The Department of Health and the National Assembly for Wales have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct an appraisal of adefovir dipivoxil and peginterferon alfa for the treatment of chronic hepatitis B 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 adefovir dipivoxil and peginterferon alfa for chronic hepatitis B.

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 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: 12 September 2005
Second Appraisal Committee meeting: 27 September 2005

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.

This guidance does not apply to people with chronic hepatitis B who are co-infected with hepatitis C, hepatitis D or HIV.

Peginterferon alfa is recommended as an option for the initial treatment of adults with chronic hepatitis B (HBeAg-positive or HBeAg-negative) in accordance with its licensed indications.

Response to treatment (in terms of HBeAg seroconversion or loss of hepatitis B viral DNA by conventional assay) and tolerance to adverse effects should be assessed at 6 months after its initiation. Treatment should be continued for no longer than 48 weeks.

Adefovir dipivoxil is recommended as an option for the treatment of chronic hepatitis B (HBeAg-positive or HBeAg-negative) in adults, if treatment with interferon alfa or peginterferon alfa has been unsuccessful in producing a response (as defined in Section 1.1), if a relapse occurs, or if the treatment with an interferon is poorly tolerated or contraindicated.

The appropriate strategy and sequencing for the use of the antiviral agents should be assessed on a case-by-case basis. The assessment should take into account a number of factors including Ag status, stage of disease process (for example, compensated or decompensated cirrhosis) and the likelihood of the emergence of virus resistance.

Chronic hepatitis B is defined as viraemia and hepatic inflammation that persists for more than 6 months after acute infection with hepatitis B virus. Hepatitis B virus is transmitted by sexual contact, through the use of infected blood and blood products, by reuse of contaminated needles and syringes, and by vertical transmission from mother to child during, or soon after, birth. The risk of becoming chronically infected with hepatitis B virus depends on the strength of the immune response to the initial infection. This varies according to the age at which the infection is acquired. Almost 100% of neonates, and about 50% of young children, develop chronic hepatitis B if infected with hepatitis B virus. In contrast, only about 2–10% of people who are infected as adults go on to develop chronic hepatitis B.

People with active chronic hepatitis B are at increased risk of liver cirrhosis (scarring of the liver tissue that may progress to liver failure) and liver cancer (hepatocellular carcinoma).

The diagnosis of chronic hepatitis B is based on the presence of various markers in the blood. Hepatitis B viral DNA (HBV DNA) is present in both acute and chronic hepatitis B. Hepatitis B surface antigen (HBsAg) is a viral protein detectable in the blood in both acute and chronic infection. Persistence of HBsAg beyond 6 months after acute infection is the definition of chronic hepatitis B viral infection. Hepatitis B ‘e’ antigen (HBeAg) is an indicator of viral replication, although some variant forms of the virus do not cause infected cells to produce HBeAg (see Section 2.4.4 below). Active infection can be described as HBeAg-positive or HBeAg-negative according to whether HBeAg is secreted.

The natural history of chronic hepatitis B can be divided into phases, each of which may last many years.

Immunotolerant phase. People who are affected at birth or in early childhood initially enter an ‘immunotolerant’ phase during which the immune system does not actively fight the virus. The virus replicates rapidly during this phase, but the person usually has no symptoms. The person is highly infectious, and may infect other members of the family and community. This phase can last for many years before progressing to active disease. In those who acquire the infection as adults the immunotolerant phase is very short (about 2–4 weeks) and represents the incubation phase of the infection.

Active chronic hepatitis B. The first stage of active disease involves a period of increasing inflammatory hepatic necrosis as the immune system begins to fight the virus. This stage of the disease is characterised by elevated levels of viral DNA in the blood, persistently raised levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and evidence of hepatic necrosis and inflammation on biopsy. The liver damage caused by infection and inflammation may eventually lead to cirrhosis of the liver. Progression to cirrhosis occurs at an annual rate of 2–5.5%, with a cumulative 5-year rate of progression of 8–20%.

HBeAg seroconversion. In people infected with an HBeAg-positive form of the virus, the next stage of the infection occurs when inflammation becomes sufficiently intense to cause lysis of infected hepatocytes. This produces a ‘flare’ of the disease with symptoms resembling acute hepatitis B, and leads to the development of antibodies against the ‘e’ antigen. This is referred to as ‘HBeAg seroconversion’. The seroconverted disease state is associated with good quality of life and a relatively low risk of disease progression. It is sometimes referred to as the ’inactive HBsAg carrier state’ because patients continue to express hepatitis B surface antigen (HBsAg). The spontaneous seroconversion rate is 5–10% per year, though this varies among populations. Once seroconversion has taken place, most people remain in the inactive HBsAg carrier state. However, increasing viraemia and recurrent hepatitis after seroconversion indicate the emergence of the HBeAg-negative strain of the virus.

HBeAg-negative chronic hepatitis B. In recent years a strain of the virus that does not cause infected cells to secrete HBeAg has been discovered (sometimes called the ‘precore mutant’ strain). People can be infected with the so-called HBeAg-negative form of the virus from the beginning, or the viral mutation can emerge late in the course of infection in people initially infected with the HBeAg-positive form of the virus. The prevalence of HBeA-negative hepatitis varies geographically; it is more common in Asia and the Mediterranean region than in Northern Europe. Infection with HBeAg-negative chronic hepatitis B is associated with a fluctuating course and a poor prognosis. Active disease is associated with either persistent elevation of ALT or an erratic pattern of ALT changes with flare-ups resembling acute hepatitis B that can be severe or even fatal. Few patients with HBeAg-negative chronic hepatitis B achieve a lasting remission. Progression to cirrhosis of the liver has been estimated to occur in 8–10% of people with HBeAg-negative chronic hepatitis B each year.

HBsAg seroconversion. The development of antibodies against HBsAg, with clearance of HBsAg, occurs spontaneously in about 0.5–2% of people with chronic hepatitis B each year in western countries. In countries where hepatitis B is endemic, the rate is much lower – between 0.05 and 0.08% per year. This is most likely to occur in the year following HBeAg seroconversion. Clearance of HBsAg signifies resolution of the chronic infection.

The aim of treatment is to prevent progression to cirrhosis or hepatocellular carcinoma. Treatment may be given as a finite course (circumscribed therapy) – with the intention of allowing the immune system to respond and control the infection without the need for further drug treatment – or as long-term viral suppressive therapy. The latter is required if short-term therapy is unsuccessful.

The first drugs to be licensed for the treatment of chronic hepatitis B were alfa interferons. Interferons are natural proteins that activate the immune system in response to viral infection. Three recombinant interferon products have UK marketing authorisation for the treatment of chronic hepatitis B: IntronA (interferon alfa-2b, Schering-Plough), Roferon-A (interferon alfa-2a, Roche) and Viraferon (interferon alfa-2b, Schering-Plough). Interferon alfa‑2a is usually given at a dose of 2.5 to 5 million units per square metre of body surface area by subcutaneous injection three times a week for 4 to 6 months. Interferon alfa‑2b is given at a dose of 5 to 10 million units three times a week for 4 to 6 months. The side effects of interferons can be severe and this means that they are not suitable for long-term treatment in chronic hepatitis B. Interferons are contraindicated in decompensated liver disease. There are no data on long-term maintenance therapy with interferon and the treatment is not licensed for this.

Lamivudine (Zeffix, GlaxoSmithKine) is a nucleoside reverse transcriptase inhibitor antiviral drug. The dose in adults is 100 mg per day. It can be given both as a circumscribed course of treatment or as long-term viral suppressive therapy. In HBeAg-positive chronic hepatitis B, treatment is usually given for a year with the aim of bringing about HBeAg seroconversion. In HBeAg- negative chronic hepatitis B, long-term control of the infection is difficult to attain after a finite course of therapy and long-term treatment with antiviral drugs is often needed. The main problem with long-term antiviral treatment is the emergence of resistance. Resistance to lamivudine occurs in more than 60% of cases after 3 years’ treatment.

Peginterferon alfa

Peginterferon alfa-2a (Pegasys, Roche) has UK marketing authorisation for the treatment of HBeAg-positive or HBeAg -negative chronic hepatitis B in adults with compensated liver disease and evidence of viral replication, increased ALT and histologically verified liver inflammation and/or fibrosis. Peginterferons are formed by attaching strands of polyethylene glycol (PEG) to the interferon molecules. This prolongs the rate of absorption and excretion of interferon, reducing the fluctuations in serum level that occur with unmodified interferon. Peginterferon is administered less frequently than the unmodified form (once a week compared with three or more times a week).

Peginterferons have a range of adverse effects similar to those of conventional interferons. These include influenza-like symptoms such as fever, chills, myalgias, arthralgias and headache. These symptoms are most likely to occur at the start of treatment and seldom require discontinuation of treatment. Other adverse effects include psychiatric effects including depression, anxiety or emotional lability, which may be severe. Cardiovascular adverse effects include hypertension or hypotension, arrhythmias, oedema, myocardial infarction or stroke. Interferons are contraindicated in chronic hepatitis with decompensated cirrhosis of the liver. For full details of side effects and contraindications, see the Summary of Product Characteristics.

A prefilled syringe containing 180 micrograms of peginterferon alfa-2a costs £132.06 (excluding VAT, British National Formulary, 49th edition [BNF 49]). The usual dose is 180 micrograms once a week. Costs may vary in different settings because of negotiated procurement discounts.

Adefovir dipivoxil

Adefovir is structurally related to the purine base adenine. It is converted intracellularly to the diphosphate, which inhibits the synthesis of hepatitis B virus DNA through competition for the enzyme reverse transcriptase and incorporation into the viral DNA. Adefovir is not well absorbed after oral administration so is given by mouth as the prodrug adefovir dipivoxil.

Adefovir dipivoxil (Hepsera, Gilead) has UK marketing authorisation for the treatment of chronic hepatitis B in adults with:

• compensated liver disease with evidence of active viral replication, persistently elevated serum ALT levels and histological evidence of active liver inflammation and fibrosis
• decompensated liver disease.

The most commonly reported adverse effects for adefovir dipivoxil are gastrointestinal effects including nausea, flatulence, diarrhoea and dyspepsia. Increases in serum creatinine are common but usually mild to moderate. However, cases of renal impairment and acute renal failure have been reported . For full details of side effects and contraindications, see the Summary of Product Characteristics.

A pack containing 30 days supply of adefovir dipivoxil 10 mg tablets costs £315.00 (excluding VAT, BNF 49). Costs may vary in different settings because of negotiated procurement discounts.

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

Peginterferon alfa

The Assessment Group found three randomised controlled trials investigating peginterferon alfa in chronic hepatitis B. Two trials were in people with HBeAg-positive chronic hepatitis B, and the third was in HBeAg-negative chronic hepatitis B.

In HBeAg-positive chronic hepatitis B, the most useful measure of response is HBeAg loss or seroconversion because this signals transition to the inactive carrier state, which is associated with a relatively benign outcome. The rate of HBeAg seroconversion was reported in both studies of peginterferon alfa in HBeAg-positive chronic hepatitis B.

One trial was an open-label study in which 194 participants were randomised to one of three doses of peginterferon alfa or standard interferon. Treatment was for 24 weeks followed by a 24-week treatment-free follow-up period. The rate of HBeAg seroconversion was higher in the patients treated with peginterferon alfa (34% for all three doses combined) than in patients treated with standard interferon (25%), but the difference was not statistically significant. ALT levels were also restored to the normal range (ALT normalisation) more frequently in the people treated with peginterferon alfa (36% for all three doses combined compared with 25% for standard interferon). This difference was also not statistically significant.

The second trial in patients with HBeAg-positive chronic hepatitis B was a comparison of peginterferon alfa with lamivudine, in which 814 people were randomised to peginterferon alfa plus placebo, peginterferon alfa plus lamivudine, or lamivudine alone. The study was partially double blind in that those who were receiving peginterferon alfa were blinded as to whether they were receiving lamivudine. Treatment was for 48 weeks followed by a 24‑week treatment-free follow-up period. The rate of HBeAg seroconversion at week 72 was significantly higher in the patients treated with peginterferon plus placebo (32%) than in those treated with lamivudine alone (19%), p < 0.001. The rate of HBeAg seroconversion in the group that received both lamivudine and peginterferon alfa was 27%, that is, addition of lamivudine to peginterferon alfa did not improve the HBeAg seroconversion rate over peginterferon alfa alone. The proportion of patients with an ALT response (normalisation) was higher in the groups taking peginterferon alfa than in the group taking lamivudine alone (41% versus 28%, p = 0.002). Again, adding lamivudine to peginterferon alfa did not improve the response rate for this endpoint.

In HBeAg-negative chronic hepatitis B, a major objective of treatment is suppressing viral replication and preventing progressive liver disease. In clinical trials these outcomes have usually been expressed in terms of ALT normalisation and decreases in the levels of HBV DNA found in the serum.

The only study of peginterferon alfa in HBeAg-negative chronic hepatitis B was a three-way comparison of peginterferon alfa plus placebo, peginterferon alfa plus lamivudine, and lamivudine alone (n = 537). Treatment was for 48 weeks followed by a 24-week treatment-free follow up period (72 weeks in total). The study had two predetermined primary measures of efficacy: the normalisation of ALT levels and the suppression of HBV DNA levels to below 20,000 copies/ml. At week 72 the percentage with normalised ALT was significantly higher in the groups treated with peginterferon alfa than in the lamivudine group (59% with peginterferon alfa monotherapy and 60% for peginterferon alfa plus lamivudine, versus 44% for lamivudine; p = 0.004 and p = 0.003 respectively). For the outcome of virological response (HBV DNA < 20,000 copies/ml) at week 72, the percentage of responders was significantly higher in the groups treated with peginterferon alfa than in the lamivudine group (43% for peginterferon alfa monotherapy and 44% for peginterferon alfa plus lamivudine, versus 29% for lamivudine; p = 0.007 and p = 0.003 respectively).

Treatment-resistance mutations were detected in 32 people (18%) in the lamivudine group and one person (< 1%) in the peginterferon plus lamivudine group (p < 0.001).

Adefovir dipivoxil

The assessment report included five randomised controlled trials of adefovir dipivoxil in chronic hepatitis B. Four of the studies were conducted in people with HBeAg-positive chronic hepatitis B and one was in people with HBeAg-negative chronic hepatitis B.

The largest study (n = 515) was a comparison of two doses of adefovir dipivoxil (10 mg and 30 mg) with placebo in people with HBeAg-positive chronic hepatitis B and compensated liver disease. The primary endpoint was histological improvement (defined in terms of a reduction in Knodell necroinflammatory score) . Histological improvement was seen in 59% of patients in the adefovir dipivoxil 30 mg group, 53% of patients in the adefovir dipivoxil 10 mg group and 25% of patients in the placebo group (p < 0.001 for both comparisons with placebo). The HBeAg seroconversion rates were 14%, 12% and 6% in the adefovir dipivoxil 30 mg, adefovir dipivoxil 10 mg, and placebo groups, respectively. The rates of ALT normalisation were 55%, 48% and 16% in the 30 mg, 10 mg, and placebo groups respectively.

Another study (n = 59) investigated adefovir dipivoxil in people with HBeAg-positive chronic hepatitis B and genotypic evidence of lamivudine-resistance, raised ALT, together with a serum HBV DNA level ≥ 10 6 copies/ml despite ongoing treatment with lamivudine. The patients were randomised to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine treatment. The primary endpoint was time-weighted change from baseline in serum HBV DNA level. Reductions in this endpoint were seen in all recipients of adefovir dipivoxil. HBV DNA levels were ‘undetectable’ (< 1000 copies/ml) in 26% of patients receiving adefovir dipivoxil plus placebo, in 35% of patients receiving adefovir dipivoxil plus lamivudine, and in none of the patients receiving lamivudine plus placebo (p < 0.05). ALT was normalised in 53% and 47% of the adefovir dipivoxil plus lamivudine and adefovir dipivoxil groups respectively, compared with 5% (1/19) of the lamivudine group (p = 0.001 and p = 0.004, respectively)

The remaining two studies in HBeAg-positive chronic hepatitis B investigated the combination of adefovir dipivoxil with lamivudine compared with lamivudine alone. One was in treatment-naïve patients (n = 112) and the other was in patients with lamivudine resistance (n = 94). In the study in treatment-naïve patients (which was still ongoing at the time of this appraisal) there was no advantage in adding adefovir dipivoxil to lamivudine at one year. In the other study of patients with lamivudine resistance, adefovir dipivoxil plus lamivudine was more effective than lamivudine alone in terms of both virological and ALT responses. Of those taking adefovir dipivoxil plus lamivudine 85% reached a HBV DNA level of ≤ 10 5 copies/ml, compared with 11% of patients taking lamivudine alone (p < 0.001). ALT was normalised in 37% of those taking the combined treatment, compared with 9% of those taking lamivudine (p = 0.003).

One study compared adefovir dipivoxil with placebo in people with HBeAg -negative chronic hepatitis B. This was a double-blind study in which 185 people were randomised in a 2:1 ratio to adefovir dipivoxil or placebo for 48 weeks. The primary endpoint was histological improvement defined in terms of a reduction in Knodell necroinflammatory score with no worsening of fibrosis. A total of 167 patients (91%) had assessable pre-treatment and post-treatment liver biopsy specimens. Significantly more patients in the adefovir dipivoxil group had histological improvement than in the placebo group (64% versus 33%, p < 0.001). At week 48, 51% of the adefovir dipivoxil group had undetectable HBV DNA levels (< 400 copies/ml), compared with no one in the placebo group (p < 0.001), and 72% showed normalised ALT levels compared with 29% in the placebo group (p < 0.001).

Long-term follow-up data have been published recently. After week 48, 123 people who had been assigned to adefovir dipivoxil in the initial study were randomised to continue adefovir dipivoxil at a dose of 10 mg daily or to switch to placebo. Of the 61 patients who had initially been randomised to placebo, 60 switched to treatment with adefovir dipivoxil 10 mg daily. At week 96, undetectable levels of HBV DNA were found in 71% of the group continuing with adefovir dipivoxil, compared with 8% of the placebo group. In the group who received adefovir dipivoxil for 48 weeks having previously received placebo for 48 weeks, undetectable levels of HBV DNA were found in 76% of patients. The cumulative incidence of resistance to adefovir dipivoxil among all patients was 3% at 96 weeks and 5.9% at 144 weeks. This trial will continue until all patients have completed 5 years follow-up.

Evidence from clinical experts

The Committee heard from the clinical experts that the decision to treat chronic hepatitis B was determined by the degree of fibrosis and/or necroinflammation on liver biopsy, combined with evidence of active viral replication (HBV DNA levels) and the persistent elevation of serum ALT. Treatment was not necessarily indicated for people with minimal elevation of ALT (1.5–2 times the upper limit of normal) and low necroinflammatory scores on liver biopsy. However, these people should be carefully monitored because the disease can change rapidly from a quiescent to an active state.

The experts expressed concern about the development of viruses with mutations rendering them resistant to antiviral drugs. Lamivudine resistance develops in a high proportion of patients on monotherapy, and could limit the options for future treatment through cross-resistance to related drugs. The experts noted that a strategy of treating chronic hepatitis B with lamivudine followed by adefovir dipivoxil for those in whom lamivudine-resistance developed reflected current practice and was appropriate for most people. However, the experts noted that there was a subgroup of people with highly replicative HBeAg-negative disease in whom resistance could develop rapidly; in these people a strategy of using adefovir dipivoxil alone or in combination with lamivudine might be appropriate.

In principle, the use of combination therapies should minimise the risk of developing resistant variants, although long-term follow-up data from studies are lacking. The clinical experts stressed the need for further research on the long-term effectiveness of combination regimens in preventing resistance.

Cost effectiveness

The Committee considered evidence from four economic models: one by the Assessment Group, one by each of the two manufacturers involved, and one published analysis by Kanwal and colleagues (a recent model published after the Assessment Report’s deadline for inclusion). The models have similar structures and parameters, and their results are in broad agreement.

Assessment Group model

The Assessment Group model presents analyses for people with HBeAg-positive disease and HBeAg-negative disease separately, and also as a single group, with proportions of people with HBeAg-positive disease and HBeAg-negative disease determined from the parameters of the model.

Results are presented for peginterferon alfa (48 weeks treatment) compared with standard interferon alfa (24 weeks treatment for HBeAg-positive disease or 48 weeks for HBeAg-negative disease), and for adefovir dipivoxil compared with lamivudine. The incremental cost-effectiveness ratios (ICERs) for these two comparisons in HBeAg-positive and HBeAg-negative groups combined were £6,100 and £16,500 respectively. However, this analysis assumes that people in whom the first therapy does not produce a sustained response receive no further treatment other than best supportive care. This does not reflect the real situation, whereby people may go on to receive further treatment with an alternative agent. The Assessment Group therefore produced an analysis that considered more clinically relevant scenarios in which people could receive a sequence of drug treatments as necessary.

It is assumed that all patients are first given a course of treatment with either interferon alfa (for 24 or 48 weeks, depending on HBeAg status) or peginterferon alfa for 48 weeks. If HBeAg or HBsAg seroconversion occurs on one of the interferons, the patients are assumed to take no further antiviral medication; if not, they proceed to one of the following sequences of treatment, which form the basis of the comparison:

• best supportive care, that is, no further antiviral medication
• lamivudine, then best supportive care on seroconversion or development of resistance
• adefovir dipivoxil, then best supportive care on seroconversion or development of resistance
• lamivudine, then adefovir dipivoxil on development of resistance, then best supportive care on seroconversion or development of resistance.

The Assessment Group analysis also reports ICERs for the use of lamivudine then best supportive care without first using an interferon, and of adefovir dipivoxil then best supportive care without first using an interferon. It did not report on sequences of both lamivudine and adefovir dipivoxil that were not preceded by an interferon. However, because of the underlying assumptions used in the model, these ICERs can be inferred from the equivalent comparisons for sequences including peginterferon alfa or standard interferon alfa.

In comparing these sets of sequences, a large number of ICER estimates were generated. However, some of these strategies can be excluded from consideration using the notion of extended dominance. This means that when strategies A, B and C (in order of increasing cost) are compared, if the ICER for B compared with A is higher than that for C compared with A then B is excluded (dominated).

For HBeAg-positive disease, the treatment sequences that are not excluded by extended dominance are as follows:

• lamivudine then best supportive care (estimated ICER £3500 per quality-adjusted life year [QALY] compared with best supportive care)
• standard interferon alfa then lamivudine then adefovir dipivoxil then best supportive care (estimated ICER £9900 per QALY compared with lamivudine then best supportive care)
• peginterferon alfa then lamivudine then adefovir dipivoxil then best supportive care (estimated ICER £18,800 per QALY compared with standard interferon alfa then lamivudine then adefovir dipivoxil then best supportive care)
• peginterferon alfa then adefovir dipivoxil then lamivudine then best supportive care (estimated ICER £57,000 per QALY compared with peginterferon alfa then lamivudine then adefovir dipivoxil then best supportive care). Note that this treatment sequence did not appear in the Assessment Report, but was prepared by the Assessment Group for the Appraisal Committee before its first meeting.

For HBeAg-negative disease, the treatment sequences that are not excluded by extended dominance are as follows:

• peginterferon alfa then best supportive care (estimated ICER £3000 per QALY compared with best supportive care)
• peginterferon alfa then lamivudine then best supportive care (estimated ICER £4900 per QALY compared with peginterferon alfa then best supportive care)
• peginterferon alfa then lamivudine then adefovir dipivoxil then best supportive care (estimated ICER £18,000 per QALY compared with peginterferon alfa then lamivudine then best supportive care).

Manufacturer’s model (Roche)

The model submitted by Roche reports a number of estimated cost effectiveness results, all involving either standard interferon alfa or peginterferon alfa, for HBeAg-positive and HBeAg-negative disease separately. Nothing is said about later choices for those people for whom the interferon preparation has not been clinically effective. The estimated ICERs for people with HBeAg-positive disease are as follows:

• peginterferon alfa for 24 weeks compared with standard interferon alfa for 24 weeks (ICER £2700 per QALY)
• peginterferon alfa for 48 weeks compared with standard interferon alfa for 24 weeks (ICER £13,900 per QALY)
• peginterferon alfa for 48 weeks compared with lamivudine for 48 weeks (ICER £5300 per QALY)
• peginterferon alfa for 48 weeks compared with lamivudine for 208 weeks (ICER £5900 per QALY)
• peginterferon alfa for 48 weeks compared with adefovir dipivoxil for 48 weeks (ICER £1400 per QALY)
• peginterferon alfa for 48 weeks compared with adefovir dipivoxil for 208 weeks (dominant, that is, greater benefit at lower cost than adefovir dipivoxil)
• peginterferon alfa for 48 weeks compared with no treatment (ICER £2800 per QALY).

The ICERs for people with HBeAg-negative disease are as follows:

• peginterferon alfa for 48 weeks compared with lamivudine for 48 weeks (ICER £3200 per QALY)
• peginterferon alfa for 48 weeks compared with lamivudine for 208 weeks (ICER £1900 per QALY)
• peginterferon alfa for 48 weeks compared with no treatment (ICER £1500 per QALY).

Manufacturer’s model ( Gilead)

The model submitted by Gilead presents estimated cost-effectiveness ratios for a number of single treatments and treatment sequences. However, the cost effectiveness of adefovir dipivoxil compared with best supportive care is not reported. The interferons are not considered as treatment options, and the analyses are for a combined population of people with HBeAg-positive and HBeAg-negative disease. The estimated ICERs are as follows:

• lamivudine then adefovir dipivoxil (when lamivudine resistance emerges), compared with best supportive care (ICER £6700 per QALY)
• lamivudine then adefovir dipivoxil (when lamivudine resistance emerges), compared with lamivudine then best supportive care (when lamivudine resistance emerges) (ICER £9200 per QALY)
• adefovir dipivoxil then lamivudine (when adefovir dipivoxil resistance emerges), compared with best supportive care (ICER £8200 per QALY)
• adefovir dipivoxil then lamivudine (when adefovir dipivoxil resistance emerges), compared with lamivudine then best supportive care (when lamivudine resistance emerges) (ICER £11,400 per QALY)
• adefovir dipivoxil then lamivudine (when adefovir dipivoxil resistance emerges) compared with lamivudine then adefovir dipivoxil (when lamivudine resistance emerges) (ICER £29,400 per QALY).

Published model

The published model (Kanwal and colleagues) evaluated a ’do nothing‘ strategy (equivalent to best supportive care), standard interferon alfa, lamivudine, adefovir dipivoxil, and lamivudine then adefovir dipivoxil. For HBeAg-positive disease, the estimated ICERs for the non-dominated strategies are as follows:

• standard interferon alfa compared with best supportive care (ICER $2300 [£1300 at an exchange rate of $1.75 per £1] per QALY)
• lamivudine then adefovir dipivoxil, compared with standard interferon alfa (ICER $16,600 [£9500] per QALY)
• adefovir dipivoxil, compared with lamivudine then adefovir dipivoxil) (ICER $91,000 [£52,000] per QALY).

In the analysis for HBeAg-negative disease, lamivudine then adefovir dipivoxil (as salvage therapy after resistance to lamivudine develops) is both cheaper and more effective than all other treatment options.

The models show that standard interferon alfa or peginterferon alfa therapies followed by lamivudine then adefovir dipivoxil, where necessary, appear to be cost effective relative to alternative strategies. In most of the analyses, strategies in which adefovir dipivoxil is used before lamivudine, or without lamivudine, in the sequence are dominated by the alternative strategies. The exceptions are Gilead’s estimated ICER of £29,400 per QALY for adefovir dipivoxil then lamivudine, compared with lamivudine then adefovir dipivoxil, and the Assessment Group’s estimated ICER of £57,000 per QALY (for HBeAg-positive patients) for peginterferon alfa then adefovir dipivoxil then lamivudine, compared with peginterferon alfa then lamivudine then adefovir dipivoxil.

Consideration of the evidence

The Committee reviewed the data available on the clinical and cost effectiveness of adefovir dipivoxil and peginterferon alfa for the treatment of chronic hepatitis B, having considered evidence on the nature of the condition and the value placed on the benefits of adefovir dipivoxil and peginterferon alfa by people with chronic hepatitis B, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.

The Committee considered that peginterferon alfa was both clinically and cost effective compared with standard interferon alfa therapy for the treatment of chronic hepatitis B. The Committee concluded, therefore, that peginterferon alfa should be considered as a direct alternative option to standard interferon for the management of chronic hepatitis B during the initial phase of treatment.

The Committee heard from the clinical experts that peginterferon alfa 2a is licensed to be prescribed for 48 weeks, but the direct alternative treatment (interferon alfa 2a or 2b) has a recommended 4- to 6‑month prescription period. For patients prescribed peginterferon alfa, reviewing treatment after 4 or 6 months will allow a decision to be made as to whether the benefits of continued treatment are likely to outweigh the costs and the side effects. The Committee was sympathetic to the view that, in consultation with and with the agreement of the patient, the clinician may advise stopping treatment with peginterferon alfa at any time after the 4–6 month review up to a maximum of 48-weeks.

The experts stated that the effects of initial treatment with peginterferon alfa in achieving a good response were different for HBeAg-positive and HBeAg-negative disease. The Committee was persuaded, however, that the response to peginterferon alfa as measured by HBeAg seroconversion (in the case of HBeAg-positive disease) or an adequate reduction in viral load (in the case of HBeAg-negative disease) was clinically important in both cases. Thus the Committee concluded, on the basis of this effect taken in conjunction with the cost-effectiveness analysis presented by the assessment group that peginterferon alfa should be recommended as an option in first-line therapy for both HBeAg-positive and HBeAg-negative chronic hepatitis B.

The Committee next considered the use of the oral antiviral agents (specifically adefovir dipivoxil) for the long-term treatment of both HBeAg-positive and HBeAg-negative chronic hepatitis B.

The Committee considered the cost-effectiveness analysis presented by the assessment team on the use of adefovir dipivoxil compared with lamivudine in the long-term treatment of chronic hepatitis B. In addition the Committee discussed the cost-effectiveness analysis of the various treatment sequences that could be used in the management of the entire disease process. It was apparent that adefovir dipivoxil was cost effective when compared directly with lamivudine for long-term therapy, if it was assumed that the alternative treatment could not be used if resistance developed. However, when considering the use of adefovir dipivoxil in the various treatment sequences, the Committee heard that the most cost-effective option was for it to be used after failure of lamivudine or following the emergence of virus resistance to lamivudine.

The Committee heard the concerns of the clinical experts about the potential impact of the development of resistant viral mutations on future treatment options, based on the current experience of lamivudine use. The experts also stated that adefovir dipivoxil was less likely to result in viral resistance over the short term. They also expressed the view that viral resistance may be encouraged by the use of single agents and discussed with the Committee the possibility of recommending combination therapies for long-term treatment.

The Committee was persuaded that it was likely that drug-resistance might be attenuated by using anti viral drugs in combination. The Committee felt unable to recommend combination therapies in the absence of trial evidence on the effect of combination therapy on drug resistance and cost effectiveness analysis of this approach. However the Committee considered that it was not appropriate under these circumstances to recommend the use of adefovir dipivoxil only after resistance had already developed to another anti viral agent. It was persuaded also by the expert testimony that it was possible to identify groups of people for whom lamivudine resistance is more likely to occur rapidly. Consequently it was sympathetic to the experts’ view that it was appropriate to use adefovir dipivoxil where the development of lamivudine-resistance would be considered particularly hazardous. The Committee was also sympathetic to the experts’ view that under these circumstances the use of either combination treatments or adefovir dipivoxil alone might be more appropriate.

The Committee concluded that it was appropriate to recommend adefovir dipivoxil as an option for the treatment of chronic hepatitis B where prolonged oral antiviral treatment is required. It was also persuaded that this should only be after the use of an interferon as initial treatment unless this was contraindicated. However, the Committee considered that issuing recommendations about treatment sequencing for the antiviral agents was premature and they accepted that, currently, the use of antiviral agents would need to be decided on a case by case basis taking into account factors including HBeAG status, stage of disease process (for example, compensated or decompensated cirrhosis) and the likelihood of the emergence of virus resistance.

There is considerable concern about viral resistance in the long-term treatment of chronic hepatitis B. Further research is needed on the role of combination therapy with antiviral drugs in reducing the development of resistance to treatment. There is at least one ongoing study comparing lamivudine alone with lamivudine in combination with adefovir dipivoxil in treatment naïve people with chronic hepatitis B.

Preliminary views on the resource impact for the NHS

This section outlines the Appraisal Committee’s preliminary assessment concerning the likely impact on NHS resources if the recommendations in Section 1 were to be implemented. When guidance is issued, this section is intended to assist NHS planners and managers in its implementation. Therefore the Institute particularly welcomes comments and information from those who would be involved in the implementation of the guidance so that this section can be made as helpful and robust as possible.

The resource impact is subject to considerable uncertainty. For the purposes of this estimate, it is assumed that currently 500 people are being treated annually with an interferon alfa (mostly peginterferon alfa). In the absence of this guidance, it is estimated that the numbers being prescribed peginterferon alfa would increase to about 1000 per year within 3 to 5 years. The effect of this guidance is assumed to be to add an additional 1000 people per year to the numbers treated with peginterferon alfa, at a net cost of a little more than £5 million per year.

It is assumed that currently 1800 people are being treated with lamivudine until resistance occurs, after which these people would receive no treatment. If such people transfer to adefovir dipivoxil on the emergence of lamivudine resistance, it is estimated that the net cost would be £1.3 million in the first year, rising to £4.5 million in the fifth year. This calculation excludes the cost attributable to the anticipated small proportion of patients who may be prescribed adefovir dipivoxil before lamivudine resistance has emerged.

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 B should review their current 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 B should incorporate the guidance.

To measure compliance locally