From the voices of people with haemophilia A and their caregivers: Challenges with current treatment, their impact on quality of life and desired improvements in future therapies.

INTRODUCTION: Haemophilia A is a chronic disease requiring frequent intravenous infusions of recombinant factor VIII. Previous studies have shown that challenges associated with current treatments may have significant impacts on quality of life (QoL) that are as important as the health outcomes conferred by the therapy. Emerging therapeutic innovations offer the potential to mitigate treatment-related challenges, and it is therefore important to develop a better understanding of patient and caregiver experiences with existing haemophilia A treatments in order to characterize the full value of new treatments. AIM: To gather firsthand perspectives from people with haemophilia A (PWHA) and caregivers on the challenges with current treatment, their impact on QoL and desired improvements in future therapies. METHODS: Qualitative insights were gathered from 20 non-inhibitor PWHA or caregivers of PWHA across Canada through one-on-one interviews; insights were further explored through focus group sessions to uncover overarching themes and prioritize issues with current treatments. RESULTS: PWHA and caregivers identified several challenges, including administration of intravenous infusions, coordination of treatment schedules and ensuring adequate medication and supplies. Participants described how these challenges impact psychosocial well-being, physical health, personal/social life and work. Alternate modes of administration and longer-lasting treatment effects were identified as desired improvements over current treatments. CONCLUSION: This study emphasizes the impact that existing haemophilia A treatments have on psychological well-being, employment opportunities and adherence to treatment regimens. These considerations may help to inform decision-making for policymakers and health systems around the true value of new therapies entering the haemophilia market.

Supply and demand for hemophilia treatments-Systems-based approaches to mitigate the risk.

Treatment of hemophilia consists of replacement of the missing coagulation factor, either prophylactically or at the time of injury or bleeding. Because of the high cost of these products, which can present a barrier to care, different procurement strategies have been developed at national and regional levels. The emergence of novel therapeutic agents adds complexity to these strategies. This paper examines the benefits and challenges of these strategies, with primary reference to the Canadian context and a consideration of the concepts of value-based care.

Joint health scores in a haemophilia A cohort from Pakistan with minimal or no access to factor VIII concentrate: correlation with thrombin generation and underlying mutation.

Haemophilia A is associated with recurrent joint bleeding which leads to synovitis and debilitating arthropathy. Coagulation factor VIII level is an important determinant of bleed number and development of arthropathy . The aim of this study was to compare the haemophilia joint health score (HJHS) and Gilbert score with severity, age, thrombin generation (TG) and underlying mutation in a haemophilia A cohort which had minimal access to haemostatic replacement therapy. Ninety-two haemophilia A individuals were recruited from Pakistan. Age, age at first bleed, target joints, haemophilic arthropathy joints, HJHS and Gilbert score were recorded. A strong correlation was found between HJHS and Gilbert score (r = 0.98), both were significantly higher in severe (n = 59) compared with non-severe (n = 29) individuals before the age of 12 years (P ≤ 0.01) but not thereafter. When individuals were divided according to developmental age (<12 years, 12-16 years and >16 years), both HJHS and Gilbert score were significantly lower in the youngest group (P ≤ 0.001), there was no difference between 12-16 years and >16 years. In severe individuals there was no correlation between in vitro TG and joint score, whereas in non-severe individuals there was a weak negative correlation. In the severe group, no significant difference was observed for either joint score according to the underlying mutation type (inversion, missense, nonsense, frameshift). In this cohort of haemophilia A individuals with minimal access to haemostatic treatment, haemophilic arthropathy correlated with severity and age; among severe individuals, joint health scores did not relate to either the underlying mutation or in vitro TG.

Benefits associated with a broad selection of dosage strengths for recombinant factor VIII products.

Factor VIII (FVIII) concentrates for haemophilia A patients are dosed according to body weight. This results in a continuous range of prescribed doses, which challenges pharmacies to find dosage strengths closest to the prescribed dose while utilizing the least number of vials. This study was conducted to determine whether a broader selection of FVIII dosage strengths results in improved dispensing accuracy and an increased number of single-vial users. This research retrospectively analyzed a US pharmacy database of prescriptions filled in 2008. Recombinant FVIII (rFVIII) therapies were classified by the range of dosage strengths offered in 2008: Group 1 had three dosage strengths; Group 2 had four dosage strengths; and Group 3 had six dosage strengths. A total of 76,584 dispensed doses of rFVIII for 1,244 patients were included in this analysis. Dispensing accuracy (calculated as both the absolute and relative difference between dispensed and prescribed dose) was significantly better for Group 3 (23.2 IU, 1.2%) than Groups 1 (33.5 IU, 1.6%) and 2 (50.2 IU, 2.4%) (both P < 0.01). In addition, the average number of unique actual rFVIII potencies dispensed per month was highly correlated (-0.977) with dispensing accuracy for each dosage strength group. Among Groups 1, 2 and 3, 23.0%, 44.9% and 73.4% of patients, respectively, had at least one single vial option dispensed (P < 0.0001). A broader selection of rFVIII dosage strengths and more actual rFVIII potencies were associated with improved dispensing accuracy and more single-vial users. This may translate into less waste, cost savings, increased convenience and improved adherence to physician-prescribed regimens.

Haemophilia: provision of factors and novel therapies: World Federation of Hemophilia goals and achievements.

For nearly 50 years, the goal of the World Federation of Hemophilia (WFH) has been to achieve 'Treatment for All' patients with inherited bleeding disorders, regardless of where they live. With proper diagnosis, management and care, people with bleeding disorders can live perfectly healthy lives. Without treatment, the reality is that many will die young or, if they survive, suffer joint damage that leaves them with permanent disabilities. Only about 25% of the estimated 400 000 people with haemophilia worldwide receive adequate treatment. The percentage is far lower for those with von Willebrand Disease (VWD) and the rarer bleeding disorders. The achievements of the WFH to close the gap in care for people with bleeding disorders are measureable over time by using three key indicators; the difference in the estimated and actual number of people known with bleeding disorders, the amount of treatment products needed versus that available, and the number of people born with bleeding disorders and the number who reach adulthood. There are five essential elements to achieve a sustainable national care programme: ensuring accurate laboratory diagnosis, achieving government support, improving the care delivery system, increasing the availability of treatment products, and building a strong national patient organization.

Freeze dried cryoprecipitate: a clinical evaluation.

Freeze dried cryoprecipitate was used in the treatment of 14 patients with haemophilia A. The in vivo recovery was 91.2% which is comparable to that reported from other parts of Europe. The product was efficacious and no adverse effects were reported. Freeze dried cryoprecipitate is the high yield product of a low technology process and as such may be of value in reducing any possible shortfall in the factor VIII requirements of the haemophiliac population of the UK.

Can the supply and demand for plasma-derived products ever be reconciled? Self-sufficiency from the viewpoint of a blood transfusion service.

Sufficiency is the balance between supply and demand. The problems of estimating future demands and of maintaining adequate supplies of blood for the preparation of blood products, will be discussed from the viewpoint of a well-established blood transfusion service.

Can the supply and demand for plasma-derived products ever be reconciled?

With regard to self-sufficiency, supply and demand for plasma-derived products can only be reconciled if there is a free exchange of source materials and products with European harmonization of products. It is essential that safety aspects are agreed upon internationally and free access is guaranteed.

Should clinical freedom be constrained in the name of self-sufficiency?

Clinical freedom should enable a physician to decide in a free and unbiased manner which is the most appropriate therapy to use for a particular patient. In order to implement the four aims of the German Haemophilia Society an average of 4-4.5 units of Factor VIII per capita of the general population per year is needed. At present European countries do not produce this amount, but to reduce the consumption of F VIII in therapy lowers treatment levels. Until plasma collection services in Europe can be expanded it is necessary that the additional, imported, sources of plasma are available, otherwise clinical freedom will be curtailed.

Economic issues in European self-sufficiency.

Future clinical practice in haemophilia care must make optimum use of resources and provide the highest quality products and services in an efficient and effective manner. Studies show that prophylactic therapy, compared with on-demand therapy, results in less time off work--that is, a smaller loss in productivity. However, prophylactic therapy requires a three- to five-fold greater annual amount of factor VIII than does on-demand therapy. Further study is needed to determine the optimum therapeutic strategy that gives the best cost v. benefit situation.

Do safety issues of plasma products constrain self-sufficiency?

The ultimate responsibility for selecting and administering plasma products to patients rests with the prescribing physician, and it is for him/her to choose the safest product available. However, liability for a product with a full licence rests exclusively with the licence holder. After the problems of HIV and hepatitis C the safety of plasma-derived products has become of paramount importance. Particularly in the public sector, financial, strategic and political obstacles may adversely influence the quantity, quality and safety of plasma collection. The safety of blood products can be substantially enhanced by the harmonization of technical standards across both public and private sectors, thus supporting EC Directive 89/381. Additionally, the goal of European rather than national self-sufficiency should be encouraged.

How will immune tolerance protocols affect self-sufficiency goals?

Inhibitor development is a serious complication in haemophilia, and its treatment, immune tolerance therapy, is an expensive part of haemophilia treatment. However, the therapy can lead to an increased lifespan and improved quality of life. If commenced sufficiently early in the disease, it can help to reduce the overall amount of factor VIII concentrate, or other plasma derived therapeutic agents required during life.

Will recent innovations in therapy save perceived deficiencies in self-sufficiency policies.

Future treatment for patients with haemophilia may include the use of either gene therapy, recombinant factor VIII, recombinant factor IX, or high-purity factor IX. Studies on gene therapy are still at the pre-clinical stage, while clinical trials of recombinant factor IX are expected to start by mid-1995. High-purity factor IX concentrates are available and are the treatment of choice for patients with haemophilia B in the absence of a source of recombinant factor IX. Recombinant factor VIII provides a renewable and unlimited source of factor VIII, and is a safe and effective treatment for haemophilia A.

Is haemophilia prophylaxis achievable in the context of self-sufficiency?

In Sweden prophylactic treatment in haemophilia was introduced in 1958. Patients receiving prophylactic treatment have less time off school or work, require less hospitalization, have fewer joint bleeds, and generally lead as near normal life as possible. Although prophylaxis is expensive the cost is off-set by the improvement in quality of life and in productivity. At present, Sweden is almost self-sufficient in blood products for prophylactic treatment of haemophiliacs.

Plasmapheresis for the preparation of HIV free cryoprecipitate.

Single donor cryoprecipitate was prepared by blood cell separator for treatment of hemophilia A and von Willebrand patients to reduce a risk of transfusion associated HIV infection. A total of 7 plasmapheresis (range 1-1.5 plasma volume) was performed in 4 donors. Then fresh frozen plasma (FFP) was processed to cryoprecipitate and cryoprecipitate removed plasma (CRP). Donors were replaced with 0.9% normal saline solution (NSS) and 5% albumin for the first donation or their own CRP and 5% albumin for the second and third donation. After plasmapheresis total protein, albumin, IgG, IgA and IgM were below normal level in 71.43% (5/7), 14.3% (1/7), 28.57% (2/7), 14.3% (1/7) and 28.57% (2/7), respectively. All of these parameters returned to normal level within 3 days. Factor VIII:C was decreased after plasmapheresis in all donors and the low level of F VIII:C returned to normal within 24 hours. The donor was not exposed to any harmful effect. Donor reactions observed were mild. One donor was chilled due to unwarmed replacement solution. When this donor donated for the second time and was replaced with prewarmed replacement solution, no reaction was observed. We conclude that a preparation of single donor cryoprecipitate by plasmapheresis is safe and can reduce a risk of transfusion associated HIV infection. The donors are not at risk as the result of changes in the measured plasma protein and factor VIII:C level following plasmapheresis.

Clinical and serological study of the human immunodeficiency virus infection in a cohort of multitransfused persons.

A group of 64 multitransfused individuals with hemophilia or congenital hemolytic anemias were tested for antibodies against the human immunodeficiency virus. Thirty five of them were also evaluated clinically and their blood products supply was investigated. Only four hemophiliacs were found to be seropositive. The major risk factor that seemed associated with the acquisition of the virus was the transfusion of lyophilized factor VIII concentrate imported from the USA. A suggestion for control of transfusion associated infection and of contamination of hemophiliacs is presented.

[Current status and future prospects of hemophilia treatment]. / Stan obecny i perspektywy leczenia hemofilii.

Over the past decade, with the use of plasma-derived factor VIII and factor IX, treated with virucidal methods, as well as with recombinant factor VIII, the replacement therapy of hemophilia has been intensified. In developed countries, a majority of patients are being treated at home, and large groups of children benefit from primary prophylaxis. A serious task in these countries for the coming years is the management of patients infected with HIV. In Poland and less-developed countries, the supply of antihemophilic factor concentrates is inadequate. Patients with inhibitor antibodies should be included in programmes of immune tolerance inducement. Many patients who had been multitransfused with cryoprecipate or received lyophilized concentrates before 1985, have developed chronic hepatitis associated with viral infections. About 15-30% show evidence of cirrhosis. Recombinant technologies should be improved and become more accessible in order to provide patients with safe and cheap antihemophilic factor concentrates. A true break-through in the hemophilia treatment would be a repair of the inherited clotting defect with gene therapy.