Abstract

Hemophilia A is a rare bleeding disorder caused by a deficiency of clotting factor VIII, leading to recurrent bleeds, joint damage, and disability. Low-dose prophylaxis has been shown to achieve better clinical outcomes than on-demand treatment in reducing bleeding frequency. However, in Indonesia, access and affordability remain key challenges. This study aimed to develop a conceptual model for conducting a health economic evaluation of low-dose prophylaxis treatment for children with severe hemophilia A in Indonesia. This study followed the ISPOR-SMDM Modeling guidelines, outlining two-stage processes: conceptualization of the clinical problem and model development. A systematic literature review was conducted to identify relevant clinical and economic evidence on low-dose prophylaxis and on-demand treatment in pediatric hemophilia A. Indonesian clinical guidelines and expert input from two hematologists were incorporated to contextualize the model. Thirteen studies (three clinical and ten economic evaluations) consistently reported improved outcomes with low-dose prophylaxis. Most models applied health state transitions involving bleeding episodes, joint damage, complications, and death. Based on this review and discussion, the conceptual model was established to support the cost-effectiveness analysis of low-dose prophylaxis. A rigorous conceptual model serves as the key foundational step in developing a valid, health economic model for the Indonesian setting.

References

1. Berntorp E, Fischer K, Hart DP, et al. Hemophilia. Nat Rev Dis Primers. 2021; 7: 45. DOI: 10.1038/s41572-021-00278-x.

2. Mehta P, Reddivari AKR. Hemophilia. Treasure Island, FL: StatPearls Publishing: 2023.

3. Salen P, Babiker HM. Hemophilia A. Treasure Island, FL: StatPearls Publishing: 2023.

4. Franchini M, Mannucci P. Past, present and future of hemophilia: A narrative review. Orphanet J Rare Dis. 2012; 7: 24. DOI: 10.1186/1750-1172-7-24.

5. Munawar Ali R, Abid M, Zafar S, et al. Management of Severe Hemophilia A: Low-Dose Prophylaxis vs. On-Demand Treatment. Cureus. 2023; 15 (7): e41410. DOI: 10.7759/cureus.41410.

6. Berntorp E, Hermans C, Solms A, et al. Optimising prophylaxis in hemophilia A: The ups and downs of treatment. Blood Reviews. 2021; 50: 100852. DOI: 10.1016/j.blre.2021.100852.

7. Zhao Y, Xiao J, Yang R, et al. Efficacy of standard prophylaxis versus on-demand treatment with bayer’s sucrose-formulated recombinant FVIII (rFVIII-FS) in Chinese children with severe hemophilia A. Pediatr Hematol Oncol. 2017; 34 (3): 146–56. DOI: 10.1080/08880018.2017.1313921.

8. Chozie NA, Primacakti F, Gatot D, et al. Comparison of the efficacy and safety of 12-month low-dose factor VIII tertiary prophylaxis vs on-demand treatment in severe hemophilia A children. Hemophilia. 2019; 25 (4): 633–639. DOI: 10.1111/hae.13770.

9. Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Hemophilia. 2020; 26 (S6): 1–158. DOI: 10.1111/hae.14046.

10. Rezende SM, Neumann I, Angchaisuksiri P, et al. International Society on Thrombosis and Hemostasis clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology. J Thromb Hemost. 2024; 22 (9): 2629–2652. DOI: 10.1016/j.jtha.2024.05.026.

11. Menteri Kesehatan Republik Indonesia. Keputusan Menteri Kesehatan Republik Indonesia Nomor HK.01.07/Menkes/243/2021 Tentang Pedoman Nasional Pelayanan Kedokteran Tata Laksana Hemofilia. Jakarta: Kementerian Kesehatan Republik Indonesia; 2021.

12. Angchaisuksiri P, Amurao-Abiera M, Chou S, et al. Hemophilia care in Asia: Learning from clinical practice in some Asian countries. Hemophilia. 2024; 30 (3): 609–616. DOI: 10.1111/hae.14998.

13. Perolla A, Kalaja B. Improving Hemophilia Care in Low- and Middle-Income Countries: Addressing Challenges and Enhancing Quality of Life. Cureus. 2024; 16 (6): e62817. DOI: 10.7759/cureus.62817.

14. Moonla C, Sosothikul D, Pongtanakul B, et al. Practices and challenges for hemophilia management under resource constraints in Thailand. Orphanet J Rare Dis. 2023; 18: 110. DOI: 10.1186/s13023-023-02718-1.

15. Sidharthan N, Narayana Pillai V, Mathew S, et al. Low Dose Secondary/Tertiary Prophylaxis Is Feasible and Effective in Resource Limited Setting in South India for Children with Hemophilia. Blood. 2016; 128 (22): 2336. DOI: 10.1182/blood.V128.22.2336.2336.

16. Sidharthan N, Sudevan R. Low Dose Prophylaxis in Hemophilia Care. Indian J Hematol Blood Transfus. 2020; 36: 16–25. DOI: 10.1007/s12288-019-01147-0.

17. Hutasoit RH. World Hemophilia Day 2024, Hemophilia in Indonesia and Legal Safeguards. Jakarta: ARFP Lawyers; 2024.

18. Briggs AH, Weinstein MC, Fenwick EAL, et al. Model Parameter Estimation and Uncertainty Analysis: A Report of the ISPOR-SMDM Modeling Good Research Practices Task Force Working Group–6. Med Decis Making. 2012; 15 (6): 835–42. DOI: 10.1177/0272989X12458348.

19. Roberts M, Russell LB, Paltiel AD, et al. Conceptualizing a Model: A Report of the ISPOR-SMDM Modeling Good Research Practices Task Force–2. Med Decis Making. 2012; 32 (5): 678–689. DOI: 10.1177/0272989X12454941.

20. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med. 2021; 18 (3): e1003583. DOI: 10.1136/bmj.n71.

21. Hong QN, Pluye P, Fàbregues S, et al. Mixed Methods Appraisal Tool (Mmat) Version 2018: User Guide. Montreal; McGill University; 2018.

22. Husereau D, Drummond M, Augustovski F, et al. Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) Statement: Updated Reporting Guidance for Health Economic Evaluations. BMJ. 2022; 376: e067975. DOI: 10.1136/bmj-2021-067975.

23. Konkle BA, Fletcher SN. Hemophilia A Synonym: Factor VIII Deficiency. Seattle, WA: University of Washington; 2022.

24. Chaudhry R, Killeen RB, Babiker HM. Physiology, Coagulation Pathways. Treasure Island, FL: StatPearls Publishing; 2024.

25. Mannucci PM. Hemophilia treatment innovation: 50 years of progress and more to come. J Thromb Hemost. 2023; 21 (3): 403–412. DOI: 10.1016/j.jtha.2022.12.029.

26. Verma SP, Dutta TK, Mahadevan S, et al. A randomized study of very low-dose factor VIII prophylaxis in severe hemophilia – A success story from a resource limited country. Hemophilia. 2016; 22 (3): 342–348. DOI: 10.1111/hae.12838.

27. Djambas Khayat C, Iosava G, Romashevskaya I, et al. Efficacy, Efficacy, Safety and Pharmacokinetic Results of a Phase III, Open-Label, Multicenter Study with a Plasma-Derived Von Willebrand Factor (VWF)/Factor VIII (FVIII) Concentrate in Pediatric Patients <12 Years of Age with Hemophilia A (SWIFTLY-HA Study). J Blood Med. 2021; 12: 483–495. DOI: 10.2147/JBM.S299130.

28. Miners AH, Sabin CA, Tolley KH, et al. Cost-Utility Analysis of Primary Prophylaxis versus Treatment On-Demand for Individuals with Severe Hemophilia. PharmacoEconomics. 2002; 20: 759–774. DOI: 10.2165/00019053-200220110-00005.

29. Risebrough N, Oh P, Blanchette V, et al. Cost-utility analysis of Canadian tailored prophylaxis, primary prophylaxis and on-demand therapy in young children with severe hemophilia A. Hemophilia. 2008; 14 (4): 743–752. DOI: j.1365-2516.2008.01664.x.

30. Daliri AAK, Haghparast H, Mamikhani J. Cost-effectiveness of prophylaxis against on-demand treatment in boys with severe hemophilia A in Iran. Int J Technol Assess Healthcare. 2009; 25 (4): 584–587. DOI: 10.1017/S0266462309990420.

31. Miners A. Revisiting the cost-effectiveness of primary prophylaxis with clotting factor for the treatment of severe hemophilia A. Hemophilia. 2009; 15 (4): 881–887. DOI: 10.1111/j.1365-2516.2009.02019.x.

32. Colombo G, Matteo SD, Mancuso ME, et al. Cost utility analysis of prophylaxis versus treatment on demand in severe hemophilia A. Clinicoecon Outcomes Res. 2011; 3: 55-61. DOI: 10.2147/CEOR.S16670.

33. Farrugia A, Cassar J, Kimber MC, et al. Treatment for life for severe hemophilia A– A cost-utility model for prophylaxis vs. on-demand treatment. Hemophilia. 2013; 19 (4): e228-e238. DOI: 10.1111/hae.12121.

34. Castro Jaramillo HE, Moreno Viscaya M, Mejia AE. Cost-Utility Analysis of Primary Prophylaxis, Compared With On-Demand Treatment, for Patients with Severe Hemophilia Type A In Colombia. Int J Technol Assess Healthcare. 2016; 32 (5): 337–347. DOI: 10.1017/S0266462316000544.

35. Salinas-Escudero G, Galindo-Suárez RM, Rely K, et al. Cost-effectiveness analysis of prophylaxis vs. “on demand” approach in the management in children with hemophilia A in Mexico. Bol Méd Hosp Infant México. 2013; 70 (4): 290–297.

36. Zahedi Z, Karimi M, Keshavarz K, et al. A cost-effectiveness analysis of the prophylaxis versus on-demand regimens in severe hemophilia A patients under 12 years old in southern Iran. Hematol. 2021; 26 (1): 240–248. DOI: 10.1080/16078454.2021.1885123.

37. Seth T, Garg K, Mandal PK, et al. Cost-effectiveness analysis of low-dose prophylaxis versus on-demand treatment for moderate-to-severe hemophilia A in India. Hematol. 2023; 28 (1): 2277497. DOI: 10.1080/16078454.2023.2277497.

38. Nemzoff C, Shah HA, Heupink LF, et al. Adaptive Health Technology Assessment: A Scoping Review of Methods. Value Health. 2023; 26 (10): 1549–1557. DOI: 10.1016/j.jval.2023.05.017.

39. Alemao E, Al MJ, Boonen AA, et al. Conceptual model for the health technology assessment of current and novel interventions in rheumatoid arthritis. PLoS ONE. 2018; 13 (10): e0205013. DOI: 10.1371/journal.pone.0205013.

40. Putri S, Ciminata G, Lewsey J, et al. The conceptualization of cardiometabolic disease policy model in the UK. BMC Health Serv Res. 2024; 24: 1060. DOI: 10.1186/s12913-024-11559-y.

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