Objective:
The Centers for Disease Control and Prevention (CDC) conducts inhibitor testing for the Community Counts Registry for Bleeding Disorders Surveillance, a public health monitoring program led by CDC’s Division of Blood Disorders along with its partners, the American Thrombosis and Hemostasis Network, and the U.S. Hemophilia Treatment Center Network.
Inhibitor testing at CDC involves a panel of inhibitor-related tests, including a CDC-modified Nijmegen-Bethesda assay (NBA), a chromogenic Bethesda assay (CBA) (for hemophilia A only), fluorescence immunoassays (FLI), and dilute Russell viper venom time (DRVVT). An algorithm aimed at reducing false positive inhibitor results that utilizes this panel of tests has been developed by CDC. Several novel hemophilia treatment products, including extended half-life factor products and a bi-specific antibody that mimics clotting factor VIII (emicizumab), have been approved by the US Food and Drug Administration (FDA). CDC has validated inhibitor testing methods in the context of these novel treatment products and adjusted the testing algorithm when appropriate. The objective of this analysis is to demonstrate the impact of novel hemophilia treatment products on the CDC inhibitor testing workflow for Community Counts.
Methods:
The number and relative proportions of NBA, CBA, FLI, and DRVVT results reported for Community Counts were compared across fiscal years 2018 (10/1/2017-9/30/2018) and 2019 (10/1/2018-9/30/2019). Because emicizumab interferes with the NBA, all specimens from patients using emicizumab are subjected to an alternative testing algorithm that excludes the NBA and tests all specimens with the CBA. The proportion of CBA results reported because the specimen was subjected to this alternative algorithm was also compared across fiscal years.
Summary:
CDC has reported over 11,500 inhibitor test results on over 10,000 specimens for Community Counts (Table). The introduction of novel treatment products has shifted the types of factor VIII tests the CDC conducts. Between 2018 and 2019, the proportion of results reported that were NBA results decreased 12%, whereas the proportion of results reported that were CBA or FLI results increased (125% and 150%, respectively). This shift appears to be driven by the introduction of emicizumab. The proportion of CBA tests conducted because the specimen was low-positive decreased 64%, but the proportion of CBA tests conducted because the patient was currently using emicizumab increased 150%.
Conclusions:
The introduction of novel hemophilia treatment products, notably emicizumab, has impacted the CDC inhibitor testing workflow for Community Counts. Future efforts to validate the currently-used inhibitor testing algorithm in order to assure the algorithm is efficient, cost-effect, and accurate are needed.