Análise de custo dos fatores de coagulação nos períodos pré, durante e pós-indução de Imunotolerância em Hemofilia A Hereditária

Abstract

Hemophilia A (HA) is a bleeding disorder caused by factor VIII (FVIII) deficiency. Development of neutralizing antibodies to exogenous FVIII is the most serious complication of HA which occurs in approximately 30% of severe cases. Immune Tolerance Induction (ITI) is the gold standard treatment for eradicating FVIII inhibitors. The objective of this study was to assess the costs of clotting factor replacement before, during and after ITI in persons with hemophilia A (PwHA) according to ITI outcomes. We conducted a non-concurrent cohort study in Hemophilia Treatment Centers (HCTs) in four Brazilian states. Data from medical records of PwHA between 2011 and 2021 was collected. We evaluated the consumption and costs of FVIII and bypassing agents (activated Prothrombin Complex - aCCP and recombinant activated Factor VII - rFVIIa) per kilogram (kg) in three periods: i) pre-ITI (12 months before ITI), ii) during ITI (variable duration) and iii) post-ITI (12 months after ITI) and their relationship with ITI outcomes. The outcomes were previously defined as complete success, partial success and failure, according to the Brazilian ITI Protocol. Costs were adjusted for the Brazilian Extended National Consumer Price Index (IPCA – June 2022) and purchasing power parity – PPP dollar (2022). We compared categorical variables (frequencies and percentages) among the groups (complete success, partial success and failure) using chi-square or Fischer’s exact test. We calculated continuous variables (mean values/standard deviation and median values/range) among the groups using the Mann-Whitney U test or Kruskal-Wallis. The Paired t-test was used to compare measurements within the same group. We considered p-values <0.05 to be statistically significant. The study was approved by the Research Ethics Committees of Universidade Federal de Minas Gerais (UFMG) and HCTs. A total of 91 PwHA were enrolled, of whom 87 (95,60%) had severe HA (< 1% FVIII level). Complete success, partial success and failure were achieved in 29/91 (31.87%), 35/91 (38.46%) and 27/91 (29.67%) PwHA, respectively. The median duration of ITI was 2.20 years (interquartile range [IQR] 1.80 – 2.70), 2.70 years (IQR 1.20 – 3.20) and 3.10 years (IQR 2.70 – 3.70) in complete success, partial success and failure, respectively (p<0.05). The annualized bleeding rate (ABR) during ITI was 2.0 (IQR 0.5 – 4.1), 3.7 (IQR 1.7 – 5.5) and 6.0 (3.0 – 7.5) in complete success, partial success and failure, respectively (p<0.05). When comparing the ABR before and after ITI, there was a decrease in all outcomes (paired mean = 4.58 of bleeding reduction). The age at time of ITI start was similar among all groups (p=0.23). The exclusive use of plasma-derived factor VIII (pdFVIII) was reported in 49/91 (53.85%) PwHA, with no difference among the groups (p=0.52). Before ITI, the consumption/kg of pdFVIII, rFVIII, aCCP and rFVIIa differed among the groups (p<0.05). The mean cost/kg (± standard deviation [SD]) of all clotting factors before ITI in PPP dollars was 5,468.57 (± 6,150.06); 5,441.41 (± 4,341.18) and 9,344.79 (± 8,285.61) in complete success, partial success and failure, respectively (p<0.05). During ITI, the consumption/kg of pdFVIII, aCCP and rFVIIa differed among the groups (p<0.05), but there was no difference in rFVIII consumption/kg (p=0.27). The mean cost/kg (± SD) of all clotting factors during ITI in PPP dollars was 11,168.16 (± 9,055.81), 20,917.05 (± 34,316.15) and 77,888.00 (± 36,265.93) in complete success, partial success and failure, respectively (p<0.05). After 12 months of ITI, the use of bypassing agents was exclusively reported in the failure group. There was no difference in the consumption of pdFVIII/kg or rFVIII/kg between the total and the partial success groups. The mean cost/kg (± SD) of all clotting factors post-ITI in PPP dollars was 2,767.89 (± 1,242.61), 4,246.28 (± 8,616.35) and 20,835.99 (± 12,972.86) in complete success, partial success and failure, respectively (p<0.05). When comparing the costs before and after ITI, PwHA who achieved complete and partial success showed a reduction of 49,4% and 22,0%, respectively, but the failure group had an increase of 123,0%. In conclusion, compared with the total and the partial success groups, ITI failure was associated with the highest cost and the highest ABR in all periods. ABR decreased during the 12 months after ITI, including in the failure group.