4 Consideration of the evidence
4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of tenofovir disoproxil, having considered evidence on the nature of the condition and the value placed on the benefits of tenofovir disoproxil 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 clinical experts of the importance of having a variety of treatments available in order to combat the problem of viral resistance. The Committee heard from the patient experts that tenofovir disoproxil was well tolerated with few adverse effects. The patient experts also explained that treatments which are associated with a low risk of viral resistance would increase peace of mind and hence quality of life. 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.
4.3 The Committee considered the treatment options available for patients with chronic hepatitis B in the UK. The Committee discussed the relevance of previous NICE guidance on chronic hepatitis B and where in the treatment pathway tenofovir disoproxil should be considered. The Committee understood that tenofovir disoproxil could be considered an alternative to other antiviral drugs as primary first-line therapy if an interferon is considered inappropriate (because of a contraindication or intolerance) or as second-line therapy when either a course of an interferon has not brought about seroconversion, or resistance has developed to another antiviral drug.
4.4 The Committee discussed the clinical effectiveness of tenofovir disoproxil in treating chronic hepatitis B and considered all of the available evidence. It acknowledged that in the RCTs tenofovir disoproxil was more effective than adefovir dipivoxil in terms of surrogate endpoints. The Committee then considered the indirect mixed-treatment comparison undertaken by the manufacturer to compare tenofovir disoproxil with entecavir, lamivudine and adefovir dipivoxil in people with HBeAg-positive and HBeAg-negative disease. The Committee noted discrepancies between the results from the mixed-treatment comparison and those from the individual RCTs. The Committee also took into account the ERG's remarks on the quality of the analysis of the mixed-treatment comparison. However, the Committee agreed that the identified weaknesses in the analysis were not sufficiently serious to prevent it making a decision on the use of tenofovir disoproxil in chronic hepatitis B in the light of the evidence available from the individual RCTs.
4.5 The Committee discussed the limitations and the degree of uncertainty in the economic models presented. The Committee noted that both the manufacturer's and ERG's estimates of the ICERs for tenofovir disoproxil as first-line monotherapy in both HBeAg-positive and -negative disease were below £20,000 per additional QALY gained. The Committee also noted that the results of the probabilistic sensitivity analysis showed a 60% and 58% probability that first-line therapy with tenofovir disoproxil is the most cost-effective antiviral strategy for treatment of HBeAg-positive and HBeAg-negative disease at a willingness to pay threshold of £20,000 per QALY. The Committee noted that the effectiveness estimates used in the economic model were taken from the mixed-treatment comparison and that concern had been expressed about this comparison. However, the Committee was satisfied that the effectiveness of tenofovir disoproxil was at least comparable to that of other currently recommended options, notably entecavir, and that the acquisition cost of tenofovir disoproxil was lower. Therefore the Committee concluded that tenofovir disoproxil is a cost-effective option for the treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B.
4.6 The Committee understood the high-degree of mutability of the hepatitis B virus and noted that tenofovir disoproxil appeared to have a low potential for inducing viral resistance. The Committee also noted that the estimates of resistance rates for tenofovir disoproxil and other antiviral drugs used in the cost-effectiveness analysis were based on a pooled analysis of resistance data undertaken by the manufacturer. Taking into account the ERG's comments and the clinical expert views on the biological plausibility of the findings, the Committee agreed that tenofovir disoproxil had a similar or more favourable resistance profile at 1 year compared with other available treatments for chronic hepatitis B. However, the Committee agreed that given the data available it could not be assumed that this low rate of resistance would be maintained in the long term.
4.7 The Committee discussed the possibility that tenofovir disoproxil might be used as combination therapy with another antiviral agent as a strategy to reduce resistance. They heard from the clinical experts that this strategy would be based on experience gained in treating HIV, and that there was little evidence to support such a strategy in chronic hepatitis B at present. Furthermore, the experts noted that current European guidelines recommended entecavir or tenofovir disoproxil monotherapy as first-line therapy. The Committee heard that there was a lack of data from RCTs to allow an evaluation of the effectiveness of tenofovir disoproxil in combination with other agents as first-line or subsequent therapy. The Committee also heard that data on long-term resistance would be needed to guide decisions on whether combination therapy should be given, and these data are presently unavailable. However, the Committee noted comments from the consultees that there may be circumstances in which combination therapy might be appropriate (for example, tenofovir disoproxil could be added to another drug as rescue therapy when resistance to the first drug has developed). Although acknowledging that evidence on the long-term clinical effectiveness and cost-effectiveness of combination therapy was lacking, the Committee agreed that using tenofovir disoproxil in combination regimens might be acceptable when evidence supporting its clinical effectiveness becomes available. The Committee concluded that the available evidence only supported the use of tenofovir disoproxil as monotherapy, but it accepted that there may be exceptional circumstances in which tenofovir disoproxil might be used in combination with other antiviral agents. Therefore in recommending tenofovir disoproxil as an option for the treatment of chronic hepatitis B, the Committee did not specify that the treatment should be restricted absolutely to use as monotherapy, but noted that this was the approach that was supported by the evidence.