Christine L. Kempton

How we treat a hemophilia A patient with a factor VIII inhibitor

The most significant complication of treatment in patients with hemophilia A is the development of alloantibodies that inhibit factor VIII activity. In the presence of inhibitory antibodies, replacement of the missing clotting factor by infusion of factor VIII becomes less effective. Once replacement therapy is ineffective, acute management of bleeding requires agents that bypass factor VIII activity. Long-term management consists of eradicating the inhibitor through immune tolerance. Despite success in the treatment of acute bleeding and inhibitor eradication, there remains an inability to predict or prevent inhibitor formation. Ideally, prediction and ultimately prevention will come with an improved understanding of how patient-specific and treatment-related factors work together to influence anti-factor VIII antibody production.

Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART)

The benefits of routine prophylaxis vs. on‐demand treatment with factor VIII products have not been evaluated in controlled clinical trials in older patients with hemophilia A.

Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial.

Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.

In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: A case-control study

Summary.  Background: Twenty‐five percent of new anti‐factor VIII (FVIII) antibodies (inhibitors) that complicate hemophilia A occur in those with mild and moderate disease. Although intensive FVIII treatment has long been considered a risk factor for inhibitor development in those with non‐severe disease, its strength of association and the influence of other factors have remained undefined. Objective: To evaluate risk factors for inhibitor development in patients with non‐severe hemophilia A. Methods: Information on clinical and demographic variables and FVIII genotype was collected on 36 subjects with mild or moderate hemophilia A and an inhibitor and 62 controls also with mild or moderate hemophilia A but without an inhibitor. Results: Treatment with FVIII for six or more consecutive days during the prior year was more strongly associated with inhibitor development in those ≥ 30 years of age compared with those < 30 years of age [adjusted odds ratio (OR) 12.62; 95% confidence interval (CI), 2.76–57.81 vs. OR 2.54; 95% CI, 0.61–10.68]. Having previously received < 50 days of FVIII was also not statistically associated with inhibitor development on univariate or multivariate analysis. Conclusions: These findings suggest that inhibitor development in mild and moderate hemophilia A varies with age, but does not vary significantly with lifetime FVIII exposure days: two features distinct from severe hemophilia A.

Incidence of inhibitors in a cohort of 838 males with hemophilia A previously treated with factor VIII concentrates

Summary.  Background: Development of an inhibitory antibody to factor VIII is currently the most serious complication of hemophilia A treatment. The rate of inhibitor development in those that have been previously treated with factor concentrates is poorly defined. Understanding the baseline rate of inhibitor development in the population of previously treated patients (PTPs) is important when evaluating the effect of exposure to new factor replacement products on inhibitor formation. Objectives: To determine the rate of inhibitor development in PTPs with hemophilia A. Methods: A cohort of males with hemophilia A who had data collected on four or more occasions prior to 30 March 2003, as part of the Center for Disease Control and Preventions Universal Data Collection Project, were eligible for inclusion in the cohort. Patients were included in the cohort if they had at least two Bethesda assay measurements and did not have an inhibitor prior to or at the start of the study period. The overall incidence rate was estimated as the number of verified incident inhibitor cases divided by the total follow‐up time in years multiplied by 1000 (cases per 1000 person‐years). Results: A total of 838 patients were included in the study. The overall incidence rate was calculated to be 2.14 cases per 1000 person years. All incident cases had more than 50 exposure days prior to inhibitor development. Conclusions: Given the low rate of inhibitor development in PTPs with hemophilia A, small, non‐randomized studies are inadequate to determine the rate of inhibitor development after exposure to novel products. Ongoing, standardized, postmarketing surveillance is needed to determine if novel factor products pose an increased risk of inhibitor development.

Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A

Summary.  OBI‐1 is a recombinant B‐domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti‐FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI‐1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI‐1 in a double‐blind fashion. FVIII levels were assayed using both a one‐stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti‐porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean Cmax appeared higher for OBI‐1 (OSCA: 176.00 U dL−1, standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL−1) than Hyate:C (OSCA: 82.3 ± 19.22 U dL−1; chromogenic: 52.67 ± 13.8 U dL−1). Mean AUC also appeared higher for OBI‐1 (OSCA: 2082.87 ± 1323.43 U h−1dL−1; chromogenic: 1817.28 ± 625.14 U h−1dL−1) than Hyate:C (OSCA: 1177.8 ± 469.49 U h−1dL−1; chromogenic: 707.61 ± 420.05 U h−1dL−1). Two infusion‐related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti‐porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI‐1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti‐porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.

Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa

Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors.

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors

The development of anti‐factor VIII (FVIII) antibodies (inhibitors) is the most serious treatment‐related complication in patients with hemophilia A, rendering standard replacement therapy ineffective, heightening the risk for uncontrollable bleeding and morbidity, decreasing quality of life, and increasing healthcare costs.

A study of prospective surveillance for inhibitors among persons with haemophilia in the united states

Inhibitors are a rare but serious complication of treatment of patients with haemophilia. Phase III clinical trials enrol too few patients to adequately assess new product inhibitor risk. This project explores the feasibility of using a public health surveillance system to conduct national surveillance for inhibitors. Staff at 17 U.S. haemophilia treatment centres (HTC) enrolled patients with haemophilia A and B into this prospective study. HTC staff provided detailed historic data on product use and inhibitors at baseline, and postenrolment patients provided monthly detailed infusion logs. A central laboratory performed inhibitor tests on blood specimens that were collected at baseline, annually, prior to any planned product switch or when clinically indicated. The central laboratory also performed genotyping of all enrolled patients. From January 2006 through June 2012, 1163 patients were enrolled and followed up for 3329 person‐years. A total of 3048 inhibitor tests were performed and 23 new factor VIII inhibitors were identified, 61% of which were not clinically apparent. Infusion logs were submitted for 113 205 exposure days. Genotyping revealed 431 distinct mutations causing haemophilia, 151 of which had not previously been reported elsewhere in the world. This study provided critical information about the practical issues that must be addressed to successfully implement national inhibitor surveillance. Centralized testing with routine monitoring and confirmation of locally identified inhibitors will provide valid and representative data with which to evaluate inhibitor incidence and prevalence, monitor trends in occurrence rates and identify potential inhibitor outbreaks associated with products.