Sergio Iannazzo

Individualized treatment of HBeAg-negative chronic hepatitis B using pegylated interferon-α2a as first-line and week-12 HBV DNA/HBsAg stopping rule: a cost-effectiveness analysis.

BACKGROUND Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) is the most frequent and difficult-to-treat viral hepatitis worldwide. HBV DNA and hepatitis B surface antigen (HBsAg) serum levels, which help the early identification of non-responders to pegylated interferon (PEG-IFN), prompt more flexible individualized therapeutic strategies exploiting the benefits of both PEG-IFN and nucleoside/nucleotide analogues (NAs). We assessed the cost-effectiveness of week-12 HBV DNA/HBsAg stopping rule for early interruption and switch to currently most effective NA treatments (entecavir [ETV] or tenofovir disoproxil fumarate [TDF]). METHODS A decision-analytic Markov model was developed in the following health-related states: CHB, compensated cirrhosis (CC) and decompensated cirrhosis, hepatocellular carcinoma, liver transplant, post-liver transplant, death, virological response, relapse and HBsAg clearance. Simulated strategies included: ETV/TDF in CHB; ETV/TDF delayed until CC; first-line PEG-IFN followed by switch to ETV/TDF for either patients meeting the week-12 stopping rule or week-48 null-responders/relapsers; and first-line PEG-IFN followed by switch to ETV/TDF delayed until CC. ETV and TDF were considered alternatively for a total of eight strategies. A lifetime simulation horizon was applied. RESULTS Early treatment strategies using NAs with or without first-line PEG-IFN provided the highest results (approximately 22 life-years and 15 quality-adjusted life years [QALYs]). Delayed treatments until cirrhosis development resulted in poorer outcomes. The average per-patient lifetime costs ranged from €33,500 (TDF in CC) to €68,900 (TDF in CHB). Costs using ETV were 20-50% higher. First-line PEG-IFN strategies ranged from dominant (that is, more effective and less costly) to highly cost-effective, although differences in QALYs were always very narrow. CONCLUSIONS The cost-effectiveness of antiviral therapy of HBeAg-negative CHB could be improved significantly using first-line PEG-IFN followed by a switch to NAs in either patients meeting the week-12 HBV DNA/HBsAg stopping rule or week-48 non-responders/relapsers.

A cost-utility analysis of cinacalcet in secondary hyperparathyroidism in five European countries

Background and ObjectiveA probabilistic patient-level Markov model was previously developed to simulate lifetime clinical and economic outcomes of cinacalcet treatment in secondary hyperparathyroidism (SHPT) patients using local data from Italy. The present study extends the application of the model to four other European countries — Spain, Portugal, Switzerland and the Czech Republic — in order to assess the consistency of results.MethodsCinacalcet influences the levels of parathyroid hormone, serum calcium and phosphorous. Our simulation was based on data from the OPTIMA (Open-Label, Randomized Study Using Cinacalcet to Improve Achievement of KDOQI Targets in Patients with End-Stage Renal Disease) randomized controlled trial and from published correlations between bone-metabolism parameters, mortality and morbidity (cardiovascular [CV] events, fractures and parathyroidectomy). Local epidemiological and cost data for dialysis, drugs and event management were incorporated into the model. The simulation horizon was patient lifetime; standard treatment for SHPT (vitamin D sterols and phosphate binders) and cinacalcet plus standard treatment were compared. Effectiveness was measured in terms of life expectancy (LE) and quality-adjusted life expectancy (QALE). Health utility indexes derived from published literature took into account dialysis, CV events and fractures.ResultsThe simulated mean LE extension in patients receiving cinacalcet was 1.20 life-years (LY) in Italy, 1.10 LY in Spain, 1.18 LY in Portugal, 1.10 LY in the Czech Republic and 1.40 LY in Switzerland. QALE increase was 0.89, 0.82, 0.89, 0.80 and 1.01 QALY in the same countries, respectively. The incremental cost-effectiveness ratio (ICER) result was €23 500/LY and €31600/QALY in Italy, €21800/LY and €29 300/QALY in Spain, €23 700/LY and €31 200/QALY in Portugal, €29 700/LY and €40 800/QALY in the Czech Republic and €24 700/LY and €34 200/QALY in Switzerland. Including dialysis costs as a part of the total costing doubled the ICER, from a minimum of €42 800/LY in Spain to a maximum of €82 800/LY in Switzerland and in the range from €57 500/QALY (Spain) to €114 700/QALY (Switzerland).ConclusionTaking into consideration the limited clinical, epidemiological and health economics data available, cinacalcet treatment showed a relatively good cost-effectiveness profile in all the countries analysed, despite the differences in their healthcare systems and economic wealth.

Economic evaluation of treatment with orlistat in Italian obese patients

ABSTRACT The XENDOS study showed that behavioural and pharmacological therapy can decrease the risk of metabolic disorders in obese patients. Methods: A probabilistic Bayesian Markov model simulating the outcomes of orlistat treatment on the obese Italian population has been developed with the WinBUGS software. The model integrates an algorithm to estimate cardiovascular risk based on Framingham Heart Study equations. Analyses adopted the societal cost perspective, including direct medical costs borne by both the National Health Service and the patient, since orlistat is not included in the Italian reimbursement list. Results: The simulation on the Italian obese population estimated an average increase in quality-adjusted life expectancy, a reduction of cardiovascular events and new diabetes cases. The average incremental cost–utility ratio is €75.3 (7.6–180.6) × 1000/QALY. The subgroup analysis showed that the benefits are relatively greater in older patients and in patients with impaired glucose tolerance (IGT). Two hypotheses have been explored to estimate the impact of a potential reimbursement decision by the Italian NHS: (1) orlistat is given to every obese patient; (2) orlistat is given only to obese IGT patients with a previous glucose tolerance general screening program to assess their eligibility. The cost utility of the strategies are €42.3 (−22.16–108.7) and €10.16 (−60.4–38.76) × 1000/QALY, respectively. Conclusion: Orlistat shows a good pharmacoeconomic profile and, in particular, the strategy of a screening programme to identify and treat the IGT subgroup has a cost–utility value of about €10 000/QALY. This value is lower than that of several therapeutic strategies commonly accepted and reimbursed in developed countries.

Cost-effectiveness analysis of LHRH agonists in the treatment of metastatic prostate cancer in Italy

OBJECTIVES Luteinizing hormone-releasing hormone (LHRH) agonists represent one of the main cost factors in the management of patients with metastatic prostate cancer. We compared the cost-effectiveness of the five different 3-month formulations of LHRH agonists currently available for advanced prostate cancer in Italy, because these differ both in their capacity to suppress testosterone and in their acquisition costs. METHODS A probabilistic, patient-level simulation model was developed to compare the cost-effectiveness, from the perspective of the Italian National Health Service (INHS), of leuprorelin 11.25 mg and 22.5 mg, triptorelin 11.25 mg, buserelin 9.9 mg, and goserelin 10.8 mg. The model incorporated testosterone-dependent progression-free and cancer-specific survival functions, LHRH agonist effectiveness data, and national costs and tariffs. Coxs proportional hazard models were used to compute total and progression-free survival functions based on clinical data from 129 patients with metastatic prostate cancer treated in an Italian center. Bayesian random effects models were employed to summarize evidence from published literature on testosterone suppression obtained with the available LHRH agonists. RESULTS Estimated total survival was ≈5 years, with a maximum difference between treatment options of ≈2 months. There was a mean difference of almost €2,500 in lifetime total costs between the least costly option (leuprorelin 22.5 mg) and the most expensive (goserelin). In the incremental cost-effectiveness analysis, leuprorelin 22.5 mg dominated all alternatives except buserelin, which had an incremental cost-effectiveness ratio versus leuprorelin 22.5 mg of ≈€12,000 per life-month gained. CONCLUSIONS Based on modelling with meta-analysis of comparative survival data, leuprorelin 22.5 mg was the most cost-effective treatment of the available depot formulation LHRH agonists.

The cost effectiveness and cost utility of valsartan in chronic heart failure therapy in Italy: a probabilistic markov model.

ObjectiveTo evaluate the cost effectiveness and cost utility of the use of valsartan in addition to standard therapy for the treatment of patients with chronic heart failure with low left ventricular ejection fraction (LVEF).MethodsThe study was conducted by means of a cohort simulation based on a probabilistic Markov model and projecting the 23-month follow-up results of the Val-HeFT (Valsartan Heart Failure Trial) study over a 10-year time horizon. The model included four states (New York Heart Association [NYHA] classes II, III, IV, and death), and had a cycle duration of 1 month. Probabilistic simulations were performed using the WinBUGS software for Bayesian analysis. The distribution of patient parameters (sex, age, use of β-adrenoceptor antagonists, and ACE inhibitors) in the simulated population were derived from the Italian heart failure patient population. Individual mortality data were derived from general mortality data by multiplying by a NYHA state-specific relative risk, while the probability of changing NYHA class was taken from the Val-HeFT data. Costs (2007 values) were calculated from the perspective of the Italian Health Service (IHS) and included costs for drugs and heart failure hospitalizations. Quality-of-life (QOL) weights were obtained byusing published health-related QOL data for heart failure patients.A 3.5% annual discount rate was applied. Probabilistic sensitivity analysis was performed on each parameter using original-source 95% confidence interval (CI) values, or a ±10% range when 95% CI values were unavailable.ResultsFor the 10-year time horizon, patients were estimated to live for an average of 2.3 years or 1.7 quality-adjusted life-years (QALYs), with slight increases in the valsartan group. In this group, hospitalizations for worsening heart failure were predicted to be significantly reduced and overall treatment costs per patient to decrease by about €550. In subgroup analyses, valsartan lost dominance in patients in NYHA II, and in those receiving β-adrenoceptor antagonists or ACE inhibitors; the mean incremental cost-utility ratio for these groups was 21 240, 129 200, and 36 500 €/QALY, respectively.ConclusionsValsartan in addition to standard therapy is predicted to dominate standard therapy alone in Italian patients with mild to severe heart failure and low LVEF. There are relevant differences among various patient subgroups, and valsartan is expected to be good value for money particularly in the treatment of the most severe and less intensively treated (no ACE inhibitors, no β-adrenoceptor antagonist) heart failure patients.

A review of cost–effectiveness evaluations as part of national health technology assessments of biologic DMARDs in the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune chronic disease which is associated with an increasing disability in patients and high socioeconomic burden. Given the large number of economic evaluations considered by national health technology assessments (HTAs), this review attempts to clarify whether results from biologic disease-modifying antirheumatic drugs (DMARDs) economic evaluations form the basis of official recommendation by national HTA agencies in Australia, Canada, Scotland and England. The results show that evidence of cost–effectiveness was not equally perceived by decision makers and did not have equal weightage in defining the official listing of biologic DMARDs for the treatment of RA. As it has been demonstrated in previous studies, major barriers exist for the integration of cost–effectiveness and cost-utility results with national HTA activity. In fact, as shown in this review, even when such analysis are available, cost-minimization and comparative effectiveness studies seemed to be preferred by some HTA agencies as tools to inform allocation of healthcare resources.

ECONOMIC EVALUATION OF INTRAVENOUS IODINATED CONTRAST MEDIA IN ITALY

BACKGROUND Contrast-induced acute kidney injury (CI-AKI) is defined as a deterioration in renal function after administration of radiologic iodinated contrast media (CM). Iodixanol, showed a lower CI-AKI incidence than low-osmolar contrast media (LOCM). A cost-effectiveness analysis was performed comparing iodixanol and LOCM in intravenous (IV) setting in Italy. METHODS A Markov model was developed. Patients moved across four health states: CI-AKI free, CI-AKI, myocardial infarction, and death. The simulation horizon was lifetime with 1-month cycles. Costs and outcomes were discounted at 3.5 percent rate. CI-AKI incidence was considered from published literature across different definitions. Cost-effectiveness of iodixanol was assessed in terms of incremental cost per life-year gained. Net monetary benefit (NMB) was also calculated. Both deterministic and probabilistic sensitivity analyses were performed. RESULTS Base-case results showed an average survival increase of 0.51 life-years and a savings of €7.25 for iodixanol versus LOCM. The cost-effectiveness of iodixanol was confirmed when other scenarios were explored, such as varying CI-AKI definition, sub-populations with specified risk factors, CM hospital bids prices, and inclusion of adverse drug reactions of allergic nature. An NMB ranging between €6,007.25 and €30,007.25 was calculated. CONCLUSION Base-case results show that IV iodixanol is cost-effective compared with LOCM in the Italian clinical setting of a hospital computed tomography radiology practice. However, some caution is due, mainly linked to inherent limitations of the modeling technique and to the lack of agreement on CI-AKI incidence data in the clinical literature.

Cost-effectiveness analysis of pharmacokinetic-driven prophylaxis vs. standard prophylaxis in patients with severe haemophilia A.

&NA; The objective of this study was to assess the cost-effectiveness of pharmacokinetic-driven prophylaxis in severe haemophilia A patients. A microsimulation model was developed to evaluate the cost-effectiveness of pharmacokinetic-driven prophylaxis vs. standard prophylaxis and estimate cost, annual joint bleed rate (AJBR), and incremental cost-effectiveness ratio over a 1-year time horizon for a hypothetical population of 10 000 severe haemophilia A patients. A dose of 30 IU/kg per 48 h was assumed for standard prophylaxis. Pharmacokinetic prophylaxis was individually adjusted to maintain trough levels at least 1 and 5 IU/dl or less. AJBR was estimated on the relationship between factor VIII (FVIII) levels and bleeding rate reported in the literature. Sensitivity analyses were performed to assess the stability of the model and the reliability of results. The FVIII dose was reduced in the 27.8% of patients with a trough level more than 5 IU/dl on standard prophylaxis, with a negligible impact on AJBR (+0.1 bleed/year). The FVIII dose was increased in the 10.6% of patients with trough levels less than 1 IU/dl on standard prophylaxis, with a significant reduction of AJBR (−1.9 bleeds/year). On average, overall, pharmacokinetic-driven prophylaxis was shown to decrease the AJBR from 1.012 to 0.845 with a slight reduction of the infusion dose of 0.36 IU/kg, with total saving of 5 197&OV0556; per patient-year. Pharmacokinetic-driven prophylaxis was preferable (i.e. more effective and less costly) compared with standard prophylaxis, with savings of 31 205&OV0556; per bleed avoided. Pharmacokinetic-driven prophylaxis, accounting for patients’ individual pharmacokinetic variability, appears to be a promising strategy to improve outcomes with efficient use of available resources in severe haemophilia A patients.

[Cost-effectiveness analysis of peginterferon beta-1a in Italian relapsing remitting multiple sclerosis management]

BACKGROUND: Peginterferon beta-1a is indicated in adult patients for the treatment of relapsing remitting multiple sclerosis (RRMS). The efficacy and safety of peginterferon beta-1a was demonstrated in the placebo-controlled ADVANCE trial. OBJECTIVE: The objective of this study was to assess the cost-effectiveness of peginterferon beta-1a as compared with injectable first-line treatments for RRMS in Italy. METHODS: The cost-effectiveness analysis was developed through a Markov model with lifetime simulation in the perspective of the Italian National Healthcare Service (NHS). It was added an alternative scenario to take into account the Italian societal perspective. Outcomes were measured in terms of life years (LYs), quality adjusted life years (QALYs), lifetime costs and incremental cost-effectiveness ratio (ICER). The natural progression of the disease was informed by the published literature and previously published modelling exercises. The efficacy of treatments was simulated as reduction of disability progression (EDSS) and relapse rate. Efficacy data were derived from a published network meta-analysis. Unit costs were based on current prices and tariffs, and the published literature. A 3.5% discount rate was applied to costs and outcomes. One-way and probabilistic sensitivity analyses were developed and cost-effectiveness acceptability curves generated. RESULTS: Peginterferon beta-1a was more effective than the comparators in terms of survival (19.94 vs.19.68-19.81 discounted LYs, respectively), and QALYs (9.07 vs. 8.06 and 8.55 discounted QALY, respectively). In the perspective of the Italian NHS, the ICER was € 11,111/QALY vs. interferon beta-1a 30 µg, € 12,604/QALY vs. interferon beta-1a 22 µg, € 10,580/QALY and € 16,702/QALY vs. interferon beta-1b 250 µg and € 22,023/QALY vs. glatiramer acetate 20 mg. Peginterferon beta-1a dominated interferon beta-1a 44 µg. In the societal perspective, peginterferon beta-1a was dominant due to being more effective and with a lower social cost compared to first-line injectable treatments (interferon beta -1a, interferon beta-1b, glatiramer acetate) for RRMS. The outcomes of the sensitivity analyses confirmed the trend of the base case results. CONCLUSIONS: Peginterferon beta-1a shows a favourable pharmaco-economic profile for the treatment of RRMS. Even if an official threshold for the cost-effectiveness does not exist in Italy, the ICER values obtained were far below the commonly accepted thresholds (30,000-50,000 €/per QALY gained). [Article in Italian]

A cost-effectiveness model to personalize antiviral therapy in naive patients with genotype 1 chronic hepatitis C.

BACKGROUND AND AIMS Rapid virologic response is the best predictor of sustained virologic response with dual therapy in genotype-1 chronic hepatitis C, and its evaluation was proposed to tailor triple therapy in F0-F2 patients. Bio-mathematical modelling of viral dynamics during dual therapy has potentially higher accuracy than rapid virologic in the identification of patients who will eventually achieve sustained response. Studys objective was the cost-effectiveness analysis of a personalized therapy in naïve F0-F2 patients with chronic hepatitis C based on a bio-mathematical model (model-guided strategy) rather than on rapid virologic response (guideline-guided strategy). METHODS A deterministic bio-mathematical model of the infected cell dynamics was validated in a cohort of 135 patients treated with dual therapy. A decision-analytic economic model was then developed to compare model-guided and guideline-guided strategies in the Italian setting. RESULTS The outcomes of the cost-effectiveness analysis with model-guided and guideline-guided strategy were 19.1-19.4 and 18.9-19.3 quality-adjusted-life-years. Total per-patient lifetime costs were €25,200-€26,000 with model-guided strategy and €28,800-€29,900 with guideline-guided strategy. When comparing model-guided with guideline-guided strategy the former resulted more effective and less costly. CONCLUSIONS The adoption of the bio-mathematical predictive criterion has the potential to improve the cost-effectiveness of a personalized therapy for chronic hepatitis C, reserving triple therapy for those patients who really need it.