Estimating the broader fiscal consequences of acute hepatic porphyria (AHP) in Belgium using 1 a public economic analytic framework

Acute hepatic porphyria (AHP) is a rare, debilitating disease characterized by potentially life- 31 threatening attacks often resulting in chronic symptoms that negatively impact daily functioning 32 and quality of life. Symptoms of AHP prevent many individuals from working and achieving 33 lifetime work averages. The aim of this study was to apply a public economic framework to 34 evaluate AHP in Belgium, taking into consideration a broad range of costs that are relevant to 35 government in relation to social benefit payments and lifetime taxes paid. A public economic framework was developed exploring lifetime costs for government attributed 38 to an individual with AHP in Belgium. Work-activity and lifetime direct taxes paid, indirect 39 consumption taxes and requirements for public benefits were estimated based on established 40 clinical pathways for AHP and compared to the general population (GP). The model includes AHP- 41 related healthcare costs and non-AHP healthcare costs for the GP. could also lead to eductions in disability payments of p.p. and healthcare cost savings of reduced healthcare costs, reduced disability payments and improved tax revenue.

6 attacks, defined at 3 or more porphyria attacks within the 12 months prior to the start of the 88 study. Sixty-five percent of the patients reported experiencing chronic symptoms, 20% 89 experienced 6 to 10 attacks in the preceding 12 months, while as many as 32% reported having 90 suffered more than 10 attacks in the preceding 12 months [5]. Furthermore, AHP is associated 91 with serious long-term, health-limiting complications, including liver disease such as cirrhosis and 92 cancer, chronic kidney disease and systemic arterial hypertension [5]. A patient-level data analysis 93 of 88 patients observed that patients with recurrent porphyria attacks (n = 11) and those who 94 were symptomatic (n = 24) experienced multiple chronic comorbidities. Of those rated as 95 "recurrent cases", 72.7%, 63.6% and 9.1% also had hypertension, chronic kidney disease and 96 hepatocellular carcinoma, respectively [8]. 97 The attacks and complications related to AHP can lead to absenteeism from work, or even an 98 inability to work. In the natural history study by Gouya et al (2020), of those who were employed 99 (part-time or full-time), 52% missed work due to their porphyria, with a mean of 40.2 day's work 100 missed, and at least 21% of the patients had received disability allowances because of their 101 porphyria in the past 12 months [5]. In the cohort data analysis by Neeleman et al (2018), 63.6% 102 and 33.3% were unemployed in the recurrent cases and symptomatic group, respectively [8]. 103 Current evidence suggests that there is significant unmet need in the treatment of AHP which 104 results in substantial burden to patients, absenteeism and loss of productivity, and the associated 105 financial burden for the healthcare system. This study sought to apply a public economic 106 framework taking into consideration a broad range of costs that are relevant to government in 107 relation to transfer payments and taxes paid by people with AHP. 108 109

Methods 110
Analytic framework 111 A public economic model was developed to assess lifetime tax contributions and government 112 payments received for disability, pensions and healthcare for a person with AHP compared to the 113 GP. The analytic framework is similar to methodologies used by governments to assess the impact 114 of policy changes on public accounts; and, in the present context, how different health conditions 115 influence government accounts [9,10] Hemin treatment is associated with several serious (grade 3 or 4) adverse events. The cost for 171 treating these adverse events is calculated as an additional cost during the hospitalization for an 172 acute attack and considers only an extension of the hospitalization period by 3-5 days [19]. The 173 details of costs per event are provided in the supplemental data, Table A. 174 The average annual AHP-related cost per co-morbidity or chronic disorder and AHP-related acute 175 attacks were derived from the literature and adjusted to 2020 values where necessary 176  There are several weaknesses of the modeling approach described here. Firstly, to reflect the 245 heterogenous nature of AHP, a scenario-based modeling approach was applied compared to a 246 cohort model that would rely on statistical norms for disease outcomes and disease progression. 247 The different scenarios reflected in our analysis are based on different credible clinical 248 manifestations observed in real life, but not necessarily based on a cohort of subjects. As such, 249 there is no statistical variance on which to perform sensitivity analysis that would lead to any 250 13 meaningful statistical mean. In this regard, scenarios were used to reflect the range of plausible 251 clinical expressions and how they impact work activity. Furthermore, due to limited information 252 on AHP associated mortality, we applied the average life-expectancy to the AHP individuals. This 253 may be an over-estimate of current life-expectancy. Early mortality in people with AHP would 254 have an impact on government public accounts by reduced spending on healthcare and disability 255 benefits. Additionally, the fiscal modeling framework does not include the option for liver 256 transplantation which is common in people with AHP that can improve outcomes, however it would 257 also increase medical costs with only limited influence on the likelihood of returning to work. Finally, 258 one of the major cost drivers in the analysis relates to how AHP influences work force participation 259 and whether people discontinue work or not. In two of our scenarios, we assumed that AHP would 260 cause people to withdraw permanently from the work force and in the third scenario we assumed 261 10 years of employment inactivity. This may not reflect the actual employment trajectory of 262 people with AHP, but, in this regard, our work reflects the likely benefits for government from 263 preventing disease progression and keeping people in the work force. 264 265 266

Conclusion 267
The constant attacks associated with AHP designate this condition as a severe disability and cause 268 significant public costs. As these attacks occur during peak earning and working years, work 269 activity and lifetime taxes paid are reduced. Decreasing AHP attacks can present significant fiscal 270 benefits for government, including reduced health costs, reduced disability payments and 271 improved tax revenue. 272

Ethics Approval and Consent 274
This study did not involve any primary data collection and no patient level data is included in the 275 analysis. 276

Not applicable 278
Availability of data 279 The results described here are a modeling study comprised from secondary data sources. No 280 primary data collection was performed in relation to this work. All supporting data used for 281 constructing the model is available in the public domain and has been cited or has been provided 282 directly in the manuscript. 283

Competing interests 284
There are no competing interests 285