Graham Foster, Consultant Hepatologist, Queen Mary • Mr Charles Gore, Chief Executive, The Hepatitis C Trust• Mr Robert James, Chair of Birchgrove, on behalf of The • Dr Elizabeth McCruden, Senior Lecturer and Honorary Consultant Virologist, Institute of Virology, University ofGlasgow and North Glasgow NHS University Trust • John Morris, Hepatitis Worker and Robert James, Chair of Birchgrove, on behalf of The Haemophilia Society UK • Professor Howard Thomas, Professor of Medicine, Department of Medicine, Imperial College at St Mary'sHospital, British Society of Gastroenterology Appendix C
Detail on criteria for audit of the use of interferon
alfa (pegylated and non-pegylated) and ribavirin in
the treatment of chronic hepatitis C
Possible objectives for an audit
An audit on the use of pegylated and non-pegylated interferon alfaand ribavirin in the treatment of CHC could be carried out to ensurethat combination therapy is used appropriately. Possible patients to be included in the audit
An audit could be carried out on a reasonable number of peoplebeing treated for CHC, for audit purposes. If a large number ofpeople is being treated, a representative sampling strategy issuggested.
Definition of terms
Pegylated interferon alfa includes peginterferon ‘Moderate to severe CHC’ means there is histological evidence of significant scarring carrying out a liver biopsy for this purpose Clinicians will need to agree locally on how to measure compliance with licensed indications for audit purposes and will need to agree on how to define lack of response to treatment (for debilitating medical conditions (particularly of gastrointestinal complaints such as anorexia or Exception
Measures that could be used as a basis for audit
The measures that could be used in an audit of pegylated and non-pegylated interferon alfa and ribavirin in the treatment Criterion
Definition of terms
If an individual is infected with more than one ‘Reduced to less than 1% of the level at the start of treatment’ = at least a 2-log reduction adverse event after undergoing a previous liver Clinicians will need to agree locally on how to define severe extra-hepatic HCV infection and Exception
treatment is
or
its level at the start of treatment.
Criterion
Compliance (%) with each measure described in the table above iscalculated as follows.
Number of patients whose care is consistent with the
criterion plus number of patients who meet any
exception listed
Number of patients to whom the measure applies
Clinicians should review the findings of measurement, identifywhether practice can be improved, agree on a plan to achieve anydesired improvement and repeat the measurement of actual practiceto confirm that the desired improvement is being achieved.
NHS
National Institute for
Clinical Excellence
National Institute for
Clinical Excellence

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