TA896 · STA
Bulevirtide is recommended for treating chronic hepatitis D in adults with compensated liver disease only if there is evidence of significant fibrosis (METAVIR stage F2 or above or Ishak stage 3 or above) and their hepatitis has not responded to peginterferon alfa-2a (PEG-IFN) or they cannot have interferon-based therapy. Only recommended if the company provides it according to the commercial arrangement.
Source documents
Intervention
Conditions
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| peginterferon alfa-2a (peg-ifn) | active drug | Yes | — |
| standard care (symptomatic treatment, antivirals for hepatitis b) | standard of care | Yes | — |
| standard care | best supportive care | Yes | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| MYR 301 | RCT | 3 | Yes |
Economic model
ICER
Methodological decisions (19)
Proportion of population with compensated cirrhosis at baseline
Company: 55% have compensated cirrhosis based on post-hoc analysis of MYR 301 fibrosis distributions
ERG: 47% have compensated cirrhosis based on primary MYR 301 data
Committee: Preferred baseline distribution based on MYR 301 primary data
ICER impact: uncertain_direction
Mean age at diagnosis for severity modifier calculation
Company: Use mean age from UKHSA cohort of people in UK with hepatitis D currently alive
ERG: Use alternative estimates from primary MYR 301 data
Committee: Preferred use of baseline mean age from full UKHSA dataset
ICER impact: uncertain_direction
MYR 301 included data from people not yet treated with interferon. Company positioned bulevirtide for post-PEG-IFN failure or contraindication population, but trial data included people with all scenarios.
Company: Most people in MYR 301 had already had IFN treatment; those who had not were likely to have contraindication or intolerance
ERG: Concerned that company evidence included people not relevant to specified decision problem
Committee: Accepted that response rates should reflect full trial population; accepted that evidence from full MYR 301 population was reasonable
ICER impact: uncertain_direction
Use of METAVIR fibrosis stages as health states in Markov model when population may be identified by transient elastography in clinical practice
Company: Presented Markov model with 10 health states based on METAVIR fibrosis stages F0-F4
ERG: Not explicitly stated but implied concern about mismatch between model structure and clinical practice
Committee: Noted that using METAVIR-based health states may not be appropriate if company positions bulevirtide in narrower population; would be acceptable if company amended positioning to cover entire marketing authorisation
ICER impact: uncertain_direction
Company used Markov model with METAVIR fibrosis staging (F0-F4 plus complications). Committee preferred elastography-based model due to narrow population positioning (F2+) not aligned with full marketing authorisation. Company maintained METAVIR approach at second meeting.
Company: Markov model using METAVIR staging appropriate; maintained this position despite committee preference
Committee: Elastography-based model preferred if bulevirtide positioned narrowly (F2+); METAVIR staging acceptable only if marketing authorisation expanded to full population
ICER impact: uncertain_direction
How to estimate fibrosis progression and hepatocellular carcinoma risk in hepatitis D
Company: Apply hazard ratios from publications comparing hepatitis D co-infected with hepatitis B to hepatitis B only, due to limited direct hepatitis D evidence
ERG: Use alternative sources of data that directly estimated natural history of disease in hepatitis D population
Committee: Preferred the EAG's approach to estimate natural history based on direct evidence in hepatitis D population
ICER impact: increases
Natural history and disease progression modelling for hepatitis D. Company used hazard ratios comparing HDV+HBV to HBV-only due to limited HDV-specific data. EAG preferred direct HDV natural history sources. Committee concerned about systematic approach to literature validation.
Company: Applied hazard ratios from HDV+HBV vs HBV-only comparisons due to limited HDV-specific data and noted natural history of HDV not yet established; provided literature sources for compensation cirrhosis, HCC, liver-related mortality
ERG: Preferred alternative sources directly estimating natural history of disease in hepatitis D; could not validate company's data in model
Committee: EAG's approach preferred to estimate natural history in population of interest; company's approach lacked systematic methodology
ICER impact: uncertain_direction
Probability of hepatocellular carcinoma in combined responders
Company: Combined responders have lower risk of hepatocellular carcinoma
ERG: Combined responders have same risk as partial responders
Committee: Preferred company's assumption that clinical expert opinion supports lower risk for combined responders
ICER impact: decreases
When fibrosis regression can start after treatment initiation
Company: Not explicitly stated in company position
ERG: Fibrosis regression can only start from 96 weeks
Committee: Accepted EAG's assumption that fibrosis regression can only start from 96 weeks
ICER impact: increases
Application of 1.2 QALY weight for rare disease severity
Company: Weight of 1.2 should apply based on QALY shortfall calculations
ERG: Severity modifier did not apply according to EAG's preferred scenarios
Committee: Agreed 1.2 severity modifier should be applied; in all but 1 scenario QALY shortfall was over 12 QALYs
ICER impact: decreases
Baseline characteristics for UK population: age and proportion with cirrhosis at baseline. Company initially used Spaan et al. median age (35 years, 60% cirrhosis) but MYR 301 had baseline age 42 years with 47% cirrhosis.
Company: Updated base case to use median age (35 years) from UKHSA study; preferred to use age of people with hepatitis D currently alive (n=570)
ERG: Preferred mean age rather than median; preferred mean age from full UKHSA dataset of all people diagnosed with hepatitis D in UK (n=602)
Committee: Agreed mean age from full UKHSA dataset (n=602) was most appropriate measure of central tendency and bigger dataset
ICER impact: uncertain_direction
Fibrosis staging assessment method: METAVIR fibrosis staging via liver biopsy (invasive) vs. transient elastography/FibroScan (non-invasive)
Company: Used METAVIR staging (F2 or above) based on liver biopsy; later provided scenario analyses using transient elastography thresholds of 7.25 kPa and 8.0 kPa from external literature (Qi et al. 2018, EASL 2021)
ERG: Unable to validate EASL threshold; considered 8.0 kPa most validated threshold to rule out advanced fibrosis (F3+); unclear if company used systematic approach
Committee: Preferred non-invasive transient elastography assessment over invasive liver biopsy; noted high uncertainty about appropriate elastography threshold; accepted that in clinical practice fibrosis could be assessed by either transient elastography or biopsy
ICER impact: uncertain_direction
Baseline characteristics for NHS population: company used Spaan et al. (2020) retrospective UK analysis (n=107, age 35 years, 60% cirrhosis) vs MYR 301 trial (age 42 years, 47% cirrhosis). Committee preferred UKHSA data on mean age at diagnosis from full dataset (n=602) over median age estimate or cohort of currently alive patients (n=570).
Company: Used Spaan et al. baseline characteristics; later updated to median age (35 years) from UKHSA study; then updated to reflect currently alive HDV population (n=570)
ERG: Preferred mean age from full UKHSA dataset of people diagnosed with hepatitis D (n=602)
Committee: Mean age from full UKHSA dataset (n=602) is most appropriate as larger dataset and better reflects age at diagnosis
ICER impact: uncertain_direction
Treatment duration in model vs trial. Company assumed: combined responders indefinite; virological responders to week 72; non-responders to week 48. Trial allowed all to continue regardless of response. Committee preferred clinical assumptions based on expert input.
Company: Combined responders continue indefinitely; virological responders stop week 72; non-responders stop week 48. Later updated to combined responders with undetectable RNA stop week 100 (48+52), partial/non-responders stop week 72
ERG: Model duration mismatches trial protocol which allowed continued treatment regardless of response status
Committee: Combined responders likely continue but with some uncertainty; virological responders continuation uncertain; accepted week 72 stopping for partial/non-responders but acknowledged uncertainty remains
ICER impact: increases
Company extrapolated response beyond 48-week MYR 301 data to 72 weeks, assuming maintained response for all non-stopping patients. EAG preferred limiting to 48-week data. Committee noted trend of response loss over time despite some gaining response.
Company: Extrapolated response to 72 weeks; later clarified no extrapolation beyond 48 weeks as trend showed response increase during first 48 weeks
ERG: Limit response assessment to 48 weeks without extrapolation due to uncertainty in assumptions beyond trial data
Committee: Response limited to 48-week trial data; longer-term data would help but not yet available
ICER impact: decreases
Transition probabilities for fibrosis progression. Company assumed combined responders had zero progression and could regress (8.8% annual F4→F3, 13.3% annual F3→F2). Clinical experts and committee agreed responders still at some risk and regression rates seemed high. EAG assumed residual HCC risk in combined responders; company later assumed 20% of partial responder progression for combined responders.
Company: Combined responders: zero progression through fibrosis, 8.8% F4→F3 regression, 13.3% F3→F2 regression, no HCC risk. Later updated to 20% progression/HCC risk vs partial responders.
ERG: Combined responders should have residual HCC risk equal to partial responders, referencing Alfaiate et al. (2020)
Committee: Combined responders at risk of HCC; 20% of partial responder rates for progression/HCC acceptable and addressed uncertainties
ICER impact: increases
Health-state utility values from EQ-5D-3L in MYR 301 vs hepatitis B meta-analysis. Company argued EQ-5D lacked face validity for fibrosis differences and did not capture hepatitis symptoms. EAG and committee disagreed.
Company: EQ-5D-3L from MYR 301 lacks face validity; utility values from hepatitis B meta-analysis preferred
ERG: Impact of fibrosis on quality of life very small; EQ-5D appropriate; experts noted advanced liver disease often silent
Committee: Utilities based on MYR 301 EQ-5D-3L data appropriate
ICER impact: decreases
Source of health state utility values
Company: Utilities based on MYR 301 trial
ERG: Not explicitly differentiated
Committee: Committee concluded utilities based on MYR 301 were appropriate
ICER impact: negligible
Utility gain for combined responders was key cost-effectiveness driver. Company fitted Tobit regression to 48-week MYR 301 data using cirrhosis status and response at week 48. Committee concerned about lack of justification for Tobit approach and non-significance of resulting utility gain.
Company: Tobit regression appropriate due to ceiling effect (many at highest utility); utility gain plausible; later tested 50% and 75% reductions and incorporated maximum utility from prior hepatitis guidance
ERG: Preferred testing utility gain using lowest and highest values from previous NICE hepatitis B/C guidance rather than arbitrary 50%/75% reductions
Committee: Utility gain uncertain; preferred EAG's approach using maximum utility gain from previous hepatitis technology appraisals; accepted this in base case
ICER impact: increases
Evidence gaps
Commercial arrangement
Special considerations