FVIII prophylaxis in children with severe haemophilia A : A nationwide survey of outcome and costs in Finland

Haemophilia is an X-linked congenital bleeding disorder caused by a partial or complete lack of coagulation factor VIII (FVIII) in haemophilia A (HA) or factor IX (FIX) in haemophilia B (HB), both mainly occurring in males. Severe haemophilia (FVIII or FIX activity < 0.01 IU mL−1) is characterized by serious bleeding episodes, often by spontaneous bleeds in soft tissue, especially in joints, sometimes progressing to chronic arthropathy. Full prophylaxis, which means regular coagulation factor infusions, offers almost complete protection against traditional haemophilia-associated complications such as intracranial haemorrhage, prevents joint damage, and gives patients a nearnormal life with a life expectancy similar to that in the general population. In Finland, the standard practice for nearly two decades has been early primary prophylaxis, started before the age of one and before even the onset of the first joint bleed, mainly via surgically inserted central venous access devices (CVADs). These ports secure long-term and reliable venous access, enabling early home treatment. The most serious and costly complication in the treatment of severe HA is the development of FVIII-neutralizing antibodies, called inhibitors, suddenly rendering the treatment ineffective. In this retrospective nationwide study, we investigated the effects of early primary prophylaxis in Finnish paediatric haemophilia patients during the past two decades. We evaluated the incidence of, and risk factors for, complications associated with CVAD usage; we also examined the incidence of, and risk factors for, inhibitor development (ID) in previously untreated patients (PUPs) with severe HA. The long-term clinical and economic outcomes of regular high-dose prophylaxis were evaluated. We provide real-world data on total treatment costs per body weight in non-inhibitor and inhibitor patients, representing nearly 700 patient-years of follow-up. Regular high-dose primary prophylaxis of PUPs with severe HA leads to excellent long-term joint health, annualised bleeding rates being near zero. The CVAD-related bloodstream infection rate was lower, and port duration (median of 3.2 years) longer, than earlier described. The cumulative incidence of ID was low (21%) despite the majority having a high-risk genotype. ID incidence was 3040% lower than the incidence internationally where prophylaxis is mainly started as secondary prophylaxis and administered via peripheral veins. ID risk significantly increased in patients who experienced major bleeds. Rapid immune tolerance induction therapy during early childhood was successful and cost-neutral due to its relatively short expected payback period. In conclusion, our results emphasize the importance of early primary prophylaxis via ports to prevent bleeds and thereby to decrease inhibitor incidence. This prophylaxis management leads to excellent long-term clinical outcomes and may reduce the health care costs of bleeding events and their longterm complications in the future. National Library of Medicine Classification: QW 575, WH 325 Medical Subject Headings: Haemophilia A; Haemorrhage; Primary Prevention; Antibodies, Neutralizing; Treatment Outcome; Health Care Costs; Child