Immune Tolerance Induction Treatment Research Articles

Immune Tolerance Induction Treatment Is Cost-Effective in Adult Patients with Long-Standing High-Responding Inhibitors

Introduction: Despite treatment of hemophilia having achieved considerable improvement over the last decades, inhibitor development remains a major complication for these patients. Inhibitors are alloantibodies that neutralize factor (F) VIII coagulation activity, and occur in approximately 25% of hemophilia A patients. Immune tolerance induction (ITI) is the choice therapy to eradicate these antibodies. There are several ITI protocols with similar success rates, approximately 70%. The presence of long-standing inhibitors in the adult population has usually been associated with poor ITI outcome. In Brazil, as in other countries with constrained resources, limited access to factor concentrates prevented the use of ITI. Thus, almost all patients with inhibitors remained a long time with this complication. Only after 2013 with increased availability of factor concentrates in the country, has assured long-term prophylaxis and ITI treatment been possible.Objective: This study aimed to describe the Brazilian experience in managing ITI in adult patients from seven Hemophilia Treatment Centers with long-standing inhibitor using bypassing agents to control bleeding episodes, considering bleeding frequency, treatment barriers and economic impact of therapy.Patients and Methods: We retrospectively analyzed clinical and laboratory data of hemophilia A patients with high-responding inhibitors (peak titer > 5 Bethesda Unit (BU), anamnestic response to FVIII) over 18 yo who underwent ITI treatment and were using bypass agents before ITI. The initial ITI protocol used was low-dose FVIII concentrate (25-50 IU/kg 3x/week)Results: In Brazil, since the availability of ITI, 39 adult hemophilia A patients with inhibitors, have been submitted to ITI for the first time. In this study, we accessed data from 26 patients, of these 13 (50%) already achieved complete ITI success criteria (inhibitor titer < 0.6 BU; FVIII recovery ≥ 66%, and half-live ≥ 6 h). Another 4 patients with ongoing ITI achieved inhibitor titer < 5 BU and are no longer using bypassing agents. Thus, 17/26 (65%) patients discontinued the bypassing agents in a median period of 2 mo (range 0 to 18 mo) after starting ITI. After 24 months of irregular treatment 2 patients abandoned ITI protocol. Analyses of the 13 patients with complete success revealed mean age at first reported inhibitor of 16.21y (SD ± 11.6; median 21y, range 0.7 to 37y), and mean age at ITI onset of 31.2y (SD ± 10.6; median 27y, range 19 to 47y). The mean period from the first inhibitor detected until starting ITI was 15y (SD ± 5.1), with a 16y median (range 7 to 22y). The historical peak inhibitor mean was 53.1 BU (SD ± 49.5; median 39.4 BU, range 5.5 to 163 BU). The mean pre ITI inhibitor titer was 6.6 BU (SD ± 5.5; median 5.5 BU, range 0.6 to 20.8 BU). Low-dose ITI protocol was initially used for all patients, however 3 patients had the dose increased during treatment (100 IU/kg from 3 to 7 x/week). During ITI, 10/13 patients received prophylaxis with bypassing agents, and 9 began prophylaxis before ITI started. The mean time to achieve inhibitor titer < 0.6 BU was 11.6 mo (SD ± 12.5; median 7 mo, range 0.5 to 44 mo). All 13 patients achieved other ITI success criteria. However, a delay was observed in the majority of patients in FVIII recovery and half-life. Regarding clinical outcome, we observed a significant reduction in both, annualized bleeding rate (ABR), and annualized joint bleeding rate (AJBR), comparing 12 months before ITI, during ITI, and after achieving complete success (figure 1). Regarding economic evaluation, we observed a significant reduction in the median cost of clotting factor consumption, comparing 12 months before starting ITI, and the following years after achieving ITI success. No significant difference was observed between the median cost of 12 months before, and ITI period (figure 2).Conclusion: This study indicated that this treatment is worthwhile even for inhibitor patients with poor prognostic factors for ITI considering both effectiveness to control and prevent bleeding episodes, and economic impact. In this group, 65% of adult hemophilia A high-responding inhibitors patients stopped using bypassing agents after a median period of 2 months after starting ITI. Despite being a high cost treatment, ITI can be cost-effective, especially for patients using bypassing agents. These results reinforce the positive impact of the ITI even in long time inhibitor adult patients. [Display omitted] [Display omitted] DisclosuresOzelo:Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Biogen: Research Funding.

Immune tolerance induction in patients with haemophilia a and inhibitors: effectiveness and cost analysis in an European Cohort (The ITER Study).

Although immune tolerance induction (ITI) is considered the first choice treatment to eradicate inhibitors in haemophilia A patients, little is known about outcomes determinants and cost magnitude. A retrospective, multicentre study was conducted to assess the relationship between ITI outcome, clinical and treatment characteristics and cost of ITI treatment in haemophilia A patients. Data from 12 months before inhibitor diagnosis to 12 months after ITI completion were collected. Treatment cost was calculated in the third-party perspective and expressed as mean € per patient-month. Cox regression models were used to identify predictors of better outcome and the time taken to achieve tolerance. Seventy-one patients, aged 0.4-41 years (median: 3.8 years) at ITI start, were enrolled. Undetectable inhibitor was achieved in 84.5% of patients and inhibitor eradication with normal factor VIII (FVIII) pharmacokinetics in 74.2%. Median time to successful tolerance was 10.7 months (range 2.0-90.0 months). Peak inhibitor level on ITI was a significant predictor of ITI success. Breakthrough bleeding event incidence during ITI was associated with time to success. The mean cost of treatment for the time period between inhibitor diagnosis and ITI start was €3188 per patient-month (92.1% for bypassing agents), and €60 078 during ITI (76.8% for FVIII use in ITI). Immune tolerance induction in this patient cohort was successful in 84.5% of patients with a mean cost of €60 000 per patient-month. This high cost is dwarfed by comparison with the prospect of lifelong care of an inhibitor patient, in addition to gains in life expectancy and health-related quality of life.

Immune tolerance induction in patients with severe hemophilia A with inhibitors.

BackgroundInhibitory antibodies to factor VIII (FVIII) are an important complication when managing patients with hemophilia A. Immune tolerance induction (ITI) has been regarded as a useful method for eradicating inhibitors. We report the results of a retrospective study in Korean patients with hemophilia A who underwent ITI.MethodsWe reviewed the records of patients with hemophilia A with inhibitors who underwent ITI from March 2004 to December 2014. ITI was started with FVIII concentrates at 100 IU/kg, 3 times per week. The dose of FVIII was reduced according to the inhibitor titer and recovery of FVIII. Inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life.ResultsIn total, 17 patients with severe hemophilia A were evaluated. Complete tolerance was achieved in 14 of 17 patients (83%). The mean peak inhibitor titer before ITI was 38.4 BU/mL. The mean treatment duration was 26.2 months. The mean duration between inhibitor detection and ITI was 5.1 years in the complete tolerance group and 10.8 years in the partial tolerance and failed group.ConclusionThis study shows that ITI can be an effective and well-tolerated method for eradicating inhibitors. Possible influencing factors for ITI success were age at the start of ITI treatment and duration after inhibitor detection. More research to provide further insight about other factors and conditions is needed.

New predictive approaches for ITI treatment.

Immune tolerance induction (ITI) therapy in patients with haemophilia A and inhibitors constitutes a huge burden for affected patients and families and poses a large economic burden for a chronic disease. Concerted research efforts are attempting to optimize the therapeutic approach to the prevention and eradication of inhibitors. The Italian ITI Registry has provided data on 110 patients who completed ITI therapy as at July 2013. Analysis of independent predictors of success showed that, together with previously recognized factors - namely inhibitor titre prior to ITI, historical peak titre and peak titre on ITI - the type of causative FVIII gene mutation also contributes to the identification of patients with good prognosis and may be useful to optimize candidate selection and treatment regimens. Numerous studies have demonstrated that inhibitor reactivity against different FVIII products varies and is lower against concentrates containing von Willebrand factor (VWF). An Italian study compared inhibitor titres against a panel of FVIII concentrates in vitro and correlated titres with the capacity to inhibit maximum thrombin generation as measured by the thrombin generation assay (TGA). Observations led to the design of the PredictTGA study which aims to correlate TGA results with epitope specificity, inhibitor reactivity against different FVIII concentrates and clinical data in inhibitor patients receiving FVIII in the context of ITI or as prophylactic/on demand treatment. At the immunological level, it is known that T cells drive inhibitor development and that B cells secrete FVIII-specific antibodies. As understanding increases about the immunological response in ITI, it is becoming apparent that modulation of T-cell- and B-cell-mediated responses offers a range of potential new and specific approaches to prevent and eliminate inhibitors as well as individualize ITI therapy.

When is enough…enough? Developing consensus of definition of failure of immune tolerance induction in patients with haemophilia and inhibitors.

Immune tolerance induction (ITI) is the preferred management of haemophilia A patients who develop high titre inhibitors against factor VIII. However, the optimal ITI regimen, predictors of ITI outcome and definitions of successful and unsuccessful ITI remain unclear. The aim of this project was to develop a consensus on the definition of ITI treatment failure for Australian clinical practice using a modified Delphi approach. Three consecutive surveys were distributed to the directors of 17 haemophilia treatment centres in Australia. Participants were asked to rate their agreement with definitions of ITI treatment failure generated from a literature review. Thirty-five statements regarding ITI achieved consensus (majority agree or strongly agree) during the three survey rounds. After round 3, four statements achieved majority disagreement, and for two statements no consensus was reached. Our study demonstrates that clinicians in Australia necessitate an arbitrary time to assess ITI failure, but that clinical outcomes of ITI are important in assessing response. Assessment over any 3- to 6-month period without a 20% reduction in inhibitor titre is suggestive of failure, but a reduction in bleeding phenotype alone may be sufficient to continue ITI. Overall, a period of 3 or 5 years of ITI may be required to determine response to ITI. Documentation of improvement in clinical measures, supported by the laboratory features of factor VIII inhibitor levels and pharmacokinetics, is essential in assessing the success of failure of ITI in these patients.

Therapeutic management and costs of severe haemophilia A patients with inhibitors in Italy.

Haemophilia A (HA) patients with high responding inhibitors require therapies with bypassing agents to control bleedings or Immune Tolerance Induction (ITI) to attempt inhibitor eradication and restore FVIII therapy. The aim of this study was to assess the therapeutic management and product consumption of HA inhibitor patients and the relative costs in Italy. A retrospective survey was performed utilizing data from the National Registry of Congenital Coagulopathies and from a specific questionnaire on product consumption of HA inhibitor patients over the year 2011. Among HA patients, 10% had currently detectable inhibitors; 24% of patients were undergoing ITI (mostly children) and 76% utilized bypassing agents. Patients on ITI consumed 45,000,000 IU of FVIII (median consumption/patient of 1,200,000 IU year(-1)). Patients receiving bypassing agents utilized 21,000,000 IU of aPCC (median consumption/patient of 360,000 IU year(-1)), and 38,000 mg of rFVIIa (median consumption/patient of 440 mg year(-1)). The annual cost/patient on ITI and on bypassing agents therapy was analysed. Recombinant products represented the product of choice for children therapies in >90% of the cases. FVIII prophylaxis of severe HA patients without inhibitor costs about half than therapy with bypassing agents and is three times less expensive than prophylaxis with such agents. Therefore, the possibility to restore FVIII prophylaxis, having eradicated the inhibitor through ITI, can justify the high costs of ITI treatment needed in the short term. Consistent with this notion, over the last years a 50% increase in the number of patients undergoing ITI in Italy was registered.

Economic Comparison Of Treating Hemophilia Patients Who Have Developed Inhibitors Via Immune Tolerance Induction Versus Prophylaxis and On-Demand Treatment With Bypassing Agents

▪ ObjectiveThe most serious complication of treatment for patients with severe hemophilia A is the development of FVIII alloantibody inhibitors. Treating hemophilia is expensive at best; however, incurring an inhibitor substantially increases those costs. As a result, a cost-efficient strategy for treating patients with inhibitors is desirable. Three approaches have been used to treat patients with inhibitors: 1) administer bypassing agents such as activated prothrombin complex concentrate (aPCC) or activated recombinant factor VII (rFVIIa) only when a bleed occurs (on-demand); 2) administer bypassing agents prophylactically to prevent bleeds from occurring; or 3) initiate immune tolerance induction (ITI) with factor VIII (FVIII) concentrate in an attempt to eradicate the inhibitor and then long term follow up with a lower dose prophylaxis regimen to maintain the inhibitor free status. In this study, we compare the costs and outcomes of these treatment strategies in order to assist healthcare providers in making more informed treatment decisions. MethodsA decision-analytic model (Figure 1) was developed to compare commonly used treatment regimens for severe hemophilia A patients with inhibitors over the course of an average patient's lifetime. On-demand patients were treated for their acute bleeding events with a conventional dose of rFVIIa (based on the FENOC study, a mean of 105 µg/kg) administered every 2-3 hours until the bleed stopped. Patients treated prophylactically received 85 IU/kg of aPCC 3 times per week (from Pro-FEIBA study). The International Immune Tolerance Study compared ITI treatment with either a low dose (50 IU/kg 3 times a week) or a high-dose regimen (200 IU/kg daily) of FVIII concentrate. The high dose regimen was selected for inclusion in this decision-analytic model due to its more rapid induction of immune tolerance with fewer break-through bleeds. When ITI was successful, FVIII replacement dosing was resumed at a prophylactic level (30 IU/kg FVIII 3 times per week). Data from the International and North American ITI Registries were used to estimate the success of inhibitor eradication on ITI. Relapse of inhibitors was assumed to occur in 15% of patients 15 years after inhibitors had been eradicated. Patients who failed primary and secondary ITI or who succeeded and then relapsed were treated prophylactically with bypassing agents (85 IU/kg of aPCC 3 times per week). The rate of reduced bleeding events for patients on prophylaxis was derived from the results observed in previously published clinical studies. The lifetime projections of product dosing requirement considered changes in patient weight over time. Life expectancy was modeled via US life tables and an increased risk of death was ascribed to the presence of inhibitors (as per CDC data reported by Soucie). Costs were obtained from standard US costing sources and are reported in 2013 US dollars. Hemophilia-specific utility weights were estimated from the published literature. Costs and outcomes were discounted at 3% per annum. [Display omitted] ResultsTreating patients with inhibitors via an ITI approach can successfully eradicate the inhibitors 74% of the time. Based on the model, the estimated lifetime costs of treating patients with inhibitors was substantially lower for the ITI approach compared with either treating on-demand or prophylactically with bypassing agents (discounted costs of $22,201,832 versus $38,656,756 and $42,104,865, respectively). In addition, patients treated via ITI are projected to live longer (74.3 years versus 69.6 and 69.6 years, respectively) and have greater discounted quality-adjusted life years (25.1 versus 14.7 and 20.5, respectively). Patients treated via ITI or prophylactically with bypassing agents incur less than half the number of bleeding events over their lifetime compared to patients treated via on-demand therapy (801 and 694 versus 1,819 bleeding events). ConclusionTreating patients via ITI in an attempt to eradicate inhibitors results in lower lifetime costs and a greater number of life years and quality-adjusted life years than when treating on-demand or prophylactically with bypassing agents. Disclosures:Earnshaw:RTI Health Solutions: Employment, Grifols has contracted RTI-HS to do research Other, Research Funding. McDade:Grifols: Research Funding. Spears:Grifols Inc: Employment. Kessler:Baxter: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Grifols: Consultancy, Research Funding; Biogen-Idec: Consultancy; Octapharma: Consultancy, Research Funding; NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy.

High rate of spontaneous inhibitor clearance during the long term observation study of a single cohort of 524 haemophilia A patients not undergoing immunotolerance.

BackgroundThe natural history of inhibitors in patients with haemophilia A not undergoing immune tolerance induction (ITI) is largely unknown. A recent randomized controlled trial suggests that the higher the FVIII dose used for ITI, the faster the clearance and the lower the rate of bleeding, without any difference in the rate of tolerance. We aimed at assessing the rate of spontaneous inhibitor clearance in a large cohort of patients not undergoing ITI.MethodsA retrospective analysis of anti-FVIII inhibitors of long-term registry data in a single centre cohort of 524 haemophilia A patients considered for synovectomy was performed. Patients were tested for inhibitors before and 15 days after any and each surgical episode and thereafter did not undergo immune tolerance at any time.ResultsThe cumulative incidence of inhibitors overall was 34% (180 out of 524) with the highest percentage of 39% (168 out of 434) in severe patients which represented 83% of the cohort. Among the 180 inhibitor patients: 63 had permanent inhibitors; 70 fulfilled current criteria for transient inhibitors but a third category of 47 additional patients cleared the alloantibody spontaneously in >6 months. At logistic regression, both the inhibitor titre and the gene mutation were shown to predict time to clearance.ConclusionsSpontaneous clearance of inhibitors over variable time in the absence of ITI treatment was found in up to 2/3 of the cases.

Immune tolerance induction in haemophilia A patients with inhibitors by treatment with recombinant factor VIII: a retrospective non‐interventional study

Immune tolerance induction (ITI) can overcome inhibitory factor VIII (FVIII) antibodies in haemophilia A patients receiving FVIII replacement therapy. The objective was to evaluate the use of sucrose-formulated, full-length recombinant FVIII (rFVIII-FS) for ITI therapy. Patients (<8 years at ITI start) with severe haemophilia A and a peak inhibitor titre >5 Bethesda units (BU) who underwent ITI with any rFVIII-FS dose for ≥ 9 months (or until success) were eligible for this retrospective study. Efficacy analyses included descriptions of ITI treatment regimens and outcomes; ITI success was determined solely at the discretion of the investigator. Safety analyses included assessment of adverse events. Of 51 enrolled patients, 32 [high dose (≥ 85 IU kg(-1) day(-1)), n = 21; low dose, n = 11] were eligible for analysis. ITI was successful in 69% (22/32) of patients (high dose, 66.7%; low dose, 72.7%) after a median of 1.4 years (range, 0.1-3.6 years). Influencing factors for ITI success were start of ITI <1 year after inhibitor detection and an inhibitor titre <10 BU at ITI start. All patients successfully tolerized with ITI continued to receive rFVIII-FS prophylaxis as maintenance therapy, with no inhibitor recurrence from the end of ITI until study enrolment. Use of rFVIII-FS for ITI was effective and well tolerated; success rates were similar to those in published studies.

Venous access in haemophilic children: choice and management

Current haemophilia treatment in children is based on regular intravenous infusions of concentrates for prolonged periods, according to prophylaxis regimens or immune tolerance induction treatment, in cases of inhibitor development. Therefore, a stable and uncomplicated venous access is required and as such peripheral veins represent the preferred option. However, frequent infusions in the home setting can be problematic in very young children and for this reason, central venous access devices (CVADs) have been widely used to improve treatment feasibility. Unfortunately CVADs' use is associated with a high rate of complications, and infections and thrombotic occlusion can influence treatment outcome by causing unwanted treatment interruption. CVADs can be grouped into three main categories: external non-tunnelled, external tunnelled and fully implantable devices known as ports. The management of CVADs at home often represents a challenge because a strict adherence to sterile procedures is required. Indeed, the incidence of infections with ports is much lower than that reported for external devices; however, ports carry the inconvenience of needle sticks. More recently, arteriovenous fistula was shown to be a suitable alternative to CVADs because it is easy to use and is associated with a lower rate of complication.

Improved treatment feasibility in children with hemophilia using arteriovenous fistulae: the results after seven years of follow-up

An easy and stable venous access is essential in hemophilic children who receive regular prophylaxis or immune tolerance induction treatment. Central venous access devices improve treatment feasibility, but their use is complicated by infection and/or thrombosis. Arteriovenous fistula (AVF) has been evaluated as an alternative to central venous access devices in hemophilic children since 1999. This study provides results obtained in a large series after seven years of follow-up. From 1999 to 2008, 43 procedures were performed in 38 children (median age: 2.7 years). Thirty-five AVFs (81%) achieved maturation after a median of 58 days and were used for a median of five years (range: 0.4-8.5). A brachial artery caliber larger than 1.2 mm was associated with successful maturation (p<0.05). Complications with some impact on arteriovenous fistula use or duration were observed in 14/43 procedures (32%) and in 13/38 children (34%). Age at arteriovenous fistula creation was younger in children who lost arteriovenous fistula patency (p<0.05) and aneurysms were more frequent in children who were on daily treatment regimen and thus had a greater cumulative number of arteriovenous fistula accesses (p<0.05). At the end of the follow-up period, 22 AVFs were still in use and 9 had been surgically dismantled. Arteriovenous fistula use allowed long-term prophylaxis (up to 8.5 years) in 11 children and the completion of immune tolerance induction without interruptions in 18 children. This study confirms the feasibility of arteriovenous fistula with an acceptable rate of complications and suggests that its use is particularly favorable in children with inhibitors in whom it should be considered as first-choice venous access.

VWF/FVIII concentrates in high‐risk immunotolerance: the RESIST study

Immune tolerance induction (ITI), through the regular infusion of coagulation factor concentrates over a time period ranging from 1 to more than 24 months, is successful in about 75% of high responders. Among the issues of ITI treatment that are still open, the choice of the product to use is one of the most difficult. In fact, common practice is to start with the same product that induced the inhibitory response, but recent findings indicated that plasma-derived products containing large amounts of von Willebrand factor (VWF) can play a positive role. Two retrospective cohorts in Germany and in France and one prospective cohort have shown a high rate of success when VWF/factor VIII (FVIII) products are used to induce ITI. For these reasons, two prospective studies have been planned to complement the international ITI study already started: an observational study in patients who had already experienced a failure with a VWF-free FVIII concentrate, called RESIST(exp) (experienced); a randomized, controlled study in patients who have never tried an ITI treatment before and at high risk to fail, called RESIST(naïve) (naïve).

Inhibitors in haemophilia A: current management and open issues

The incidence of inhibitors in haemophilia A is 21-33%. The development of inhibitors to factor VIII (FVIII) is one of the most serious complications in haemophilia therapy and is an important challenge in haemophilia care. The main short-term objective of the treatment of haemophilic patients with inhibitors is to control bleeding episodes, and the long-term one is to eradicate the inhibitor by means of immune tolerance induction (ITI). The choice of treatment for bleeding in inhibitor patients is dictated by the current inhibitor titre, the severity of the bleed and the previous anamnesic response to FVIII. In low responder inhibitor patients the best treatment is large doses of concentrates of FVIII to attain haemostatic levels of the factor infused. The same approach can also be considered in high responders who have a temporarily low inhibitor level and major haemorrhage. High responders patients with high inhibitors titre or with minor haemorrhage must be treated with bypassing agents, such as FEIBA (factor VIII inhibitor bypassing activity) or recombinant activated FVII (rVIIa); there is no agreement which of both agents should be chosen in the different clinical situations. Only in patients waiting to start ITI treatment the rFVIIa use is clearly recommended, in order to avoide an anamnesic responce. In case of failure with this agents, extracorporeal immunoadsortion may be considered. All haemophiliac children who develop an inhibitor should be considered for ITI. The start of ITI should be deferred until the inhibitor has declined below 10 Bethesda units/mL (BU ml(-1)) where possible. Starting the treatment when inhibitor titre is below 10 BU ml(-1) is the strongest predictor of success. However, there are many other points to clarify: recommended FVIII doses in the ITI; if the results can be affected by concomitant infections during ITI; if there are any differences using plasma derived or recombinant concentrates, even more if the plasma-derived concentrate contains large amounts von willebrand factor or not; age of starting the ITI and the delay in beginning it; if using immunosupresors can help in the treatment of patients with a bad prognosis; and when the treatment must be left in patients without a clear failure.

P050 Successful immune tolerance induction treatment of therapy-resistent acquired haemophilia with high inhibitor titer: a case report

P050 Successful immune tolerance induction treatment of therapy-resistent acquired haemophilia with high inhibitor titer: a case report

Current and Future Approaches to Inhibitor Management and Aversion

Immune tolerance induction (ITI) is the most common approach used to eliminate inhibitors that develop in hemophilia A patients following exposure to factor (F) VIII therapy. ITI generally requires ongoing long-term exposure to factor replacement therapy using FVIII or FIX. Although plasma-derived products have been the mainstay of ITI therapy in the past, recent data indicate that high-purity (i.e., recombinant) rFVIII products are probably equally effective. For patients who have failed to respond to ITI treatment, or for those at high risk to do so, immunosuppressive therapy may be helpful. Rituximab has demonstrated a possible clinical benefit in hemophilic and nonhemophilic patients developing FVIII inhibitors, but benefit in those with congenital hemophilia and inhibitors has not been established and more extensive clinical studies are needed. More recently, research on reducing the incidence of inhibitor development has included mutagenizing key epitopes of the FVIII antigenic molecule to alter its immunogenicity without affecting biological activity, as well as induction of tolerance by gene therapy with immunodominant A2 and C2 domains of FVIII presented by B cells as immunoglobulin fusion proteins.

Prophylactic Use of rFVIIa in a Young Hemophilia A Patient with Factor VIII Inhibitor.

The prevention of bleeding by prophylaxis regimen particularly for joint rehabilitation, could be considered a more effective treatment for hemophilia patients. In hemophiliacs with factor VIII inhibitor (F VIII inh) prophylaxis is not generally proposed because the bypassing agents for these patients may be less effective than F VIII concentrates. We report the regimen and results of a 6 months rFVIIa (Recombinant factor VIIa) prophylaxis, in a young hemophilia A patient (4 years old), with F VIII inh and immune tolerance induction (ITI) treatment and compared, with rFVIIa, the on demand treatment results for the 6 months prior to prophylaxis. After 2 years of a high dose regimen ITI, the FVIII inh titer was less than 50 BU and the immune tolerance treatment remains on going. Due to the development of a right knee target joint the rFVIIa prophylaxis was decided as an active rehabilitation approach to prevent the development of chronic arthropathy as well as to improve the quality of life of the child. During the 6 months period, prior to the initiation of rFVIIa prophylaxis 22 bleeds occurred i.e., 9 right knee hemarthrosis and 13 other joint bleedings and hematoma including elbow, wrist, ankle, foot, arm and chest. These bleeds were all treated with rFVIIa with a dose ranging from 100 to 200 μg/kg depending on the severity of the episodes and the duration of treatment ranged from 1 to 8 days. After 6 recurrent right knee hemarthrosis, a lavage of the joint was performed and prophylaxis with rFVIIa was subsequently initiated. A 120 μg/kg rFVIIa injection was performed 3 times a week concomitantly with the ITI treatment infusion and just before the physiotherapy course. During the 6 months of prophylaxis regimen we observed 9 bleeds with 3 major post traumatic bleedings which were treated by one 200 μg/kg/day rFVIIa injection which was resolved in one to three days. This prophylaxis treatment was effective for the arthropathy evolution and permitted the patient to return to school on a regular basis compared to the previous year. The total dose of on demand rFVIIa treatment used before prophylaxis was 458 mg/6 months. This amount decreased by 25% during the six months of prophylaxis with rFVIIa to reach 343 mg. The results of this significant observation led us to conclude that rFVIIa could be effectively used as prophylactic treatment in patients with FVIII inh and administered safely via a portacath device even in cases of high doses, as demonstrated in this young patient. This prevention approach resulted in a decrease of bleeding episodes, injections, and a significant improvement in the quality of life.