Interventional therapeutic strategies

Two different strategies of antiviral treatment were explored following the current EASL recommendations for CHB management.⁶

The first strategy (strategy 1) considered treatment for 71% of patients diagnosed with CHB and candidates to therapy based on the estimation of a survey of CHB patients management practices in the European Union.¹⁰ The second strategy (strategy 2) increased the rate of treatment assuming a full treatment coverage (100% of treated patients).

The assessed drugs were those recommended as a first line therapy, peg-IFN alpha-2a (peg-IFN; 180 μg weekly for 48 weeks of treatment) and indefinite oral antiviral with either entecavir (0.5 mg daily) or tenofovir (300 mg daily) at different proportions for each defined cohort trying to simulate the current clinical practice. Oral antivirals (tenofovir-50% and entecavir-50%) was considered in 85% of patients already treated in each scenario for HBeAg- positive cohort, and in 95% of treated patients for HBeAg- negative population.Therefore peg-IFN represented 15% of therapies in HBeAg-positive treated patients, and 5% in HBeAg-negative population.

Analyses were separately performed for both, HBeAg- positive and HBeAg-negative cohorts.⁹

Transition probabilities

The health states included in the model (CHB, compensated cirrhosis, decompensated liver disease, HCC, transplant and death) were the commonly used to reflect the progression of disease’s natural history.^{8 , 11}

One-year probabilities applied to simulate the evolution through these states were based on the virological response, depending on HBV DNA levels.¹¹ Studies have shown that persistent reduction of serum HBV DNA below the lower limit of detection by real-time PCR assays is associated to biochemical remission, histological improvement and prevention of disease-related complications.¹²

For this reason, the original model⁸ was modified, including the potential regression of cirrhosis as have shown in long term studies with tenofovir (74%, at 5-years)¹³ and entecavir¹⁴ (Figure 1).

Figure 1 Markov diagram. 

Failure, resistance and rescue therapies

Patients initially treated with peg-IFN who did not achive inmune control (HBV DNA < 2,000 IU/mL and normal ALT levels) after 48 weeks of treatment were retreated with oral antivirals (50% entecavir and 50% tenofovir). According to the literature, a first year antiHBe seroconversion of 32% was considered in HBeAg-positive patients treated with 48 weeks of peg-IFN.⁶ This seroconversion was maintained overtime in the 81% of cases¹⁵ given a lifetime adjusted seroconversion equal to 25.9%. In HBeAg-negative patients, 19% of them achieved serum HBV DNA levels < 60-80 IU/mL after 48 weeks of therapy,⁶ being a failure rate of 81%.

The antiHBe seroconversion rates^{6 , 16} in HBeAg-positive patients treated with tenofovir were 21% at year 1 of therapy,⁹ 26% at year 3,¹⁷ and up to a maximum rate of 40% at year 7.¹⁸ The same rates were applied for entecavir in absence of long-term data in clinical trials (only results for 3 years of follow-up were identified). As recommended by guidelines, oral therapy was stopped 12 months after antiHBe seroconversion.⁶ The rate of HBsAg loss considered in HBeAg-positive cohort was 12%.¹⁸ No HBsAg loss was applied to HBeAg-negative patients. No resistance to tenofovir was considered based on the results published.¹⁹ A resistance rate of 1.2% at 5 years ²⁰ was considered for entecavir. Patients with HBV resistant to entecavir were rescued by adding on tenofovir.

Treatment discontinuations

Treatment discontinuations for efficacy of oral antivirals were allowed for those HBeAg-positive patients achieving HBeAg loss and seroconversion to anti-HBe and also for HBeAg positive or negative who presented HBsAg loss.

No more discontinuations were applied further the 7 years mentioned period. After discontinuation, the patient's progression was equivalent to the natural disease.

Analysis

Expected outcomes were calculated in terms of survival, as well as the accumulated number of HCC cases at each patient cohort.

The cost-effectiveness results were expressed as incremental cost in euros, per survival increase measured as life year gained (LYG) and quality adjusted life years (QALY) gained.

QALY were derived from LYG, appliying different utility figures, obtained for each model health state.⁸

The model established the incremental cost-effectiveness ratio (ICER) for each one of the defined-antiviral strategies compared to the reference case (natural disease history). Additionally the ICER of strategy 2 compared to strategy 1 was calculated, to assess the influence to increase the treatment coverage from 71% to 100% of population.

Beyond the first year, an annual discount rate of 3% was applied to costs and health benefits to allow for time preference into current values.²¹

Costs

Only direct health care costs related to pharmaceutical and disease management costs⁸ were included in the analysis.

Drugs ex-factory prices for pharmaceutical costs calculation were taken from a national database,²² appliying the 7.5% mandatory deduction.²³ Pharmaceutical costs calculations did not consider potential discontinuations due to adverse events.

Costs were expressed in euros (€, year 2014 values). Unitary costs were updated and inflated to 2014, when applicable, with Consumer Prices Index (Table 1).

Sensitivity analysis

Sensitivity analysis was performed to test the model’s robustness. Two alternative scenarios were defined: a fast and slow disease progression scenario. In the fast progression scenario, the base case transition probabilities were increased +10%, together with reduction of -10% of the cirrhosis regression rate. In the slow progression, transition probabilities decreased 10%, while cirrhosis regression rate increased its value +10%.

Probabilistic sensitivity analysis (PSA) was also performed through 1,000 iterations of a second order Monte- Carlo simulation. Beta distribution was applied to transition probabilities, and lognormal distribution was used for disease management costs, assuming a standard deviation of 10% from mean values. Results were plotted in a cost-effectiveness plane, and acceptability curves were constructed.

RESULTS

The results of the model showed that both treatment strategies resulted more effective than no therapy for both HBeAg-positive and HBeAg-negative populations.

Strategy 1 (treating 71% of population) increased patient survival, yielding 3.50 LYG and 3.98 additional QALY in HBeAg-positive cohort and 1.51 LYG and 2.16 additional QALY in HBeAg-negative cohort, compared to natural history. Strategy 2 (full treatment coverage) increased survival up to 4.93 LYG and 5.60 additional QALY and 2.13 LYG and 3.05 QALY gained for HBeAg-positive and -negative populations, respectively.

The avoided number of HCC cases also measured health benefits of antiviral therapies. For the study horizon, the model predicted 361 and 276 HCC episodes per 1,000 patients in HBeAg-positive and -negative populations. The strategy 1 (71% of treament coverage) reduced the number of HCC to 233 and 190 cases per 1,000 patients for HBeAg-positive, and HBeAg-negative populations, respectively (Table 2).

The overall estimated total costs for untreated were €96,555 in HBeAg- positive and €66,527 in HBe Ag-negative cohort.

Total cost increased up to €102,841 and €105,408 for strategy 1 (71% of treatment coverage) and strategy 2 (100% of treatment coverage) in HBeAg-positive population. The estimated ICER was €1,581 per QALY gained vs. the natural history for both scenarios.

In HBeAg-negative population, total costs accounted €85,858 for strategy 1 with 71% of treatment coverage and €93,754 for strategy 2 with 100% of treatment coverage. The ICER resulted €8,942 per QALY gained with any of the treatment strategies assessed compared to the natural history used as reference.

The treatment strategies assessed yielded ICER below the threshold used in most (66%)²⁴ of the economic evaluations performed for Spanish setting (€30,000/QALY), therefore could be considered as cost-effective alternatives compared to no treatment. Detailed values are shown in table 3.

The estimated ICER decreased, in both HBeAg-positive and -negative cohorts, in the slow disease progression scenario tested, and increased in the fast disease progression analysis up to €1,761 per QALY gained and €8,104 per QALY gained in HBeAg-positive and -negative cohorts, respectively (Table 4).

In PSA including 1,000 Monte Carlo iterations, all the treatment strategies resulted cost-effective compared to reference case in 99.6% and 99.9% of simulations for any threshold higher than€15,000/QALY in HBeAg-positive and -negative cohorts, respectively (Figure 2).

Figure 2 Acceptability curves of treatment strategies vs. natural history.