Genetic risk stratification to reduce inhibitor development in the early treatment of hemophilia A: a SIPPET analysis

Frits R. Rosendaal, Roberta Palla, Isabella Garagiola, Pier M. Mannucci and Flora Peyvandi

Key points

  • It has been suggested that recombinant FVIII, which is more immunogenic than plasma-derived FVIII, can be safely used in low risk patients.

  • Among 235 participants in a randomized trial, genetic risk stratification did not identify a low risk group for treatment with rFVIII.


A recent randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET), showed a higher risk of inhibitor development with recombinant (rFVIII) than plasma-derived concentrates (pdFVIII). We investigated whether risk stratification by F8 mutation identifies patients who do not suffer this deleterious effect of rFVIII. Among 235 randomized patients with severe hemophilia A, previously untreated with FVIII concentrate, 197 with null mutations were classified as high risk, and 38 with non-null mutations as low risk. When treated with pdFVIII, no inhibitors occurred in those with a low genetic risk, whereas high risk patients had a cumulative incidence of 31%. The risk among low and high risk patients did not differ much when treated with rFVIII, at 43% and 47%, respectively. This implies that patients with a low genetic risk suffer the highest increment in risk (43%) when treated with rFVIII, as also shown by the Number Needed to Harm with rFVIII, which was 6.3 for genetically high-risk patients and only 2.3 for low-risk patients. This gene-environment interaction implies that genetically low-risk patients suffer disproportionate harm when treated with rFVIII. Risk stratification by F8 mutation does not identify patients who can be safely treated with rFVIII, as relates to immunogenicity. The trial is registered under EudraCT 2009-011186-88 and ClinicalTrial.Gov NCT01064284.

  • Submitted June 19, 2017.
  • Accepted August 1, 2017.