The manufacturer's submission presented an analysis of the cost effectiveness of telbivudine in patients with chronic hepatitis B whose serum alanine aminotransferase (ALT) levels are more than or equal to twice the upper normal limit. Two Markov state-transition models were provided in the manufacturer's submission: a seroconversion model (applicable to only hepatitis B e antigen [HBeAg]-positive disease) and a viral load model (applicable to both HBeAg-positive and HBeAg-negative disease). Both models used a lifetime horizon.
The viral load model submitted by the manufacturer assumed that patients entered the model in the chronic hepatitis state without cirrhosis. Health states associated with disease progression were divided by serum ALT and viral load levels, resulting in a large number of possible health states. Consequently the data available from the GLOBE trial to populate the viral load model were sparse. In an attempt to deal with this, the manufacturer used values of 0.0 and 0.5 (which they referred to as 'non-informative priors') to correct for the probabilities of health-state transitions for which there were one or more zero observations and no data available.
The base-case analysis of the viral load model (based on probabilistic sensitivity analysis) comparing telbivudine with lamivudine and assuming a 'non-informative prior' of 0.0 produced an incremental cost-effectiveness ratio (ICER) of 15,377 pounds sterling per additional quality-adjusted life year (QALY) gained for HBeAg-positive disease; the corresponding ICER with a 'non-informative' prior of 0.5 was 8,542 pounds sterling per additional QALY gained. For HBeAg-negative disease, the ICER for a comparison of telbivudine with lamivudine with a 'non-informative prior' of 0.0 was 20,256 pounds sterling per additional QALY gained. The corresponding ICER with a 'non-informative prior' of 0.5 was 27,801 pounds sterling per additional QALY gained.
Deterministic base-case analyses (requested from the manufacturer) of the viral load model comparing telbivudine with lamivudine, with a 'non-informative prior' of 0.0, produced an ICER of 12,278 pounds sterling per additional QALY gained for HBeAg-positive disease. The corresponding ICER, with a 'non-informative prior' of 0.5, was 8,669 pounds sterling per additional QALY gained. For HBeAg-negative disease, the ICER for a comparison of telbivudine with lamivudine was 20,383 pounds sterling per additional QALY gained with a 'non-informative prior' of 0.0; the corresponding ICER, with a 'non-informative prior' of 0.5, was 57,419 pounds sterling per additional QALY gained.
The manufacturer's economic analysis based on the seroconversion model (HBeAg-positive disease only) gave an ICER of 13,193 pounds sterling per additional QALY gained (95% confidence interval [CI] 7,788 to 25,194 pounds sterling) for a comparison of telbivudine alone (followed by best supportive care [BSC] if appropriate) with BSC alone. A comparison of telbivudine followed by adefovir dipivoxil and then BSC against BSC alone gave an ICER of 15,684 pounds sterling per additional QALY gained (95% CI 9,491 to 28,151 pounds sterling). Adefovir dipivoxil followed by telbivudine and then BSC compared with BSC alone gave an ICER of 18,388 pounds sterling per additional QALY gained (95% CI 11,707 to 30,357 pounds sterling). Adefovir dipivoxil followed by lamivudine and then BSC compared with BSC alone gave an ICER of 17,398 pounds sterling per additional QALY gained (95% CI 11,063 to 28,322 pounds sterling).
The Evidence Review Group (ERG) carried out scenario analyses on the viral load model (with a 'non-informative prior' of 0.0) using non-constant age-specific utilities, increasing the proportion of cirrhotic patients at treatment initiation to 15% and applying model calibration factors (for risk of advanced liver disease). The cumulative effects of varying these parameters for HBeAg-positive disease gave an ICER of 16,100 pounds sterling per additional QALY gained. The corresponding ICER for HBeAg-negative disease was 26,200 pounds sterling per additional QALY gained.
- The ERG conducted exploratory scenario analyses on the seroconversion model
- Assuming no treatment with telbivudine for people with decompensated liver disease
- Removing treatment-resistant patients from the denominators used to calculate transition probabilities for HBeAg seroconversion
- Increasing the proportion of cirrhotic patients at the start of treatment to 15%
- Assuming treated people with cirrhosis seroconvert at the same rate as people with treated non-cirrhotic chronic hepatitis B
The cumulative effects of varying the first three parameters gave an ICER of 20,200 pounds sterling per additional QALY gained for telbivudine followed by adefovir compared with lamivudine followed by adefovir in the HBeAg-positive group. Adding the last assumption results in an ICER of 8,400 pounds sterling per additional QALY gained for the same comparison. The cumulative effects of varying the first three parameters gave an ICER of 22,500 pounds sterling per additional QALY gained for telbivudine alone compared with lamivudine alone. Adding the last assumption results in an ICER of 10,800 pounds sterling per additional QALY gained for the same comparison.
The ERG conducted a probabilistic sensitivity analysis using the viral load model with a 'non-informative prior' of 0.0 only. It replaced constant health-state utilities with non-constant age-specific utilities and applied the model calibration factors for risk of advanced liver disease listed in the appendices to the manufacturer's submission. This reduced the probability of telbivudine being cost effective for any given willingness to pay (cost-effectiveness) threshold when compared with lamivudine. For the HBeAg-positive group, the probabilities that telbivudine was cost effective at willingness to pay thresholds of 20,000 and 30,000 pounds sterling per additional QALY gained were 0.53 and 0.82, respectively. For the HBeAg-negative group, the probabilities of telbivudine being cost effective at willingness to pay thresholds of 20,000 and 30,000 pounds sterling per additional QALY gained were 0.01 and 0.54, respectively. The ERG also conducted a probabilistic sensitivity analysis using the seroconversion model, and the results differed from the manufacturer's analysis: in particular, lamivudine is optimal over a wider range of willingness to pay, with lamivudine followed by adefovir being optimal over a cost-effectiveness threshold range of 22,000 to 24,000 pounds sterling per additional QALY, whereas telbivudine was the optimal strategy over this range in the manufacturer's probabilistic sensitivity analysis. At higher cost-effectiveness thresholds (greater than 25,000 pounds sterling per QALY gained), telbivudine followed by adefovir remained the optimal strategy.
The Appraisal Committee considered that the transparency of the viral load model for assessing the cost effectiveness of telbivudine for the treatment of HBeAg-negative patients was reduced by the lack of detail in the manufacturer's submission about which parameters were used. The Committee concluded that, in light of the uncertainty about the cost effectiveness of telbivudine in HBeAg-negative chronic hepatitis B and the sensitivity analyses presented by the ERG, telbivudine could not be recommended as a cost-effective use of National Health Service (NHS) resources.
Overall, the Committee agreed that there was evidence that telbivudine was likely to be more clinically effective and have a more favourable resistance profile than lamivudine monotherapy in patients with HBeAg-positive disease. However, it did not agree with the manufacturer that the evidence presented on the cost effectiveness of telbivudine in the subgroup of patients with serum ALT levels greater than or equal to twice the upper limit of normal could be used as a reliable basis for decision-making in patients with HBeAg-positive disease.
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.
