Hepatitis B - tenofovir disoproxil fumarate (appraisal consultation document)
Background
Key dates
Appraisal Committee's preliminary recommendations
The technology
The manufacturer's submission
Consideration of the evidence
Implementation
Proposed recommendations for further research
Related NICE guidance
Proposed date for review of guidance
Appendix A: Appraisal Committee members and NICE project team
Appendix B: Sources of evidence considered by the Committee
Background
The Department of Health asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of tenofovir disoproxil 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 by the manufacturer and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of tenofovir disoproxil for the treatment of 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). This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from 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 single technology appraisal process' (this document is available on the Institute's website, www.nice.org.uk).
- 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.
- 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.
The key dates for this appraisal are:
Closing date for comments: 26 March 2009
Second Appraisal Committee meeting: 8 April 2009
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.
| 1 | Appraisal Committee's preliminary recommendations |
| 1.1 | Tenofovir disoproxil used as monotherapy is recommended, within its marketing authorisation, as an option for adults with HBeAg-positive or HBeAg-negative chronic hepatitisB in whom antiviral treatment is indicated |
| 2 | The technology |
| 2.1 | Tenofovir disoproxil (Viread, Gilead) is a nucleotide analogue. It works by blocking the enzyme reverse transcriptase, which is responsible for hepatitis B virus (HBV) replication. Tenofovir disoproxil has a marketing authorisation in the UK for the treatment of chronic hepatitis B in adults with compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis. |
| 2.2 | Adverse events associated with the use of nucleotide analogues include lactic acidosis and progression of hepatomegaly. Additional adverse events reported for tenofovir disoproxil include headache, fatigue and gastrointestinal disorders. For full details of side effects and contraindications, see the summary of product characteristics. |
| 2.3 | The acquisition cost of tenofovir disoproxil (excluding VAT; 'British national formulary' [BNF] edition 56) is £255.00 for a 30-tablet pack. Costs may vary in different settings because of negotiated procurement discounts. Tenofovir disoproxil is licensed for use in adults over 18 years. The dosage is a once-daily tablet of 245mg. The optimal treatment duration is currently unknown. |
| 3 | The manufacturer's submission |
| 3.1 | The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of tenofovir disoproxil and a review of this submission by the Evidence Review Group (ERG; appendix B). |
| 3.2 | The manufacturer approached the decision problem by comparing tenofovir disoproxil monotherapy with lamivudine, adefovir dipivoxil and entecavir in adults with compensated liver disease and active chronic hepatitisB (that is, evidence of viral replication and active liver inflammation). The manufacturer did not compare tenofovir disoproxil with any of the interferons. The primary outcome measures outlined in the decision problem were virological response (hepatitis B virus [HBV] DNA), histological improvement (inflammation and fibrosis), biochemical response (for example, ALT levels), and hepatitisB surface antigen (HBsAg) and hepatitis B 'e' antigen (HBeAg) seroconversion rate. |
| 3.3 | The manufacturer's submission presented evidence on the clinical effectiveness of tenofovir disoproxil from two randomised controlled trials (RCTs) that compared tenofovir disoproxil with adefovir dipivoxil. The protocol for both studies specified that the populations would be people who had not previously received nucleotide analogue therapy. One trial compared tenofovir disoproxil with adefovir dipivoxil in people with HBeAg-positive hepatitis B (176 participants received tenofovir disoproxil and 90 adefovir dipivoxil); another made the same comparison in people with HBeAg-negative disease (250 participants received tenofovir disoproxil and 125 adefovir dipivoxil). |
| 3.4 | The results of the two RCTs showed that at 48weeks tenofovir disoproxil gave a greater proportion of complete responses (that is, histological response and HBV DNA below 400 copies/ml) than adefovir dipivoxil in people with HBeAg-positive and HBeAg-negative disease. The difference was statistically significant (p 0.001, in both trials). A similar proportion of people with HBeAg-positive disease had seroconversion or HBeAg loss with tenofovir disoproxil and adefovir dipivoxil, but significantly more people treated with tenofovir disoproxil had hepatitis B surface antigen (HBsAg) loss at 48weeks (p=0.018). No people with HBeAg-negative disease in either treatment group had experienced HBsAg loss or seroconverted to anti-HBs at 48weeks. |
| 3.5 | Both RCTs reported a smaller proportion of people with potential future resistance (HBV mutation-conserved site changes) with tenofovir disoproxil than with adefovir dipivoxil at 48weeks. There were no cases of substitution in the HBV polymerase/reverse transcriptase associated with resistance to tenofovir disoproxil in either study. There were no cases of viral resistance. |
| 3.6 | The incidence of severe, life-threatening or disabling adverse events was similar between treatment groups, with no deaths reported in either study. However, statistically significantly more participants had at least one treatment-related adverse event in the tenofovir disoproxil treatment group in one study (p=0.018). The incidence of arthralgia was statistically significantly higher for the group receiving tenofovir disoproxil in the other study (p=0.003). |
| 3.7 | The manufacturer pointed out that there were no trials that included all treatment options in any of the patient populations and therefore a series of mixed-treatment comparison meta-analyses were carried out to assess the relative efficacy of adefovir dipivoxil, entecavir, lamivudine, tenofovir disoproxil and placebo in nucleoside-naïve and lamivudine-refractory patients. For HBeAg-positive disease, the included outcomes were the probability of achieving HBV DNA suppression (300copies/ml), and the probability of HBeAg seroconversion over 1 year of treatment. All analyses were conducted using random-effects models unless the between-studies standard deviation (tau) was close to zero. For HBeAg-positive nucleoside-naïve participants, the mixed-treatment comparison showed that tenofovir disoproxil had a statistically significantly higher predicted probability of HBV DNA suppression than all comparators. There was no statistically significant difference between the antiviral drugs for the probability of seroconversion |
| 3.8 | For HBeAg-negative disease, the manufacturer explained that no meaningful analysis could be undertaken because of the small number of trials identified. The manufacturer undertook an additional analysis combining trials on HBeAg-positive and HBeAg-negative disease in which the proportion of patients who were HBeAg positive was considered as a covariate. The results were similar to those seen in the HBeAg-positive subgroup. |
| 3.9 | Meta-analyses were undertaken by the manufacturer using a pooled analysis of rates of resistance between available treatments for HBeAg-positive treatment-naive and lamivudine-refractory patients, using data from the RCTs and the observational studies identified while undertaking the systematic review. The results suggested a lower risk of viral resistance over 5years with tenofovir disoproxil than with adefovir dipivoxil, lamivudine and entecavir in both treatment-naive and lamivudine-refractory patients. |
| 3.10 | The manufacturer submitted a cost-effectiveness analysis using a Markov model that could be applied either to a cohort of people with HBeAg-positive or HBeAg-negative disease at the start of treatment. The model had 11 main states defined as: active chronic hepatitisB (HBV DNA≥300copies/ml), viral suppression (HBV DNA300copies/ml), HBeAg seroconverted (not applicable to HBeAg-negative disease), HBsAg seroconverted, compensated cirrhosis with detectable HBV DNA, compensated cirrhosis with undetectable HBV DNA, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation (year in which transplantation occurs), post liver transplantation and death. These were based on those used in previous economic evaluations. The model was designed to compare tenofovir disoproxil, adefovir dipivoxil, lamivudine and entecavir. It incorporated sequences of first-, second- and third-line treatments and people were assumed to move on to the next treatment regimen if they developed resistance to their current treatment. For both people with HBeAg-positive and HBeAg-negative disease the model has a lifetime horizon, a cycle length of 1year, and patients are assumed to continue to receive tenofovir disoproxil (and all other therapies) until they die, undergo HBeAg seroconversion, undergo HBsAg seroconversion or develop tenofovir disoproxil resistance. |
| 3.11 |
In the base-case manufacturer's economic analysis, after treatment sequences that were dominated or extendedly dominated were excluded, the incremental cost-effectiveness ratios (ICERs) of interest in HBeAg-positive chronic hepatitisB were as follows:
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| 3.12 |
In the base-case manufacturer's economic analysis, after treatment sequences that were dominated or extendedly dominated were excluded, ICERs of interest in HBeAg-negative chronic hepatitis B were as follows:
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| 3.13 |
The manufacturer also presented results for an analysis in a cohort in which lamivudine resistance had developed:
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| 3.14 | The ERG viewed the mixed-treatment comparison methodology to be generally sound, but pointed out that it was weakened by the small number of studies and single studies in some networks, a lack of quality assessment of included studies, no discussion of potential clinical heterogeneity and limited discussion of statistical heterogeneity. Therefore the ERG concluded that the results should be treated with caution. |
| 3.15 | The ERG viewed the pooled analysis of resistance in the manufacturer's submission as appropriate, but pointed out that data for long-term resistance are currently unavailable. |
| 3.16 | The ERG pointed out that there were a number of analytical errors in the manufacturer's electronic model and therefore re-ran the model with discount factors for future health effects applied to all of the model cycles, amendments to transition matrices and a once-only application of a reduction of excess mortality for patients with compensated cirrhosis achieving viral suppression. The results for people with HBeAg-positive disease gave an ICER for first-line tenofovir disoproxil followed by lamivudine relative to lamivudine followed by tenofovir disoproxil of £17,590. The ICER for tenofovir disoproxil followed by lamivudine plus tenofovir disoproxil relative to first-line tenofovir disoproxil followed by lamivudine was £27,479. The results for people with HBeAg-negative disease gave an ICER for first-line tenofovir disoproxil followed by lamivudine relative to lamivudine followed by tenofovir disoproxil of £17,640. The ICER for tenofovir disoproxil followed by lamivudine plus tenofovir disoproxil relative to first-line tenofovir disoproxil followed by lamivudine was £28,324. |
| 3.17 | Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/TAxxx |
| 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 hepatitisB 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 hepatitisB 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 expressed concern that the results for tenofovir disoproxil in the indirect mixed-treatment comparison were not similar to those in individual RCTs, but this would be expected given that tenofovir disoproxil was linked by only one comparator. The Committee also noted the ERG's remarks on the quality of the analysis of the mixed-treatment comparison. The Committee agreed that although further clarification on this discrepancy would be useful, the discrepancy was not sufficiently serious to prevent it making a decision on the use of tenofovir disoproxil in chronic hepatitisB. |
| 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 monotherapy 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. Therefore the Committee concluded that tenofovir disoproxil is a cost-effective option for the treatment of HBeAg-positive and HBeAg-negative chronic hepatitisB. |
| 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 an equivalent or more favourable resistance profile at 1year than 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 hepatitisB at present. Furthermore the experts noted that current European guidelines recommended monotherapy (either with entecavir or tenofovir disoproxil) 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. 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 would not be available for the foreseeable future. The Committee noted that the economic analyses did not consider tenofovir disoproxil in combination with another antiviral agent as first-line therapy. The Committee concluded that there was insufficient evidence on the clinical and cost effectiveness of tenofovir disoproxil as first-line therapy in combination with other antiviral agents, and concluded that tenofovir disoproxil should be recommended as monotherapy only. |
| 5 | Implementation |
| 5.1 | The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in 'Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals. |
| 5.2 | 'Healthcare standards for Wales' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months. |
| 5.3 | NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). |
| 6 | Proposed recommendations for further research |
| 6.1 | A phase III trial of entecavir plus tenofovir disoproxil combination therapy versus entecavir monotherapy in treatment-naive people with chronic hepatitis B is currently recruiting participants. |
| 6.2 | Research on the long-term risk of resistance with tenofovir disoproxil montherapy and tenofovir disoproxil in combination with other antiviral agents is needed because few RCTs are currently available. |
| 7 | Related NICE guidance |
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| 8 | Proposed date for review of guidance |
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The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. It is proposed that the guidance on this technology is considered for review in March 2012. The Institute would particularly welcome comment on this proposed date. |
| Appendix A. Appraisal Committee members and NICE project team |
| A. Appraisal Committee members |
|
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 three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. 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 the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal. The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website. Professor David Barnett Dr David W Black Mr Mark Campbell Professor Mike Campbell Mr David Chandler Mr Peter Clarke Dr Christine Davey Dr Rachel A Elliott Dr Dyfrig Hughes Dr Catherine Jackson Dr Peter Jackson Professor Jonathan Michaels Dr Eugene Milne Dr Simon Mitchell Dr Richard Alexander Nakielny Mrs Ruth Oliver-Williams Dr Katherine Payne Dr Danielle Preedy Dr Philip Rutledge Mr Miles Scott Dr Surinder Sethi Professor Andrew Stevens (Chair) Dr Matt Stevenson |
| B. NICE Project Team |
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Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager. Helen Tucker Janet Robertson Chris Feinmann |
| Appendix B. Sources of evidence considered by the Committee | |
| A |
The Evidence Review Group (ERG) report for this appraisal was prepared by Southampton Health Technology Assessments Centre:
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| B |
The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I II and III also have the opportunity to appeal against the final appraisal determination. I Manufacturer/sponsor:
II Professional/specialist and patient/carer groups:
III Other consultees
IV Commentator organisations (did not provide written evidence and without the right of appeal)
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| C |
The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on tenofovir disoproxil by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.
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