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Inhibitor clinical burden of disease: a comparative analysis of the CHESS data.

From Europe PMC via Jisc Publications Router.Publication status: PublishedBACKGROUND:Patients with hemophilia and inhibitors generally face greater disease burden compared to patients without inhibitors. While raising awareness of relative burden may improve the standard of care for patients with inhibitors, comparative data are sparse. Analyzing data drawn from the Cost of Haemophilia across Europe - a Socioeconomic Survey (CHESS) study, the aim of this study was to compare the clinical burden of disease in patients with severe hemophilia with and without inhibitors. Hemophilia specialists (N = 139) across five European countries completed an online survey between January-April 2015, providing demographic, clinical and 12-month ambulatory/secondary care activity data for 1285 patients. Patients with hemophilia who currently presented with inhibitors and those who never had inhibitors were matched on baseline characteristics via propensity score matching. Outcomes were compared between the two cohorts using a paired t-test or Wilcoxon signed-rank or McNemar's test. RESULTS:The proportion of patients who currently presented with inhibitors was 4.5% (58/1285). Compared to PS-matched patients without inhibitors, patients with inhibitors experienced more than twice the mean annual number of bleeds (mean ± standard deviation, 8.29 ± 9.18 vs 3.72 ± 3.95; p < .0001) and joint bleeds (2.17 ± 1.90 vs 0.98 ± 1.15; p < .0001), and required more hemophilia-related (mean ± standard deviation, 1.79 ± 1.83 vs 0.64 ± 1.13) and bleed-related hospitalizations (1.86 ± 1.88 vs 0.81 ± 1.26), hemophilia-related consultations (9.30 ± 4.99 vs 6.77 ± 4.47), and outpatient visits (22.09 ± 17.77 vs 11.48 ± 16.00) (all, p < .001). More than one-half (53.5%) experienced moderate/severe pain necessitating medication compared to one-third (32.8%) of patients without inhibitors (p = .01). CONCLUSIONS:Patients with hemophilia and inhibitors exhibited greater clinical burden and higher resource utilization compared to their peers without inhibitors. Strategies for improving the standard of care may alleviate burden in this population

The cost of severe haemophilia in Europe: the CHESS study

Background Severe haemophilia is associated with major psychological and economic burden for patients, caregivers, and the wider health care system. This burden has been quantified and documented for a number of European countries in recent years. However, few studies have taken a standardised methodology across multiple countries simultaneously, and sought to amalgamate all three levels of burden for severe disease. The overall aim of the ‘Cost of Haemophilia in Europe: a Socioeconomic Survey’ (CHESS) study was to capture the annualised economic and psychosocial burden of severe haemophilia in five European countries. A cross-section of haemophilia specialists (surveyed between January and April 2015) provided demographic and clinical information and 12-month ambulatory and secondary care activity for patients via an online survey. In turn, patients provided corresponding direct and indirect non-medical cost information, including work loss and out-of-pocket expenses, as well as information on quality of life and adherence. The direct and indirect costs for the patient sample were calculated and extrapolated to population level. Results Clinical reports for a total of 1,285 patients were received. Five hundred and fifty-two patients (43% of the sample) provided information on indirect costs and health-related quality of life via the PSC. The total annual cost of severe haemophilia across the five countries for 2014 was estimated at EUR 1.4 billion, or just under EUR 200,000 per patient. The highest per-patient costs were in Germany (mean EUR 319,024) and the lowest were in the United Kingdom (mean EUR 129,365), with a study average of EUR 199,541. As expected, consumption of clotting factor replacement therapy represented the vast majority of costs (up to 99%). Indirect costs are driven by patient and caregiver work loss. Conclusions The results of the CHESS study reflect previous research findings suggesting that costs of factor replacement therapy account for the vast majority of the cost burden in severe haemophilia. However, the importance of the indirect impact of haemophilia on the patient and family should not be overlooked. The CHESS study highlights the benefits of observational study methodologies in capturing a ‘snapshot’ of information for patients with rare diseases

Shorter survival of SDF1-3'A/3'A homozygotes linked to CD4+ T cell decrease in advanced human immunodeficiency virus type 1 infection

The SDF-1 3'A allelic polymorphism has been reported to influence either positively or negatively the progression of human immunodeficiency virus type 1 (HIV-1) disease. Therefore, the SDF-1 genotype of 729 HIV-1-infected individuals pooled from 3 distinct cohorts was determined. A statistically nonsignificant association between the SDF1-3'A/3'A genotype and accelerated disease progression was evident among seroconverters (n=319), but a striking correlation of decreased survival after either diagnosis of AIDS according to the 1993 definition or loss of CD4(+) T cell counts &lt;200 was observed. The relative hazards for SDF1-3'A/3'A homozygotes, compared with heterozygotes and wild-type homozygotes were 2.16 (P=.0047), for time from diagnosis according to the 1993 Centers for Disease Control and Prevention AIDS case definition (AIDS-'93) to death, and 3.43 (P=.0001), for time from CD4(+) T cells &lt;200 to death. Because no difference in survival was observed after diagnosis according to AIDS-'87, the association of the SDF1-3'A/3'A genotype with the accelerated progression of late-stage HIV-1 disease appears to be explained for the most part by the loss of CD4(+) T lymphocytes

Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors

BACKGROUND: Patients with severe hemophilia A and factor VIII inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Effective strategies to prevent bleeding in such patients have not yet been established. METHODS: We enrolled patients with hemophilia A who were older than 2 years of age, had high-titer inhibitors, and used concentrates known as bypassing agents for bleeding in a prospective, randomized, crossover study comparing 6 months of anti-inhibitor coagulant complex (AICC), infused prophylactically at a target dose of 85 U per kilogram of body weight (±15%) on 3 nonconsecutive days per week, with 6 months of on-demand therapy (AICC at a target dose of 85 U per kilogram [±15%] used for bleeding episodes). The two treatment periods were separated by a 3-month washout period, during which patients received on-demand therapy for bleeding. The primary outcome was the number of bleeding episodes during each 6-month treatment period. RESULTS: Thirty-four patients underwent randomization; 26 patients completed both treatment periods and could be evaluated per protocol for the efficacy analysis. As compared with on-demand therapy, prophylaxis was associated with a 62% reduction in all bleeding episodes (P<0.001), a 61% reduction in hemarthroses (P<0.001), and a 72% reduction in target-joint bleeding (?3 hemarthroses in a single joint during a 6-month treatment period) (P<0.001). Thirty-three randomly assigned patients received at least one infusion of the study drug and were evaluated for safety. One patient had an allergic reaction to the study drug. CONCLUSIONS: AICC prophylaxis at the dosage evaluated significantly and safely decreased the frequency of joint and other bleeding events in patients with severe hemophilia A and factor VIII inhibitors. (Funded by Baxter BioScience; Pro-FEIBA ClinicalTrials.gov number, NCT00221195.) Copyright © 2011 Massachusetts Medical Society

VWF/FVIII concentrates in high-risk immunotolerance : the resist studies

Background: Inhibitor eradication with immune tolerance induction (ITI) is the best long-term therapeutic strategy in Haemophilia A (HA) patients with inhibitors. Several parameters are known to be related to the ITI success. One that has more recently been proposed is the type of FVIII concentrate. Recent clinical findings indicate that plasma-derived FVIII products containing von Willebrand factor (VWF/FVIII) could have an impact on ITI success rate, even in poor prognosis patients. Study design: Two key prospective clinical studies have been designed to confirm the previous results supporting the use of VWF/FVIII in ITI: RESIST experienced (RESISTexp) and RESIST na\uefve (RESIST-na\uefve). RESIST: Exp is a prospective, nonrandomized study designed to assess rescue treatment with VWF/FVIII at high dosage (200 IU/kg daily) in patients who failed a previous ITI attempt with any dose of a VWF-free FVIII concentrate (plasma-derived or recombinant). RESISTna\uefve is a prospective, controlled, randomized, open-label study comparing two types of FVIII concentrates (VWF-free FVIII and VWF/FVIII) in their ability to induce tolerance in high responding HA patients, with no previous ITI attempt and with poor prognosis for success. Both types of concentrates will be administered at high dosage (200 IU/kg daily). Enrolment criteria are: severe haemophilia A (FVIII 5 BU), any inhibitor level at study enrolment, and at least one of the following risk factors for ITI failure: (a) peak inhibitor titer > 200 BU, (b) titer at ITI start > 10 BU, (c) age > 7 years, (d) time between inhibitor occurrence and ITI > 2 years. Patient undergoing concomitant immunosuppressive treatment are not eligible for either study. Primary end point is success in achieving ITI defined as: complete or partial. Secondary endpoints are: ITI maintenance, time to success, safety/compliance to treatment and cost of care. Conclusions: The results of RESIST studies will be crucial in understanding the role of VWF/FVIII in ITI outcome and will contribute to providing effective treatment for the devastating complication of FVIII antibody development in HA patient

Long-term safety and feasibility of arteriovenous fistulae as vascular accesses in children with haemophilia : a prospective study

Infectious and thrombotic complications limit the long-term use of subcutaneous ports as venous accesses for children with haemophilia. This study has evaluated for the first time the safety and feasibility of internal arteriovenous fistulae (AVF) as alternative accesses. During the 3-year study period, 27 severe haemophiliacs, 14 with factor VIII inhibitors (52%), underwent the creation of 31 proximal AVF in the forearm. Mild forearm haematomas were observed after five procedures (16%) in five patients who had or developed inhibitors after surgery. Inadequate AVF maturation was observed after five of 31 procedures (16%) in four children. AVF were first accessed after a median of 42 d and regularly used at home by 26 patients (96%) for a median follow-up period of 29 months. Thrombosis of a venous branch occurred in one AVF (3%) after 9 months of uncomplicated use in a child with inhibitor who spontaneously recovered from the symptoms and still used AVF for nine additional months. Mild symptoms, referable to distal ischaemia, were transiently reported by two children (7%) who needed no remedial intervention. This study demonstrates that the use of AVF in haemophiliacs enabled long-term treatment at home in all patients but one

Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: Results from the Pro-FEIBA study

PubMedID: 23731246Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health-related quality of life (HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate (aPCC) on HRQoL, HRQoL was assessed using the Short-Form (SF)-36 Health Survey and the EQ-5D questionnaire in subjects ?14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on-demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on-demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF-36 dimensions except for vitality/energy and physical functioning. After prophylaxis, 'good responders,' defined as patients experiencing ?50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score (P = 0.021), role - physical (P = 0.042), bodily pain (P = 0.015), and social functioning (P = 0.036). Similarly, the EQ-5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on-demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ-5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on-demand treatment (P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on-demand treatment. © 2013 John Wiley & Sons Ltd