The value-based healthcare approach to haemophilia: Development of outcome measures for the evaluation of care of people with haemophilia.

Introduction: Considering the advances in haemophilia management and treatment observed in the last decades, a new set of value-based outcome indicators is needed to assess the quality of care and the impact of these medical innovations.

Aim: The Value-Based Healthcare in Haemophilia project aimed to define a set of clinical outcome indicators (COIs) and patient-reported outcome indicators (PROIs) to assess quality of care in haemophilia in high-income countries with a value-based approach to inform and guide the decision-making process.

Methods: A Value-based healthcare approach based on the available literature, current guidelines and the involvement of a multidisciplinary group of experts was applied to generate a set of indicators to assess the quality of care of haemophilia.

New orphan disease therapies from the proteome of industrial plasma processing waste- a treatment for aceruloplasminemia.

Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs.

Thromboembolic event rate in patients exposed to anti-inhibitor coagulant complex: a meta-analysis of 40-year published data.

Anti-inhibitor coagulant complex (AICC), an activated prothrombin complex concentrate, has been available for the treatment of patients with inhibitors since 1977, and thromboembolic events (TEEs) have been reported after infusion of AICC in patients with congenital or acquired hemophilia. With the aim of estimating the TEE incidence rate (IR) related to AICC exposure in these patients, a systematic review of the literature was carried out in Medline, according to PRISMA guidelines, from inception date to March 2017. The IR of TEEs was estimated through a meta-analytic approach by using a generalized linear mixed model based on a Poisson distribution.

Meta-analysis on incidence of inhibitors in patients with haemophilia A treated with recombinant factor VIII products.

: Recent cohort studies showed differences in inhibitor incidence in previously untreated patients (PUPs) with haemophilia A treated with recombinant factor VIII (rFVIII) concentrates. We carried out a systematic literature search and meta-analysis for all randomized clinical trials and observational studies published from 1 January 1988 to 31 August 2015, to assess the incidence of inhibitor development and the relationship with rFVIII product used in PUPs and minimally treated patients (MTPs, ≤5 previous exposure days), with severe haemophilia. The primary outcome measure was development of all inhibitors and high-titre inhibitors.

Cost-effectiveness analysis of pharmacokinetic-driven prophylaxis vs. standard prophylaxis in patients with severe haemophilia A.

: The objective of this study was to assess the cost-effectiveness of pharmacokinetic-driven prophylaxis in severe haemophilia A patients. A microsimulation model was developed to evaluate the cost-effectiveness of pharmacokinetic-driven prophylaxis vs. standard prophylaxis and estimate cost, annual joint bleed rate (AJBR), and incremental cost-effectiveness ratio over a 1-year time horizon for a hypothetical population of 10 000 severe haemophilia A patients.

An innovative outcome-based care and procurement model of hemophilia management.

Hemophilia is a rare bleeding disorder associated with spontaneous and post-traumatic bleeding. Each hemophilia patient requires a personalized approach to episodic or prophylactic treatment, but self-management can be challenging for patients, and avoidable bleeding may occur. Patient-tailored care may provide more effective prevention of bleeding, which in turn, may decrease the likelihood of arthropathy and associated chronic pain, missed time from school or work, and progressive loss of mobility.

Global Post-Authorization Safety Surveillance Study: real-world data on prophylaxis and on-demand treatment using FEIBA (an activated prothrombin complex concentrate).

This prospective, Post-Authorization Safety Surveillance (PASS) study was carried out in patients with hemophilia A or B and inhibitors treated with FEIBA for 1 year to collect real-world data on safety and effectiveness of FEIBA. The study followed a cohort design and did not make stipulations on treatment or observation schedule, as it was designed to observe routine medical practices based on physicians' treatment decisions, including whether patients received on-demand or prophylaxis with FEIBA. The attending physician maintained documentation, including medical records, laboratory reports, adverse event reports, and so on and a subject diary was used.

Individualizing prophylaxis in hemophilia: a review.

Prophylaxis is considered optimal care for patients with severe hemophilia to prevent bleeding, including hemarthroses, which may cause arthropathy with chronic pain, occupational impairment and progressive loss of mobility. Questions remain regarding the optimal delivery of prophylaxis including how to individualize prophylaxis and optimize outcomes for each patient. Designing a prophylactic regimen for severe hemophilia must account for each patient's unique disease course, bleeding pattern, presence/absence of joint damage, pharmacokinetic profile, level of physical activity and adherence to treatment.

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.

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).

Modeling costs and outcomes associated with a treatment algorithm for problem bleeding episodes in patients with severe hemophilia a and high-titer inhibitors.

Background: No evidence-based treatment guidelines are currently available for the treatment of problem bleedings in patients with hemophilia who develop clotting factor inhibitors. A treatment algorithm was developed previously to help providers optimize the approach to the treatment of this patient population. The algorithm provides the specific intervals between treatments; however, it does not specify dosing recommendations and does not offer insights into the likelihood of outcome improvements at each time interval.

Pharmacotherapy of haemophilia A.

Introduction: Haemophilia A is due to factor VIII (FVIII) deficiency. The main treatment is replacement therapy with FVIII concentrates. However, these concentrates carried a high risk of blood-borne viral infections and still have a high risk of inducing anti-FVIII inhibitors.

From theory to practice: applying current clinical knowledge and treatment strategies to the care of hemophilia a patients with inhibitors.

Two bypassing agents are currently available to circumvent the need for factor FVIII in hemophilia A patients with inhibitors: the activated prothrombin complex FEIBA VH and recombinant activated factor VII (NovoSeven. Both products are highly effective in controlling bleeding in the presence of inhibitory alloantibodies, yet their hemostatic efficacy can be unpredictable. As the results of the FEIBA NovoSeven( Comparative (FENOC) study illustrate, patients may respond better to one bypassing agent than the other.

Hepatitis C virus (HCV) coinfection in a cohort of HIV positive long-term non-progressors: possible protective effect of infecting HCV genotype on HIV disease progression.

Background And Objective: Hepatitis C virus (HCV) infection is frequent in HIV-positive subjects. We evaluated the potential impact of HCV coinfection and other determinants on HIV disease progression in a cohort of long-term non-progressors (LTNPs).

Study Design: We studied immunological and virological factors in a cohort of 49 LTNPs, 23 of whom progressed during the follow-up (late progressors; LPs).

A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study.

The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitor-bypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor VIIa (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding.

New approaches to using FEIBA in the treatment of inhibitor patients.

Managing hemophilia becomes particularly difficult in patients with inhibitory antibodies, especially in those requiring surgery or with refractory bleeding events. Equally challenging are those patients who develop autoantibodies against factor VIII (FVIII) in the absence of a prior history of FVIII deficiency (acquired hemophilia). Physicians seeking both short- and long-term treatment strategies for bleeding events must often rely on FVIII-bypassing agents such as activated prothrombin complex concentrate (e.

Long-term aspects of hemophilia B treatment: part II.

This paper focuses on the benefits of prophylaxis, compared with on-demand therapy, in achieving long-term treatment goals in hemophilia patients. While primary treatment goals are to prevent joint damage and improve quality of life, other issues such as treatment costs-balanced against improvements in health status and direct and indirect costs of hemophilic arthropathy-need to be considered. The ESPRIT study (Evaluation Study on Prophylaxis: a Randomized Italian Trial), a 10-year trial comparing on-demand and prophylactic treatment in terms of efficacy, safety, and cost, is discussed.

Efficacy and inhibitor development in previously treated patients with haemophilia A switched to a B domain-deleted recombinant factor VIII.

There have been recent reports of unexpected poor efficacy of a B-domain-deleted recombinant factor VIII (BDD-rFVIII) in haemophiliacs, and inhibitor development in previously treated patients (PTPs) switched to BDD-rFVIII. The results of a 6-month prospective study of 25 PTPs and of a retrospective survey of 94 PTPs, all switched to BDD-rFVIII, were used to evaluate efficacy and inhibitor development. The prospective study showed that 89% of 362 bleeds were controlled by one to two infusions, reproducing the efficacy profiles of other recombinant products (rFVIIIs).

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.

Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group.

Inhibitors in patients with hemophilia are a rare complication of a rare disease causing pain and disability in patients and impairment to the quality of their lives. Recent advances in treatment have brought improvements, but they have done so by absorbing larger amounts of financial resources. This study involved 52 Italian patients with hemophilia with high-responding inhibitors who were longitudinally observed for 18 months to evaluate concomitantly cost of care and quality of life.

Identification of immunodominant epitopes in inactivated Tat-vaccinated healthy and HIV-1-infected volunteers.

We analyzed the epitopes and the molecular forms of Tat recognized by the antibodies raised by Tat-toxoid vaccination in both healthy and HIV-infected volunteers. Tat-toxoid-vaccinated healthy volunteer sera reacted predominantly with peptides covering amino acids 1 through 24 and 46 through 60, corresponding to the N-terminus and basic domains of Tat. In contrast, whereas all sera from vaccinated HIV-1-positive patients reacted with the N-terminus and (with a single exception) with the basic domain, most of these sera also recognized peptides encompassing distinct domains of Tat, particularly the C-terminus (79-86).