4 Consideration of the evidence

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

4.2 The Committee was advised by the patient experts about the impact of hepatitis B on their quality of life and the importance of having a variety of treatments available. The Committee was also mindful of the long-term risk of progression to cirrhosis or hepatocellular carcinoma associated with chronic hepatitis B infection and the impact of this in terms of costs, mortality and health-related quality of life. The Committee agreed that avoiding progression to cirrhosis or hepatocellular carcinoma was the most important goal in the treatment of chronic hepatitis B and that the relationship between any surrogate endpoints measured in clinical studies and these outcomes should be fully taken into consideration.

4.3 The Committee was advised by the clinical specialists of the relative importance of the different tests in the diagnosis and management of chronic hepatitis B. It was persuaded that measurement of viral load is an important predictor of future liver damage and can be used to identify patterns of viral resistance. However, it also acknowledged the significance of seroconversion in HBeAg-positive disease, which allows for the discontinuation of treatment to be considered. The Committee was convinced that it was appropriate to use various outcomes to predict the long-term effect of the disease and apply them when defining the economic model structure and practical continuation rules. However, it noted that the relationship between surrogate and long-term outcomes was not very explicit and that some clarification would be welcomed.

4.4 The Committee considered the treatment options available for people with chronic hepatitis B in the UK. The Committee discussed with the patient experts and clinical specialists the relevance of previous NICE guidance on chronic hepatitis B and where in the treatment pathway entecavir should be considered. The Committee understood from the clinical specialists that in the treatment pathway entecavir could be seen as an alternative to interferon either as first-line treatment or where interferon is considered inappropriate (because of contraindication or intolerance) or as an alternative to lamivudine as second-line treatment. The Committee heard from the clinical specialists that in HBeAg-positive disease the rates of seroconversion achieved with entecavir were sufficiently high that it could be considered as an option for first-line treatment alongside interferon. However the Committee considered that, without having reviewed all the evidence on the range of possible treatment sequences, it was not in a position to recommend one treatment algorithm over another and that such a recommendation was beyond the scope of this appraisal. However the Committee agreed that a comparison with interferon alfa or peginterferon alfa-2a was of interest and should be taken into account when considering the cost effectiveness of entecavir.

4.5 The Committee discussed the clinical effectiveness of entecavir in treating chronic hepatitis B and considered all of the available evidence. It acknowledged that in RCTs entecavir had been demonstrated to be more effective than lamivudine in terms of surrogate endpoints. The Committee then considered the indirect comparison exercise undertaken by the manufacturer to compare entecavir with all of the other alternative treatments outlined in the scope, taking into account the ERG's remarks on the high degree of uncertainty of the indirect analysis results. The Committee was particularly concerned about the robustness of the results of the indirect comparison when considering the comparison between entecavir and peginterferon alfa-2a. On balance, the Committee considered that although the totality of the evidence submitted supported the clinical effectiveness of entecavir, it was not in a position to advise on the relative clinical and cost effectiveness of different sequential treatment strategies including peginterferon alfa-2a and those involving only oral antiviral agents.

4.6 The Committee understood the high degree of mutability of the hepatitis B virus and recognised that the development of viral resistance was likely to be a problem with all available drugs. However, it agreed with the clinical specialists that drugs with different mechanisms of action were important in the clinical management of chronic hepatitis B particularly because of their value in reducing the potential for the development of resistance to treatment. The Committee noted that the comparatively low rate of resistance reported for entecavir in the original manufacturer's submission was from one RCT with a 4-year follow-up of a subgroup of people. The Committee noted that additional data from this trial provided by the manufacturer during the consultation period showed that a low rate of resistance was still achieved over a 5-year period. It therefore concluded that low rates of resistance could reasonably be expected to be maintained for a number of years, but appreciated that there was still some uncertainty over the longer term.

4.7 The clinical specialists indicated that entecavir monotherapy could be used in place of lamivudine monotherapy in the pathway of care. The Committee also appreciated that lamivudine monotherapy was not a preferred option, in particular because of the high rate of viral resistance seen in highly replicative disease. The Committee concluded that an important advantage of entecavir over lamivudine with respect to resistance was the likelihood that treatment-resistant strains would emerge much later in the course of treatment, and that the need for the addition of another agent, such as adefovir dipivoxil, would be deferred but not necessarily avoided completely.

4.8 The Committee discussed the limitations and the degree of uncertainty in the economic models presented. It first considered the model representing the clinical management of people with HBeAg-positive chronic hepatitis B and noted the base-case ICERs presented and the degree of uncertainty associated with them. The Committee noted that the ICERs were below £20,000 per additional QALY gained, except in the comparison with telbivudine in which entecavir was dominated. The Committee acknowledged that this result was driven only by the assumption that entecavir had no incremental benefits when compared with telbivudine and that this took insufficient notice of the different rates of viral resistance between the two treatments. The Committee noted that the probabilistic sensitivity analyses showed that, for a threshold of £20,000 per QALY gained, entecavir still had a 45% probability of being cost effective in this particular comparison. Reflecting additionally on the concerns about the indirect comparison used for quantification of differences in effectiveness between entecavir and its comparators, the Committee concluded that the cost effectiveness results for these should be treated with extreme caution; particularly for the comparison of entecavir with peginterferon alfa-2a.

4.9 The Committee agreed with the view that the model of HBeAg-positive chronic hepatitis B could be limited to a relatively short treatment duration because some people could be expected to experience seroconversion and thus stop receiving treatment. The Committee considered the ERG's exploratory scenario analyses on extending the timeframe of treatment in the HBeAg-positive model and noted that an extrapolation to 5 years of treatment resulted in a cost-effectiveness estimate of £22,000 per QALY gained when comparing with lamivudine. Extrapolation to the extreme of 20 years resulted in cost-effectiveness estimates at the high end of the range usually considered appropriate for the NHS. The Committee noted that no results were available for these exploratory analyses using the comparators other than lamivudine.

4.10 In conclusion, having considered the direct and indirect evidence for clinical effectiveness and the results of the economic model submitted by the manufacturer, including the exploratory analyses of the ERG, the Committee concluded that entecavir could be considered as a cost-effective option for the treatment of people with HBeAg-positive chronic hepatitis B in whom antiviral treatment is indicated.

4.11 The Committee further considered the analysis in people with lamivudine-refractory disease, though found this less informative due to the data limitations. The Committee also noted advice from the clinical experts that pre-treatment with lamivudine and/or adefovir dipivoxil would decrease the number of mutations needed for the development of resistance to entecavir. The Committee considered that it was beyond the scope of this appraisal to provide recommendations on the optimum treatment pathway and was unable to make a specific recommendation about the clinical and cost effectiveness of entecavir in people who had developed resistance to other antiviral agents.

4.12 The Committee discussed the ICERs for entecavir in the HBeAg-negative population that had been derived from the original manufacturer's analysis, the ERG's analysis and the revised modelling provided by the manufacturer. Assuming a lifetime treatment duration and continuation of treatment with entecavir when the disease progressed to compensated cirrhosis, the cost-effectiveness estimate was just over £20,000 per QALY gained when all patients start in the pre-cirrhotic state, and £24,335 per QALY gained if 10% of patients are assumed to have cirrhosis at the start of treatment, when compared with lamivudine. The Committee noted the manufacturer's comments that progression to cirrhosis could be linked to the development of viral resistance. Therefore, accepting the lower rate of resistance development with entecavir compared to lamivudine may mean that the rate of progression was also likely to be lower. The Committee therefore agreed that there was uncertainty about the likely rate of progression to cirrhosis when comparing lamivudine to entecavir, and that use of the 1.8% estimate could have resulted in an underestimation of the cost effectiveness of entecavir. However, the Committee noted that there was still uncertainty surrounding the model – namely the lack of evidence on which to assess the plausibility of efficacy estimates of therapies over a lifetime treatment duration, and that the cost effectiveness compared with other available treatments had not been evaluated.

4.13 The Committee reviewed the additional data on the relationship between the surrogate outcomes used and final effectiveness outcomes, provided by the manufacturer during consultation. The Committee was persuaded by the observational studies presented that the estimates of the number of cases of cirrhosis and hepatocellular carcinoma averted in the original and subsequent models were plausible.

4.14 On the basis of the evidence presented during the consultation period and the previous testimonies from experts about the need for alternative treatments to be made available for people with HBeAg-negative chronic hepatitis B, the Committee was persuaded that the use of entecavir in people with HBeAg-negative chronic hepatitis B in whom antiviral treatment is indicated is clinically and cost effective.