• National Institute for Health and Clinical Excellence (NICE). Entecavir for the treatment of chronic hepatitis B. London (UK): National Institute for Health and Clinical Excellence (NICE); 2008 Aug. 25 p. (Technology appraisal guidance; no. 153).

This is the current release of the guideline.

Chronic hepatitis B

Assessment of Therapeutic Effectiveness
Treatment

Family Practice
Gastroenterology
Infectious Diseases
Internal Medicine

Advanced Practice Nurses
Physician Assistants
Physicians

To evaluate the clinical effectiveness and cost effectiveness of entecavir for the treatment of chronic hepatitis B

Patients with chronic hepatitis B e antigen (HbeAg)-positive and HbeAg-negative hepatitis B

Note: This guidance does not apply to people with chronic hepatitis B who also have hepatitis C, hepatitis D or human immunodeficiency virus (HIV).

Entecavir

• Clinical Effectiveness
  • Proportion of patients with undetectable viral load below the limit of quantification by polymerase chain reaction (PCR) at weeks 24 and 48
  • Proportion of patients achieving seroconversion
  • Proportion of patients with histological improvement
  • Proportion of patients with alanine aminotransferase (ALT) normalization
  • Viral resistance
  • Adverse events
• Cost-effectiveness

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Searches of Unpublished Data

Clinical Effectiveness

5 randomized controlled trials (RCTs). The Evidence Review Group (ERG) did not identify any additional RCTs that are relevant for inclusion.

Comparator Studies

• Entecavir – 1 additional RCTs
• Lamivudine – 11 additional RCTs
• Telbivudine – 3 RCTs
• Pegylated interferon alpha 2a – 2 RCTs
• Adefovir in combination with lamivudine (in lamivudine refractory patients) – 3 RCTs

Economic Evaluation

Published literature: 9 studies identified by the manufacturer and 1 study identified by the ERG

Expert Consensus

Not applicable

Systematic Review with Evidence Tables

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an Evidence Review Group (ERG) report. The ERG report for this technology appraisal was prepared by Southampton Health Technology Assessment Centre (SHTAC), University of Southampton (see the "Availability of Companion Documents" field).

Clinical Effectiveness

Description and Critique of Manufacturer's Approach to Validity Assessment

The manufacturer's submission (MS) provides a formal appraisal of the validity of the included trials using the quality assessment criteria developed by NICE. It is not stated whether the appraisal was conducted independently by more than one person.

Description and Critique of the Statistical Approach Used

The MS reports almost the same descriptions of the statistical methods used in the randomised controlled trials (RCTs) as reported in the published papers, but gives slightly more detail for one study.

Overall, the statistical approaches reported in the published papers and MS relating to comparisons of entecavir against lamivudine in the RCTs appear generally appropriate. However, the statistical methods are reported superficially and have not been scrutinised in detail by the ERG. Differences in mean proportions of entecavir and lamivudine treated patients were based on confidence intervals obtained from a normal approximation to the binomial distribution. Differences between means of continuous variables were tested using t-tests based on linear regression models that were adjusted for baseline characteristics or included baseline data as covariates.

According to the clinical study reports, data were analysed using two approaches. Non-completing patients were included in analyses as treatment failures (NC=F approach) and as missing data (NC=M approach). The data reported in the published papers are from the NC=F analyses. The MS does not clarify which analysis method was used; it refers sporadically to NC=F analysis for only some end-points in some RCTs.

P-values for baseline comparisons were given in only two of the published papers and exceeded 0.05 for all the reported variables. Published papers for the remaining trials provided baseline variance (standard deviation [SD]) estimates for selected variables and stated narratively that the treatment groups were well balanced at baseline for demographics and disease characteristics.

The MS presents results from the five RCTs separately, with little narrative summary and no meta-analysis undertaken of any of the five included trials for any of the outcomes to elucidate any overall effects of treatment. In general, the data presented in the year one data in the MS reflect the data reported in the published papers.

The manufacturer does not give any reasons for not undertaking a meta-analysis, but proceeds directly to a network meta-analysis.

Mixed Treatment Comparison (MTC)

The manufacturer reports the methodology used to conduct a network meta-analysis.

Separate networks were conducted for hepatitis B e antigen (HBeAg)-negative and HBeAg-positive, treatment-naïve patients at year one and year two (year two predicted probabilities are cumulative rather than annual values). It was not considered possible to create a network for lamivudine-refractory patients. The five RCTs comparing entecavir with lamivudine presented in the manufacturer's systematic review are included in the MTC, hence both direct and indirect evidence is used.

The model was constructed using a Bayesian hierarchical approach using WinBUGs 1.4 software. A burn-in period of 10,000 simulations was used to allow convergence, followed by 10,000 simulations for estimation. Entecavir is the baseline treatment common to all analyses, and absolute probabilities were estimated using the average rate observed across the entecavir arms at baseline. A fixed treatment effect model is used. However, no discussion or rationale is presented for use of a fixed over a random effects model except that 'this form of analysis is discussed in more detail by a number of authors', citing journal articles on the methodology of MTC models.

Refer to Section 3 of the ERG report (see the "Availability of Companion Documents" field) for additional information.

Economic Evaluation

Overview of Manufacturer's Economic Evaluation

The manufacturer's submission to NICE includes:

• A review of published economic evaluations of interferon alpha, pegylated interferon alpha 2a, lamivudine, adefovir and entecavir used as the first line treatment in nucleoside naïve chronic hepatitis B (CHB) patients. The MS also reviewed economic evaluations of adefovir and entecavir as a salvage therapy in patients who became resistant to lamivudine.
• A report of an economic evaluation undertaken for the NICE Single Technology Assessment (STA) process. Entecavir as a first line treatment is compared with lamivudine, pegylated interferon alpha 2a, and telbivudine as monotherapy treatments. The cost-effectiveness of entecavir in nucleoside treatment naïve CHB patients is estimated separately for two mutually exclusive sub-groups: HBeAg-positive patients and HBeAg-negative patients. In addition, the cost effectiveness of entecavir vs. a combination therapy of lamivudine with adefovir is estimated in HBeAg positive patients who have developed resistance to lamivudine. In this model it is implicitly assumed that entecavir is a second line (salvage) therapy in a sub-group of lamivudine-resistant patients and is compared to the alternative combination therapy of lamivudine with adefovir.

Sensitivity Analyses

The MS reports one-way sensitivity analyses for selected variables in the base case and results of probabilistic sensitivity analysis, and presents a range of estimates of the probabilities of entecavir being cost-effective under the assumptions of the various threshold values for HBeAg-positive and HBeAg-negative populations respectively. The means and measures of variation of costs and outcomes in the HBeAg positive population are also reported.

Model Validation

The principal validation of the model structure and key clinical assumptions appears to have been an opinion expressed by "expert clinical hepatologists and gastroenterologists". The mathematical logic and statistical calculations appear to have been reviewed by an independent statistician and a modeller not involved in the development or analyses (though no further detail is given on the scope of this or the clinicians' review nor the criteria used to establish the model's validity).

Refer to Section 4 of the ERG report (see the "Availability of Companion Documents" field) for additional information.

Expert Consensus

Considerations

Technology appraisal recommendations are based on a review of clinical and economic evidence.

Technology Appraisal Process

The National Institute for Health and Clinical Excellence (NICE) invites 'consultee' and 'commentator' organisations to take part in the appraisal process. Consultee organisations include national groups representing patients and carers, the bodies representing health professionals, and the manufacturers of the technology under review. Consultees are invited to submit evidence during the appraisal and to comment on the appraisal documents.

Commentator organisations include manufacturers of the products with which the technology is being compared, the National Health Service (NHS) Quality Improvement Scotland and research groups working in the area. They can comment on the evidence and other documents but are not asked to submit evidence themselves.

NICE then commissions an independent academic centre to review published evidence on the technology and prepare an 'assessment report'. Consultees and commentators are invited to comment on the report. The assessment report and the comments on it are then drawn together in a document called the evaluation report.

An independent Appraisal Committee then considers the evaluation report. It holds a meeting where it hears direct, spoken evidence from nominated clinical experts, patients and carers. The Committee uses all the evidence to make its first recommendations, in a document called the 'appraisal consultation document' (ACD). NICE sends all the consultees and commentators a copy of this document and posts it on the NICE website. Further comments are invited from everyone taking part.

When the Committee meets again it considers any comments submitted on the ACD; then it prepares its final recommendations in a document called the 'final appraisal determination' (FAD). This is submitted to NICE for approval.

Consultees have a chance to appeal against the final recommendations in the FAD. If there are no appeals, the final recommendations become the basis of the guidance that NICE issues.

Who is on the Appraisal Committee?

NICE technology appraisal recommendations are prepared by an independent committee. This includes health professionals working in the NHS and people who are familiar with the issues affecting patients and carers. Although the Appraisal Committee seeks the views of organisations representing health professionals, patients, carers, manufacturers and government, its advice is independent of any vested interests.

Not applicable

The manufacturer's submission presented an economic analysis comprising two Markov models (one for hepatitis B e antigen [HBeAg]-positive disease and one for HBeAg-negative disease). The HBeAg-positive disease model consisted of 14 health states that were defined as untreated chronic hepatitis B, spontaneous HBeAg seroconversion, HBsAg loss, resistance, flare, compensated/active cirrhosis, inactive cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, post-liver transplantation, treated chronic hepatitis B, treatment-induced HBeAg seroconversion and death. The HBeAg-negative disease model also differentiated between response to initial treatment and response to salvage therapy, resulting in 15 health states. The models were designed to compare entecavir with lamivudine, peginterferon alfa-2a and telbivudine, and both had a lifetime horizon. The estimated treatment duration for entecavir was 2 years in the HBeAg-positive model and 5 years in the HBeAg-negative model. The estimates of efficacy used in the economic model were based on the indirect comparison.

The base-case analysis for people with HBeAg-positive disease resulted in an incremental cost-effectiveness ratio (ICER) of 14,329 pounds sterling per additional quality-adjusted life year (QALY) gained for entecavir compared with lamivudine. A comparison of entecavir with peginterferon alfa-2a resulted in an ICER of 8403 pounds sterling per additional QALY gained. A comparison of entecavir with telbivudine resulted in telbivudine dominating entecavir.

The base-case analysis for people with HBeAg-negative disease resulted in an ICER of 13,208 pounds sterling per QALY gained for entecavir compared with lamivudine. A comparison of entecavir with peginterferon alfa-2a resulted in an ICER of 7511 pounds sterling per QALY gained and a comparison of entecavir with telbivudine resulted in an ICER of 6907 pounds sterling per QALY gained.

The base-case analysis for people with lamivudine-refractory disease, comparing entecavir with adefovir dipivoxil plus lamivudine, resulted in entecavir dominating.

The Evidence Review Group (ERG) questioned the clinical validity of some of the assumptions in the manufacturer's model, in particular the base-case treatment duration assumptions of 2 years for people with HBeAg-positive disease and 5 years for people with HBeAg-negative disease. Comparing entecavir with lamivudine, the ERG's exploratory scenario analyses found that increasing the treatment duration from 2 to 5 years for people with HBeAg-positive disease increased the ICER from 14,329 pounds sterling in the manufacturer's base case to 22,107 pounds sterling per QALY gained. Even longer treatment durations gave higher ICERs.

The ERG also conducted exploratory scenario analyses of the HBeAg-negative model, assuming a lifetime treatment duration. In this scenario people who progressed to compensated cirrhosis continued receiving treatment unless (or until) they developed decompensated cirrhosis. The same rate of progression to decompensated cirrhosis was assumed for all alternative treatments. This resulted in an ICER of 27,124 pounds sterling per QALY gained, when comparing entecavir with lamivudine.

The assumption that all people present for treatment in the pre-cirrhotic state of the disease was not supported by the ERG clinical specialists. The ERG scenario analyses for people with HBeAg-negative disease assumed that 90% of people start treatment with chronic hepatitis B without cirrhosis and 10% of people start treatment with compensated cirrhosis. This produced an ICER of 34,006 pounds sterling per QALY gained when comparing entecavir with lamivudine. When the proportion of people presenting with cirrhosis at the start of treatment is set to 20%, the ICER increases to 42,608 pounds sterling per additional QALY gained.

During the consultation period for this appraisal, the manufacturer submitted revised cost-effectiveness estimates for the HBeAg-negative population at the request of the Appraisal Committee. This revised model considered lifetime treatment duration and assumed that treatment with entecavir continued when people progressed to compensated cirrhosis. A 1.8% rate of progression from compensated to decompensated cirrhosis was used. The cost of adefovir dipivoxil treatment following the development of resistance in people who had not yet developed cirrhosis was also included and this treatment was assumed to be continued when the disease progressed to active cirrhosis. This revised base case gave an ICER for entecavir versus lamivudine of 20,463 pounds sterling per QALY gained. A further scenario was modelled in which people who developed resistance to lamivudine after developing compensated cirrhosis were also assumed to switch to adefovir dipivoxil. This resulted in an ICER of 15,531 pounds sterling per QALY gained.

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 pounds sterling 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 National Health Service (NHS).

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.

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 pounds sterling per QALY gained when all patients start in the pre-cirrhotic state, and 24,335 pounds sterling per QALY gained if 10% of patients are assumed to have cirrhosis at the start of treatment, when compared with lamivudine.

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.

Refer to Sections 3 and 4 of the original guideline document for details of the economic analyses provided by the manufacturer, the ERG comments, and the Appraisal Committee considerations.

External Peer Review

Consultee organizations from the following groups were invited to comment on the draft scope, Assessment Report and the Appraisal Consultation Document (ACD) and were provided with the opportunity to appeal against the Final Appraisal Determination.

• Manufacturer/sponsors
• Professional/specialist and patient/carer groups
• Commentator organisations (without the right of appeal)

In addition, individuals selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups were also invited to comment on the ACD.

This guidance does not apply to people with chronic hepatitis B who also have hepatitis C, hepatitis D or human immunodeficiency virus (HIV).

Entecavir, within its marketing authorisation, is recommended as an option for the treatment of people with chronic hepatitis B e antigen (HBeAg)-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated.

None provided

The type of evidence supporting the recommendations is not specifically stated.

Appropriate use of entecavir in the treatment of chronic hepatitis B

Adverse events associated with the use of nucleoside analogues include lactic acidosis and severe hepatomegaly with steatosis. Additional adverse events reported for entecavir include headache, fatigue, dizziness, and nausea. For full details of side effects and contraindications, see the summary of product characteristics.

• This guidance represents the view of the Institute, which was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. The guidance does not, however, override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
• Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.

Living with Illness

Effectiveness
Patient-centeredness

• National Institute for Health and Clinical Excellence (NICE). Entecavir for the treatment of chronic hepatitis B. London (UK): National Institute for Health and Clinical Excellence (NICE); 2008 Aug. 25 p. (Technology appraisal guidance; no. 153).

Not applicable: The guideline was not adapted from another source.

2008 Aug

National Institute for Health and Clinical Excellence (NICE) - National Government Agency [Non-U.S.]

National Institute for Health and Clinical Excellence (NICE)

Appraisal Committee

Committee Members: Professor David Barnett, Professor of Clinical Pharmacology, University of Leicester; Dr David W Black, Director of Public Health, Derbyshire County PCT; Dr Carol Campbell, Senior Lecturer, University of Teesside; Dr Peter Clarke, Consultant Medical Oncologist, Clatterbridge Centre for Oncology; Dr Christine Davey, Senior Researcher, North Yorkshire Alliance R & D Unit; Dr Mike Davies, Consultant Physician, Manchester Royal Infirmary; Dr Dyfrig Hughes, Reader in Pharmacoeconomics, Centre for the Economics of Health and Policy in Health, Bangor University; Dr Catherine Jackson, Clinical Lecturer in Primary Care Medicine, Alyth Health Centre; Dr Peter Jackson, Clinical Pharmacologist, Sheffield Teaching Hospitals NHS Foundation Trust; Professor Peter Jones, Pro Vice Chancellor for Research & Enterprise, Keele University; Ms Rachel Lewis, Practice Development Facilitator, Manchester PCT; Professor Jonathan Michaels, Professor of Vascular Surgery, University of Sheffield; Dr Eugene Milne, Deputy Medical Director, North East Strategic Health Authority; Dr Simon Mitchell, Consultant Neonatal Paediatrician, St Mary's Hospital, Manchester; Dr Richard Alexander Nakielny, Consultant Radiologist, Royal Hallamshire Hospital, Sheffield; Dr Katherine Payne, Health Economics Research Fellow, University of Manchester; Dr Philip Rutledge, GP and Consultant in Medicines Management, NHS Lothian; Mr Miles Scott, Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust; Dr Surinder Sethi, Consultant in Public Health Medicine, North West Specialised Services Commissioning Team; Professor Andrew Stevens, Chair of Appraisal Committee C; Mr William Turner, Consultant Urologist, Addenbrookes Hospital

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.

This is the current release of the guideline.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.