Risk Factors for Inhibitor Development in Mild and Moderate Hemophilia A: A Case-Control Study.

Inhibitor formation is a major complication of hemophilia A (HA). Although only 25% of new inhibitors occur in those with mild or moderate HA, they often lead to an increased frequency of bleeding with potentially devastating consequences. In contrast to severe HA, knowledge of risk factors for the development of inhibitors in those with mild and moderate hemophilia A is limited. This study was carried out to assess the role of intensive exposure to factor VIII (fVIII), in inhibitor formation in those with mild or moderate HA.

A retrospective case-control design was utilized. Cases were initially identified among participants of the Universal Data Collection (UDC) surveillance system as those with mild or moderate HA (fVIII 1-40%) having a current or past inhibitor titer of > 1 BU/ml. Hemophilia severity and inhibitor titer were verified by the Hemophilia Treatment Center (HTC) and patients were eligible for enrollment if they had an inhibitor titer > 1 BU/ml on two consecutive occasions or had one inhibitor titer > 1 BU/ml followed by initiation of immune tolerance therapy. Additional cases were identified by the HTC. Control subjects had no history of inhibitor titer > 0.6 BU/ml and had previously received fVIII. Negative inhibitor status was confirmed by Nijmegen assay performed in a central laboratory. After informed consent was obtained, exposure information during the year prior to inhibitor development (cases) or the year prior to enrollment (controls) was gathered from clinical records and subject interview. The primary risk factor of interest was intensive treatment with fVIII defined as having received 6 or more consecutive days. Other risk factors investigated include: age, baseline fVIII activity, race, prior number of fVIII exposure days, vaccination within the prior year, product type and fVIII genotype.

Forty-three cases and 65 controls met eligibility criteria and were enrolled at 16 HTCs. Seven cases and three controls were not included in the analysis after genotyping demonstrated mutations typically associated with severe disease, such as intron-22 inversion. The final analysis included 36 cases and 62 controls. Ten of these cases were originally identified in the UDC system. The mean baseline fVIII activity was similar between groups (p=0.73). The median age was 31 years (Inter-quartile range (IQR), 10-51 years) in cases and 27.5 years (IQR, 18-46 years) in controls (p=0.80). The distribution of subjects having < 50, 50-100 or > 100 prior fVIII exposure days was similar between groups (p=0.40). Fifty percent of cases had received intensive treatment with fVIII compared with 17.7% of controls (p <0.01). Amongst the cases that had received intensive treatment, the period of intensive treatment occurred within 12 weeks of inhibitor detection. The unadjusted OR associated with intensive treatment with fVIII was 4.63 (95% CI, 1.84-11.67). The OR associated with intensive treatment was significantly lower in subjects < 30 years of age compared to those > 30 years (1.55 vs. 13.54, heterogeneity p=0.02). After multivariate adjustment, intensive treatment with fVIII remained strongly associated with inhibitor formation (OR 7.65; 95% CI, 1.69-34.44). In the multivariate model, the OR for intensive treatment in those < 30 years of age was 3.36 (95% CI, 0.6-16.8) compared with 15.24 (95% CI, 2.38-97.2) in those 30 years of age or older. However, this interaction between age and intensive treatment did not reach statistical significance (Wald test p=0.23).

Intensive treatment with fVIII is a strong independent risk factor for inhibitor development in those with mild or moderate hemophilia A and the risk appears to be greater in adults 30 years of age or older.

Kempton:Biomeasure Inc: Consultancy; CSL Behring Foundation: Research Funding. Manco-Johnson:Baxter BioScience: Honoraria; Bayer HealthCare: Honoraria; CSL Behring: Honoraria; NovoNordisk: Honoraria; Octapharma: Honoraria. Abshire:CSL Behring, Novo Nordisk, Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees.