Pharmacokinetics, safety and efficacy of a recombinant factor IX product, trenonacog alfa in previously treated haemophilia B patients.

INTRODUCTION: Trenonacog alfa (IB1001) is a recombinant factor IX (rFIX) manufactured in Chinese hamster ovary (CHO) cells. IB1001 was evaluated in a multicentre clinical trial with haemophilia B patients. AIM: The aim was to establish IB1001 pharmacokinetic non-inferiority to comparator rFIX, safety and efficacy in previously treated patients (PTPs) with haemophilia B. METHODS: Subjects were severe or moderately severe haemophilia B adult and adolescent PTPs with no history of FIX inhibitors. RESULTS: IB1001 PK non-inferiority to comparator rFIX was demonstrated through ratio of AUC0-∞ in 32 subjects. IB1001 was well tolerated in all 76 treated subjects; the most common adverse drug reaction was headache (2.6% of subjects) and there were no reports of FIX inhibitors. Transient non-inhibitory binding FIX antibodies and anti-CHO cell protein antibodies developed in 21% and 29% of subjects respectively; no safety concerns were associated with development of these antibodies. Prophylaxis (mean duration ± SD: 17.9 ± 9.6 months, mean dose: 55.5 ± 12.9 IU/kg, median 1.0 infusion per week) was effective in preventing bleeds (median annual bleed rate: 1.52, interquartile range: 0.0-3.46). One or two IB1001 infusions resolved 84% of the bleeds, while for 84% of treatments haemostatic efficacy of IB1001 was rated excellent or good. IB1001 haemostatic efficacy for all 19 major surgeries was rated adequate or better than adequate. CONCLUSIONS: IB1001 is safe and efficacious for treatment of bleeds, routine prophylaxis and perioperative management in haemophilia B patients.

Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A.

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against human factor VIII (hFVIII). OBI-1 is an investigational, B-domain deleted, recombinant FVIII, porcine sequence, with low cross-reactivity to anti-hFVIII antibodies. Efficacy can be monitored with FVIII activity levels in addition to clinical assessments. This prospective, open label, phase 2/3 study was designed to evaluate the efficacy of OBI-1 treatment for bleeding episodes in subjects with AHA. After an initial dose of 200 U kg(-1) , OBI-1 was titrated to maintain target FVIII activity levels, in correlation with clinical assessments, throughout the treatment phase. All 28 subjects with AHA had a positive response to OBI-1 treatment 24 h after initiation despite inhibition of FVIII activity levels immediately after infusion in 10 subjects with baseline anti-porcine FVIII inhibitors. Control of the qualifying bleed was ultimately achieved in 24 of 28 subjects. No related serious adverse events, thrombotic events, allergic reactions or thrombocytopaenia occurred. The results of this study indicate that OBI-1 is safe and effective in treating bleeding episodes in subjects with AHA. The ability to safely and effectively titrate dosing based on FVIII activity levels in this study demonstrates that OBI-1 fulfils the unmet medical need to monitor the key coagulation parameter in AHA patients.

F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.

Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Data from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1 + H2) and inhibitor risk among individuals of genetically determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and human leucocyte antigen (HLA) were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Haplotype 3 was associated with higher inhibitor risk among those genetically identified (N = 49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N = 223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Haplotype 3 was not an independent predictor of inhibitor risk. Furthermore, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.

Pharmacokinetic properties of IB1001, an investigational recombinant factor IX, in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis.

IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double-blind, non-inferiority, cross-over study conducted in participants aged ≥ 12 years weighing ≥ 40 kg, with severe or moderately severe haemophilia B (FIX activity ≤ 2 IU dL (-1) ). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4-18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8-59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg(-1) or nonacog alfa. The lower limit of the one-sided 95% confidence interval for the ratio of AUC(0-t) and AUC(0-∞) (IB1001/nonacog alfa) was 0.90, establishing non-inferiority. Terminal phase half-lives were similar (29.7 ± 18.2 h for IB1001 and 33.4 ± 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non-inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B.

Potency and mass of factor VIII in FVIII products.

Several factor (F) VIII products of different origin and structure are being used for haemophilia A treatment worldwide. The assessment of FVIII concentration in these products is done using activity assays, which are dependent upon the assay and its modifications. To evaluate FVIII products for potency and for FVIII concentration and specific activity, three activity-based assays [activated partial thromboplastin time (APTT), intrinsic FXase and synthetic coagulation proteome] and two immunoassays (ELISA and western blotting) were used in this study with albumin-free full-length recombinant (r) FVIII as a standard. In all activity assays, products A and B (both contain full-length rFVIII) at 1 U mL(-1) showed potency similar to that of the 0.7 nm (1 U mL(-1)) rFVIII standard. Product E (contains truncated rFVIII) was less potent in the APTT (83% of standard) and product C (contains plasma FVIII) was less potent in FXase assays (66%). The ELISA immunoassay revealed that the specific activity of FVIII proteins in products A-C and E varied over a wide range (3900-13 200 U mg(-1)) and was higher for most lots when compared with the standard (5000 U mg(-1)), whereas the specific activity of product D (contains plasma FVIII) was lower than expected (3200-4800 U mg(-1)). (i) FVIII potency estimated in different assays gives dissimilar results; (ii) the specific activity of FVIII in various FVIII products is different and inconsistent. Thus, the administration of an equal FVIII potency in units means the administration of different amounts of FVIII protein, which may partly explain apparent discrepancies in product performance.

Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study.

The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.

Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC)

Stromal-derived factor (SDF-1) is the principal ligand for CXCR4, a coreceptor with CD4 for T lymphocyte cell line-tropic human immunodeficiency virus-type 1 (HIV-1). A common polymorphism, SDF1-3'A, was identified in an evolutionarily conserved segment of the 3' untranslated region of the SDF-1 structural gene transcript. In the homozygous state, SDF1-3'A/3'A delays the onset of acquired immunodeficiency syndrome (AIDS), according to a genetic association analysis of 2857 patients enrolled in five AIDS cohort studies. The recessive protective effect of SDF1-3'A was increasingly pronounced in individuals infected with HIV-1 for longer periods, was twice as strong as the dominant genetic restriction of AIDS conferred by CCR5 and CCR2 chemokine receptor variants in these populations, and was complementary with these mutations in delaying the onset of AIDS.

Diminished frequency of hepatitis C virus specific interferon gamma secreting CD4+ T cells in human immunodeficiency virus/hepatitis C virus coinfected patients.

BACKGROUND: Human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection is a common and complex clinical problem in which loss of immunological control of HCV occurs, with increased HCV viral load and more aggressive liver disease. Cellular immune responses, particularly secretion of interferon gamma (IFN-gamma) appear to be important in the control of HCV, and a detectable HCV specific CD4 response is associated with clearance of the virus. HCV specific CD8+ T cell responses, weak in chronic HCV infection, have been shown to be further impaired in HIV coinfection and this CD8+ T cell deficiency is related to the decline in CD4 T cell count. AIMS: To compare the CD4 T cell response to HCV in HIV/HCV coinfected and HCV monoinfected individuals and to determine the relationship of responses with declining CD4 count. PATIENTS: The study subjects were a cohort of 68 HCV monoinfected and 67 HCV/HIV coinfected haemophiliac children and adolescents (the Hemophilia Growth and Development Study) who were followed for a seven year period. METHODS: We analysed IFN-gamma secreting CD4+ responses to HCV proteins and peptides and HIV p24 antigen using an ELISpot assay. RESULTS: We found a significant decrease in HCV specific responses among those who were HIV coinfected (10/67 v 36/68; p<0.0001) both in numbers of responders and frequency of specific cells. This did not appear to be closely related to CD4 count. CONCLUSIONS: The reduction in HCV specific CD4 T cells in coinfection provide a cellular mechanism for the loss of control of HCV in coinfected individuals, even in those with relatively preserved CD4+ T cell counts and CD4+ T cell responses to HIV.

Reduced risk of AIDS lymphoma in individuals heterozygous for the CCR5-delta32 mutation.

Non-Hodgkin's lymphoma (NHL) has been increasing in frequency in the industrialized world, but the environmental and genetic factors that contribute to susceptibility are not known. B-cell lymphomas represent a major cause of morbidity and mortality in HIV-infected individuals. The identification of a deletion in the CCR5 chemokine receptor gene that alters the risk for infection and progression to AIDS led us to examine a potential role of this gene in AIDS lymphoma. A matched case-control analysis was performed using all eligible NHL cases in the Multicenter AIDS Cohort Study. Patients were matched for age, study center, time AIDS-free, and slope of the CD4+ T-cell decline. The CCR5-delta32 allele was found to be associated with a 3-fold lower risk of NHL among individuals after controlling for time of infection and progression toward AIDS. The CCR5 gene was not associated with a difference in risk for Kaposi's sarcoma, another common malignancy in AIDS patients, or opportunistic infections. Costimulation of normal phorbol 12-myristate 13-acetate-treated B cells with the CCR5 ligand RANTES induced a proliferative response, indicating that RANTES is a mitogen for B cells. Taken together, these findings suggest that the CCR5 gene plays a role in the risk of NHL in HIV-infected patients, perhaps through a mechanism involving a decreased response of B cells to the mitogenic activity of RANTES.

Inhibitory effects of interferon on mouse megakaryocytic progenitor cells in culture.

Mouse bone marrow cells were grown in plasma clots, megakaryocyte formation was stimulated with human urinary erythropoietin (Ep). The expression of megakaryocyte colony forming units (CFUM) and of single megakaryocyte forming units (M) was evaluated after seven days in culture. Usually ten times more M than CFUM were found. Megakaryocytic colony formation showed a linear dependence on cell dose from 0.5 to 2 X 10(5) cells/clot. The colony size frequency distribution exhibited a single peak in the two-cell size class, followed by a continuous decrease, suggesting that cell division may occur asynchronously in cells making up a colony. Mouse L cell interferon (IF) in doses from 10 to 1000 U/ml was included in clots together with Ep. This resulted in a biphasic, dose dependent reduction of colony formation and of single megakaryocyte formation. At all doses tested CFUM were more sensitive to IF than M. These observations are best explained by a differential inhibitory effect of IF on replication of two or more classes of megakaryocytic progenitor cells.

Biochemical pharmacology of zidovudine in human T-lymphoblastoid cells (CEM).

HIV is the causative agent of AIDS. The purpose of this study was to examine the biochemical pharmacology of the anti-viral agent zidovudine (AZT) in the T-cell origin line (CEM). We have shown that zidovudine is activated by thymidine kinase (TK) in CEM cells to the triphosphate anabolite, which is incorporated into DNA. One microM zidovudine is sufficient for saturation of activation by TK and also of zidovudine monophosphate, by thymidylate kinase, to the diphosphate. Zidovudine triphosphate peaked 4 h after initiation of drug administration in CEM cells and then declined biexponentially. Nucleoside triphosphate (NTP) cellular concentrations declined rapidly in the cells after exposure to zidovudine. Concomitantly phosphorylation of zidovudine to zidovudine monophosphate and zidovudine monophosphate to zidovudine diphosphate declined in a similar manner in the CEM cells. The amount of zidovudine anabolite incorporated into purified DNA peaked 1 h after zidovudine treatment and declined thereafter with first order elimination kinetics. These studies elucidate the cellular activation of zidovudine in a T-cell line, CEM, and enhance our understanding of this important anti-HIV drug.

Hemophilia therapy innovation: development of an advanced category recombinant factor VIII by a plasma/albumin-free method. Proceedings of a Special Symposium at the XIXth Congress of the International Society on Thrombosis and Haemostasis, July 12-18, 2003, Birmingham, UK.

Replacement therapy for hemophilia A has evolved from the early use of whole blood, citrated plasma, and cryoprecipitate, to purified factor VIII (FVIII) concentrates, first derived from plasma, then produced by recombinant DNA technology. Recombinant FVIII (rFVIII) concentrates have provided improved safety for patients with hemophilia A since they significantly reduce the risk of transmission of blood-borne infections. Nevertheless, human- or animal-derived plasma proteins are still included at some step in preparation of all previously licensed rFVIII, thereby introducing the potential for transmission of human or animal pathogens. Anti-hemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM), a novel advanced category rFVIII produced without the addition of human or animal plasma proteins, has been developed with the goal of providing the greatest possible margin of safety to hemophilia patients. This report, based on a symposium of the XIXth International Society on Thrombosis and Haemostasis Congress, provides an overview of the rAHF-PFM development program as well as current findings from the global clinical evaluation of rAHF-PFM in pediatric and adult previously treated patients.

Evidence of in vitro development of drug resistance to azidothymidine in T-lymphocytic leukemia cell lines (Jurkat E6-1/AZT-100) and in pediatric patients with HIV-1 infection.

Clinical reports indicate that the development of drug resistance to AZT after chronic administration is common. In order to study this phenomenon, the T-cell line Jurkat E6-1 was treated continuously in vitro with low, gradually increased, concentrations of azidothymidine (AZT). Initially, 1 microM AZT significantly retarded the cell line from reaching confluence. However, after 10 weeks the T-cell line was able to grow in 10 microM AZT without any evidence of growth inhibition. Subsequently, cell isolates could grow continuously in the presence of 20, 50, and 100 microM AZT without growth inhibition. These T-cell lines (Jurkat E6-1/AZT-10, Jurkat E6-1/AZT-20, Jurkat E6-1/AZT-50, and Jurkat E6-1/AZT-100) were tested for AZT anabolism using purified [3H]AZT, and the results were compared to the wild-type untreated Jurkat E6-1 cell line. Similar intracellular AZT anabolites concentrations were determined in all cell lines. However, a four- to sixfold lower cellular concentration of mono-, di-, and triphosphate anabolites of AZT was determined in the Jurkat E6-1/AZT-10 cell line after 1 microM AZT incubation and 6.5-fold lower after 10 microM AZT treatment. In general, a five- to sixfold reduction in the phosphorylation rates were estimated in the AZT resistant T-cell line. Pharmacology studies of [3H]AZT in the Jurkat E6-1/AZT-100 cell line showed a much lower level of activation of the pro-drug (28-fold), due to lack of thymidine kinase (TK) activity when compared to the Jurkat E6-1/AZT-10 T-cell line. A similar level of resistance was obtained at the thymidylate (dTMP) kinase level. Concurrently an additional mode of resistance (407-fold) was seen on the incorporation of the AZT triphosphate anabolite (AZTTP) into cellular DNA. The formation of this cell line in a period of < or = 4 months coincides with the evidence of the clinical development of "resistance" to AZT in patients who receive the drug continuously. In addition, these T-cell lines have been infected with HIV, and studies on the development of collaterally sensitive regimens are under way.

HIV and hemophilic children's growth.

The acquired immune deficiency syndrome (AIDS) often has profound effects on growth; however, the effects of human immunodeficiency virus (HIV) on asymptomatic children's growth are unknown. Before heat inactivation/HIV donor screening of factor concentrates, many hemophilic children became infected with HIV. We evaluated four hemophilic groups without AIDS, using age-standardized growth parameters: group 1, 41 HIV-seropositive children (median age of 13 years); group 2, 11 HIV-seronegative children (median age of 4 years); group 3, 20 children frequently receiving concentrates, evaluated before 1979 (median age of 9 years); and group 4, 11 children rarely receiving concentrates, evaluated before 1979 (median age of 6 years). Median height for age (HA), weight for age (WA), and weight for height (WH) of groups 1 and 2 exceeded the 50th percentile of referent norms. HA, WA, WH, and weight/height did not vary significantly by group, nor did these decline over periods of 11 to 70 months. However, for those less than 11 years of age in group 1, HA declined by 25 percentile points over at least a 3 year period. Also, group 1's T helper-to-suppressor cell ratios at 12 +/- 3 months following the latest growth evaluation were positively associated with both HA and WA at the last evaluation. Eight children were evaluated before 1979 and again after they seroconverted to HIV.(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous infusion of low-dose urokinase in the treatment of central venous catheter thrombosis in infants and children.

Thrombotic occlusion is a frequent complication associated with the use of central venous catheters. The purpose of this study was to evaluate the efficacy of a continuous infusion of low-dose urokinase (200 U/kg/h) in clearing catheters that had not cleared after two bolus doses of urokinase in a pediatric oncology population. Fifty-eight incidents of catheter-related occlusions (49 Hickman-type catheters/nine implantable ports) as documented by radiographic dye study occurred in 227 pediatric oncology patients with 254 central venous catheters during a 1-year period. Fourteen of 58 catheters failed to clear after two bolus instillations of urokinase (5,000 U and 10,000 U). Thirteen catheters were treated for 24 hours with urokinase, 200 U/kg/h, and one catheter with urokinase, 100 U/kg/h for 24 hours. Twelve catheters were used for study. Coagulation studies were monitored preinfusion, 12 hours into the infusion, and postinfusion. Patency was reestablished in 11/12 catheters (92%) with a mean infusion time of 28.7 hours. No coagulation abnormalities or clinical bleeding associated with the urokinase infusion occurred. Only one patient exhibited a prolonged partial thromboplastin time (greater than 150 seconds); this was associated with a heparin effect. These data indicate that low-dose urokinase may be a safe and effective means to clear occluded central venous catheters in children.

Severe antithrombin III deficiency in an infant associated with multiple arterial and venous thromboses.

Inherited antithrombin III (AT-III, heparin cofactor) deficiency is a rare condition, presenting with thrombotic disease in adult life. This paper reports an 8 months old South African Black male infant with multiple large vessel venous and arterial thromboses, and E. coli septicaemia. This was associated with an extremely low plasma AT-III level. Micronodular cirrhosis and intracytoplasmic hyaline globules in the liver cells were present. These globules were eosinophilic, and PAS-positive after diastase. They measured approximately 5 mu to 30 muin diameter, occurred singly in the liver cells and were located mainly in the periportal areas. The histological findings in the liver are similar to those observed in alpha 1-antitrypsin (AAT) deficiency in which the intracytoplasmic globules represent accumulation of altered AAT. Immunochemical studies carried out on formalin fixed tissue failed to detect cross reaction material with anti-alpha 1 antitrypsin or anti-AT III antiserum. This is the first case report of AT-III deficiency presenting in infancy. It is also the first case associated with distinctive liver pathology. The available data presented are insufficient to distinguish between an inborn defect and acquired caused of the severely depressed AT-III plasma level and the distinctive liver pathology.

The reversible antithrombin activity of incubated plasma.

The thrombin time of normal citrated plasma is progressively prolonged on incubation in open glass tubes at 37 degrees C. The phenomenon is dependent on the temperature and duration of incubation, on the pH, and on the concentration of calcium ions present. Platelet-rich citrated plasma fails to exhibit augmented antithrombin activity when similarly incubated, and the addition of washed platelets to platelet-poor plasma inhibits this activity. The clot retarding action of incubated plasma against thrombin is also manifested against Arvin (Ancrod), but not against Reptilase-R. This thrombin time lengthening may be inhibited by incubation with anti-antithrombin III antiserum thus indicating that the phenomenon of thrombin time lengthening is consistent with enhanced activity of antithrombin III. It is unlikely that alterations in the activity of alpha2-macroglobulin, is important in the reduced thrombin-coagulability of incubated plasma. Interference with the polymerisation of fibrin monomers by the physico-chemical changes may contribute to the observed phenomenon.

Dialysis and renal transplant in a hemophiliac.

Hemodialysis was initiated in a mild-moderate hemophiliac at 15 years of age. Hematuria had been a frequent and persisting feature from the age of five years without documented cause. Anemia and proteinuria was first detected at 13 years. A cadaver donor renal transplant was carried out after three months of hemodialysis. Massive intravesical bleeding complicated the immediate post-transplantation period. The allograft rejected after three months and the patient was maintained for eight years on home hemodialysis. A second cadaver donor allograft was carried out at 23 years of age. Again, massive intravesical hemorrhage was a problem post-transplant. The allograft is currently functioning 27 months post-transplant. Factor VIIIc activities have fluctuated between 5% and 40% in the absence of factor infusions.

A multicenter study of recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A. The Recombinate Previously Treated Patient Study Group.

A prospective, open-label multicenter investigation has been conducted to compare pharmacokinetic parameters of recombinant DNA-derived FVIII (rFVIII) and plasma-derived FVIII concentrate (pdFVIII) and to assess safety and efficacy of long-term home-treatment with rFVIII for subjects with hemophilia A. Following comparative in vivo pharmacokinetic studies, 69 patients with severe (n = 67) or moderate (n = 2) hemophilia A commenced a program of home treatment using rFVIII exclusively for prophylaxis and treatment of all bleeding episodes for a period of 1.0 to 5.7 years (median 3.7 years). The mean in vivo half-lives of rFVIII and pdFVIII were both 14.7 h. In vivo incremental recoveries at baseline were 2.40%/IU/kg and 2.47%/IU/kg, respectively (p = 0.59). The response to home treatment with rFVIII was categorized as good or excellent in 3,195 (91.2%) of 3,481 evaluated bleeding episodes. Thirteen patients received rFVIII for prophylaxis for twenty-four surgical procedures. In all cases, hemostasis was excellent. Adverse reactions were observed in only 13 of 13,591 (0.096%) infusions of rFVIII: none was serious. No patient developed an inhibitor to rFVIII.