The economic advantage of allergen immunotherapy over drug treatment in respiratory allergy

Allergen immunotherapy (AIT) was introduced more than one century ago as an empiric treatment for pollen induced rhinitis, but only from the 1970s did a number of double-blind, placebo-controlled trials drive it into the realm of evidence-based treatments¹. The proof of clinical efficacy was achieved through several systematic reviews and meta-analyses, first for subcutaneous immunotherapy (SCIT) and, from the 1990s, for sublingual immunotherapy (SLIT). Based on these data, but also considering the lack of success when the allergen extracts used for the treatment are of insufficient quality, the recent guidelines on AIT for allergic rhinitis (AR) from the European Academy of Allergy and Clinical Immunology (EAACI) (pg. 1) summarized the global outcome in the statement “In general, broad evidence for the clinical efficacy of AIT for AR exists, but a product-specific evaluation of evidence is recommended”². A further important accomplishment established by AIT is the capacity to modify the natural history of allergy, which is clinically expressed by preventing the development of asthma in patients treated for AR and providing a prolonged symptom control also after withdrawing the treatment when performed for an adequate length³. These outcomes result from the mechanisms of action of AIT, particularly the modulation of T- and B-cell responses and the related antibody isotypes production, and the generation of regulatory T-cells (Treg), that have a critical role as inducers of tolerance to allergens⁴. Over the latest decades, the cost-effectiveness analysis of medical treatments has become increasingly important, and consensus-based recommendations have been developed to drive the allocation of healthcare resources through a standard set of methods, enabling a reference case analysis from the societal perspective and accounting for benefits, harms, and costs to all parties⁵. The first economic evaluations on AIT concerned SCIT, but soon after also SLIT was analyzed. In 2008, Berto et al.⁶ reviewed the available studies, concluding that AIT in both forms may be very beneficial to the healthcare systems, particularly under the societal perspective, i.e. when indirect costs of lost productivity are considered and included in the economic analysis. The early studies were simply based on the calculation of money saving of AIT compared with drug treatment, while in recent years statistical methods such as the incremental cost-effectiveness ratio (ICER) and the quality-adjusted life-year (QALY) were increasingly used. A systematic review examined 40 pharmacoeconomic guidelines according to the types of analysis, sources for effectiveness, use of QALYs to measure outcomes, and use of ICER to present the results. The majority of guidelines favored a cost utility analysis expressing the outcomes in terms of QALYs; choice of the comparator, recommended costs, methods of indirect cost calculations, methods of sensitivity analysis, and discounting rate were the topics most variable. The authors claimed the need of efforts to develop homogeneous methods for pharmacoeconomic investigation⁷. A recent systematic overview investigated 23 studies on cost-effectiveness of AIT, 19 of which addressed AR, and seven were based on data from randomized controlled trials. The results indicated that SCIT and SLIT would be considered cost-effective using the National Institute for Clinical Excellence (NICE) cost-effectiveness threshold of £20,000/QALY, but the interpretation of the outcomes is likely biased by insufficient attention in characterizing uncertainty and handling missing data⁸. In addition, a meta-analysis evaluated the comparative clinical effectiveness and cost-effectiveness of SCIT and SLIT for seasonal AR, including placebo-controlled trials of SCIT or SLIT, direct comparison between the two treatments, and economic evaluations. Statistically significant effects for SCIT and SLIT compared with placebo concerning the different outcome measures were found, with a lower evidence for children. Under the economic side, both AIT forms may be cost-effective compared with drug treatment from ∼6 years (threshold of £20,000–30,000 per QALY). The authors suggested that further research is needed to ascertain the comparative effectiveness of SCIT and SLIT and to grant more robust cost-effectiveness estimates⁹. Besides, the safety issue was, thus far, overlooked. Actually, adverse effects of AIT, particularly systemic reactions, result in additional costs. In a meta-analysis comparing SCIT and SLIT, 12 anaphylactic reactions requiring emergency treatment occurred in the 960 SCIT-treated patients, compared with only one of the 4,046 SLIT-treated patients¹⁰.

As far as SLIT is concerned, the latest development was the production of pharmaceutical quality tablets of grass pollen, aimed at fulfilling the requirements from regulatory agencies, namely the European Medicine Agency (EMA) in Europe and the Food and Drug Administration in the US^11,12. A study evaluated the potential budget impact associated with market entry of the 5-grass pollen tablets in the US for adults and children with grass pollen-induced AR. The model used estimated pharmacy, medical (both obtained from the claims data analysis and existing literature), and total costs per-member-per-month with and without market entry of the 5-grass SLIT tablet, with a 3-year time horizon. The estimated target population of patients was 26,320. Pharmacy costs increased by $0.36, $0.44, and $0.51, and total costs increased by $0.15, $0.18, and $0.22 in the 1^st, 2^nd, and 3^rd year after availability of the 5-grass SLIT tablet, respectively. SLIT with the 5-grass SLIT tablet raised the pharmacy budget for a hypothetical third-party payer, but the larger pharmacy costs were partially balanced by inferior medical budget associated to decreased resource use compared with other treatment options¹³.

Concerning Europe, Lombardi et al.¹⁴ analyzed the available literature on the economic aspects of the 5-grass tablets. In particular, three studies provided interesting observations. The first study on the cost-effectiveness of 5-grass tablets was based on post-hoc analysis of the VO34.04 and VO53.06 trials¹⁵, analyzing the data from the perspective of an Italian third-party payer and from a societal perspective as well, based on the costs produced by the losses of productivity¹⁶. The likely outcomes and costs for adults and children with mild, moderate, and severe AR were estimated through a decision-tree modeling. The 5-grass tablets resulted in 0.127 QALYs in patients with moderate AR, and in 0.143 QALYs in patients with severe AR, compared to placebo. The treatment with 5-grass tablets had a cost of €1,024/QALY for patients with moderate AR and €1,035/QALY for patients with severe AR. Westerhout et al.¹⁷ performed a study in Germany on the outcomes, costs, and cost-effectiveness of the 5-grass tablets compared to the one-grass tablet and the one-grass extract for SCIT. Drug treatment alone for grass pollen-induced AR was used as a control. The costs and outcomes of a 3-year treatment for a period of 9 years were assessed by a Markov model, with an analysis including public and private health insurance payments. The predicted cost-utility ratio of the 5-grass tablet compared with drug treatment was €14,728 per QALY, with incremental costs of €1,356 and incremental QALYs of 0.092. SLIT with the 5-grass tablet was the prevailing strategy compared to one-grass tablet and SCIT, with incremental costs corresponding to −€1,142 and −€54 and incremental QALYs corresponding to 0.015 and 0.027, respectively¹⁷. The same authors compared, by a meta-analysis and cost-effectiveness analysis, the effects and costs of the 5-grass tablet vs a mix of allergoids for SCIT in grass pollen AR. Again, a Markov model with a 9-year time length was used to evaluate the costs and effects of a 3-year-long treatment. The analysis was made from the payer’s perspective in Germany, including payments of the National health system and additional payments by insurants. A cost-utility ratio of the 5-grass tablets vs the mix of allergoids of €12,593 per QALY was detected, with predicted incremental costs and QALYs of €458 and 0.036, respectively. The likelihood of the 5-grass tablets to be the most cost-effective treatment was approximated in 76% at a willingness-to-pay threshold of €20,000¹⁸. On the other hand, when comparing with the same tools (Markov model and QALY) the 5-grass pollen tablets with only one SCIT product, the latter was found to be more cost-effective, based on lower cost and higher patients compliance¹⁹.

In a paper recently published in the Journal of Medical Economics, Brüggenjürgen and Reinhold²⁰ investigated, by a Markov model with pre-defined health stages and a time-horizon of 9 years, two products—Allergovit for SCIT and Oralair for SLIT—in Austria, Switzerland, and Spain. Symptom-score based QALYs were used to evaluate the effectiveness of the treatments, also assessing the total cost and the cost-effectiveness. Concerning the effectiveness, both SCIT and SLIT preparations were dominant compared to symptomatic therapy. There were additional costs for the two AIT forms, but, when combined with the results on effectiveness, both SCIT and SLIT were cost-effective. Directly comparing Allergovit and Oralair, lower total costs of SCIT vs SLIT for Austria, Spain, and Switzerland (€1,368 vs €2,012, €2,229 vs €2,547, and €1,901 vs €2,220) and higher effectiveness (8.02 QALYs for SCIT, 7.98 QALYs for SLIT and 7.90 QALYs for drug treatment) were found. The authors concluded that, in patients with AR, both SCIT and SLIT are more cost-effective treatments over drugs and that the direct comparison of the two AIT forms favors SCIT²⁰. The latter issue does not agree with the previous report from Podladnikova et al.²¹, who found, although only costs were calculated, with no use of QALYs, that SLIT was less expensive than SCIT, mainly for the cost of the injections. Also the two studies from Germany cited above, which used a Markov model and QALYs, mentioned a better cost-effectiveness of the 5-grass tablets compared with SCIT^17,18. The cost of the injections may be a factor for the Podladnikova et al.²¹ and Westerhout et al.¹⁷ studies, based on a much higher number of injections than in the Brüggenjürgen and Reinhold²⁰ study, but not for Verheggen et al.¹⁸, who evaluated an allergoid product similar to that used by Brüggenjürgen and Reinhold²⁰. This suggests that studies comparing SLIT with 5-grass tablets with SCIT products with different schedules of administration, product-specificity, level of evidence, and length of observation, are needed to make the issue clear.

Transparency

Declaration of funding

There is no funding to report for this commentary.

Declaration of financial/other relationships

CI is a consultant/advisor for Stallergenes Italia S.R.L. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

None.