Analyses of the FranceCoag cohort support differences in immunogenicity among one plasma-derived and two recombinant factor VIII brands in boys with severe hemophilia A

Abstract

Around one third of boys with severe hemophilia A develop inhibitors (neutralizing antibodies) against their therapeutic factor VIII product. This adverse effect may result in more life-threatening bleeding, disability, impaired quality of life, and costly care. We compared the incidence of inhibitors in boys treated with the three factor VIII products most used in France: one plasma-derived (Factane) and two recombinant products (Advate and Kogenate Bayer). A previously untreated cohort of patients was created in 1994 to investigate risk factors for inhibitor development. We selected boys with severe hemophilia A (factor VIII <1 IU/dL) first treated with one of the three factor VIII products studied. Details of product infusions, inhibitor assays and main fixed and time-varying inhibitor risk factors were recorded for the first 75 exposure days. Three outcomes (all inhibitors, high-titer inhibitors and subsequently treated inhibitors) were analyzed by univariate and multivariate Cox models. We studied 395 boys first treated between 2001 and 2016 (131, 137, and 127 with Factane, Advate, and Kogenate Bayer, respectively). Clinically significant inhibitors were diagnosed in 121 patients (70 high-titer). The incidence of high-titer inhibitors was significantly associated with the factor VIII product received (P=0.005): the cumulative incidence at 75 exposure days was 12.7% (95% CI: 7.7-20.6) with Factane, 20.4% (95% CI: 14.0-29.1) with Advate, and 31.6% (95% CI: 23.5-41.7) with Kogenate Bayer. The low inhibitor incidence observed with Factane is concordant with recent findings from the SIPPET randomized trial. These consistent results from observational and experimental studies should lead to improved care for previously untreated patients and cost savings for healthcare systems worldwide.

Figure 1.

Patient selection process. At the cutoff date (December 6, 2016), 649 previously untreated patients (PUPs) with hemophilia A (factor VIII <2 IU/dL) had been included in the dedicated cohort of FranceCoag. After the selection process, three groups of boys with severe hemophilia A (factor VIII <1 IU/dL) were formed based on the first factor VIII product received. MA: marketing authorization dates in European Union (or in France for Factane^®).

Figure 2.

Kaplan-Meier representation of the cumulative incidence of inhibitors, with exposure day as the observational time unit, according to the factor VIII product received. Three outcomes are shown: all inhibitors, high-titer inhibitors and inhibitors subsequently treated with a bypassing agent and/or immune tolerance induction. (A) Kaplan-Meier estimates are shown for all patients. Tests used Cox proportional hazards model. (B) Weighted Kaplan-Meier estimates are shown for patients first treated between 2004 and 2012. This selection was made to avoid having patients with an extremely low probability of having received one of the two counterfactual treatments (see Online Supplementary Methods). Tests used weighted Cox proportional hazards model.

Figure 3.

Kaplan-Meier representation of the cumulative incidence of inhibitors, with exposure day as the observational time unit, according to the factor VIII product received. Three outcomes are shown: all inhibitors, high-titer inhibitors and inhibitors subsequently treated with a bypassing agent and/or immune tolerance induction. Tests used Cox proportional hazards model. (A) Kaplan-Meier estimates according to calendar period of first exposure to factor VIII. (B) Kaplan-Meier estimates according to treatment intensity at first exposure (peak treatment episode ≥ 3 consecutive exposure days).

Figure 4.

Hazard ratios and 95% confidence intervals for (A) Advate versus Factane and (B) Kogenate versus Factane according to several models, two propensity score methods and two sensitivity analyses. Three outcomes are shown: all inhibitors, high-titer inhibitors, and inhibitors subsequently treated with a bypassing agent and/or immune tolerance induction. Except in PS analyses and in the first sensitivity analysis, 131, 137, and 127 PUPs first treated with Factane, Advate and Kogenate, respectively, were considered. In Panel A, 110 PUPs first treated from 2004 with Factane and 137 PUPs first treated with Advate were considered in PS analyses and in the first sensitivity analysis. In Panel B, 92 PUPs first treated until 2012 with Factane and 122 PUPs first treated until 2012 with Kogenate were considered in PS analyses; 99 PUPs first treated until 2013 with Factane and 127 PUPs first treated with Kogenate were considered in the first sensitivity analysis. EDs: Exposure days; HR: hazard ratio; PS: propensity score; PUP: previously untreated patient.