Systematic Literature Review of the Indirect Costs, Humanistic Burden, Patient or Caregiver Preference, and Qualitative Outcomes in Beta-Thalassemia
Authors: Aydinok Yesim , Purushotham Sneha , Yucel Aylin , Deshpande Sohan , Potrata Barbara , Trapali Myrto , Dixit Mrinalini , Shah Farrukh 
Published: November 2021

Abstract
Introduction: Beta-thalassemia is a hereditary blood disorder with some patients requiring frequent blood transfusions. Lifelong management of the disease and its complications imposes a severe burden on patients. This study aimed to understand the indirect costs and humanistic burden, treatment preferences, and perceptions of treatment and outcomes in patients with beta-thalassemia.
Methods: Systematic literature searches were conducted in Embase, MEDLINE, and MEDLINE In-Process to identify articles on patients with beta-thalassemia published between November 2010 and 2020. Studies were included if they reported on patients with beta-thalassemia of any age regarding indirect costs, health-related quality of life (HRQoL), patient/caregiver preference, and qualitative outcomes in observational, economic, and preference elicitation studies. Search methods followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane.
Results: Searches yielded 2387 records; 95 publications were included (Figure). The mean annual costs due to productivity losses in patients with transfusion-dependent beta-thalassemia (TDT) was 24% of all treatment costs. The cost of lost welfare due to pain and suffering in TDT in Iran in 2015 was USD 1360.50 per year per patient. Lost opportunities for TDT patients in Iran were highest in the age group 31-40 years and lowest in the age group 0-10 years. Lost opportunities for patients' families were highest in the age group 11-20 years. The mean annual transportation cost for TDT patients in Iran for visits to hospitals was EUR 132.77 (standard deviation [SD] 15.50). The indirect burden of absenteeism due to transfusion ranged from 13.5 to 30 days in patients and 19 days in caregivers, annually. Mean indirect burden due to disease management in TDT patients was 592 min (SD 349) on transfusion days (for activities including undergoing transfusion, cross-matching of blood, arranging childcare, arranging insurance payments) and 91 min (SD 221) on non-transfusion days. No studies on indirect costs were identified in the non-transfusion dependent beta-thalassemia (NTDT) population.
Blood transfusion is used to reduce pain and fatigue in TDT patients and scores for fatigue and pain were worse for a period of 5 days before transfusion (mean Brief Fatigue Inventory score 5.05 vs 4.29; mean Brief Pain Inventory-Short Forms score 4.33 vs 3.85). HRQoL outcomes were reported to be associated with age (better HRQoL in ≤14 years of age, P=0.015, P=0.008), sex (better HRQoL in males, P=0.035, P=0.041, P=0.009), lower serum ferritin (better HRQoL, P=0.05, P=0.004), compliance to iron chelation therapies (better HRQoL, P&lt;0.01, P=0.004), heart failure (worse HRQoL, P&lt;0.001), higher income (better HRQoL, P&lt;0.001), being employed (better HRQoL, P=0.01), higher education (better HRQoL, P&lt;0.001). Patients with TDT and NTDT reported worse HRQoL scores on SF-36 general health domain than the general population (mean [SD] 44.1 [9.3] vs 50 [10]). Long-term HRQoL in patients who underwent hematopoietic stem cell transplantation 20 years ago was comparable to the general population (SF-36 change in HRQoL −8.9; 95% CI, −15.0 to 2.7, P=0.005). Studies indicated a high prevalence of depression in TDT patients; &gt;50% of TDT patients suffered from mild to severe stress, anxiety, and depression. In TDT children, mental health was the most affected domain of SF-36 compared to healthy peers (48.6 vs 96.6, P&lt;0.001). NTDT patients were reported to have lower scores on all domains of the FACT scale than TDT patients indicating worse HRQoL (−4.8 vs −4.7, P=0.009).
Patient preference and qualitative studies were conducted in low- and middle-income countries and findings mostly corresponded to results from HRQoL studies. Patients/caregivers frequently reported feelings of uncertainty, anxiety, depression, and thoughts of dying. Social stigma substantially affected the lives of those affected by beta-thalassemia and contributed to adverse financial impacts.
Conclusions: TDT is associated with high indirect costs, including productivity losses, absenteeism, transportation cost, and societal losses. Further research is needed to understand the indirect cost burden on NTDT patients. The findings highlight the unmet need for novel therapies, and optimal disease management approaches to decrease the economic burden of TDT in patients and their caregivers.
Figure 1 Figure 1.

Disclosures
Aydinok: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Resonance Health: Research Funding; CRISPR Therapeutics: Consultancy; SLN Therapeutics: Consultancy; Imara: Research Funding; Protagonist: Membership on an entity's Board of Directors or advisory committees, Research Funding; LaJolla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ionis Pharmaceuticals: Research Funding. Purushotham: Evidera: Consultancy, Current Employment. Yucel: BMS: Current Employment, Current holder of individual stocks in a privately-held company. Deshpande: Evidera Ltd: Consultancy, Current Employment. Potrata: Evidera Ltd: Current Employment. Trapali: Evidera Ltd: Consultancy, Current Employment. Dixit: Evidera: Current Employment. Shah: Bristol Myers Squibb: Honoraria.