Experts evaluate options for the treatment of hemophilia in the developing world

On December 16, 2016, three experts on the treatment of hemophilia shared their experiences and recommendations during the Treatment Options for Hemophilia in the Developing World webinar. The online format allowed participants from around the world to watch, listen, participate in live polling, and ask questions. The session was chaired by Marijke van den Berg, Vice President, Medical of the World Federation of Hemophilia (WFH). A recording of the event is now available for viewing on the WFH eLearning platform.

Prophylaxis, Lessons Learned from Decades of Experience

The first presentation—Prophylaxis, Lessons Learned from Decades of Experiencewas given by Professor Rolf Ljung, a pediatric hematologist from Malmö, Sweden. Professor Ljung highlighted the two key challenges faced by anyone treating hemophilia anywhere in the world. Namely, the cost of treatment and the need for frequent venous access. He explained that the Swedish model of initiating prophylaxis early in life and administering it frequently could be adapted to the developing country context.

In Sweden, children start prophylaxis at one year of age, i.e. once venous access becomes easier. Professor Ljung sees no reason to wait for the first bleed to occur before initiating prophylaxis. He recommends 25 international units (IU)/kg/dose of factor concentrate (or a 250-IU vial for a 10-kg child) and the avoidance of intensive treatments during the first 20 exposure days (EDs). Ideally, treatment should, at first, be administered weekly via a peripheral vein so that the child and parents become accustomed to venipuncture. The goal is to administer three treatments a week or one every second day, for hemophilia A, and twice a week or every third day for hemophilia B. Children can begin self-infusion at 10–12 years of age, and very physically active children may begin daily prophylaxis at 10–15 years of age.

Of particular interest to treaters in developing countries was Professor Ljung’s observation that a weekly 50/IU/kg dose was more effective when divided into three smaller prophylactic doses of 10–15/IU/kg/dose. He stated that even these low doses offered a substantial reduction in bleeds. While larger doses do permit the patient to lead a relatively normal life, he noted diminishing returns in terms of the reduction of bleeds (i.e. a 3-fold higher dose does not equate 3-fold fewer bleeds). The assertion that frequently administered low-dose prophylaxis may effectively reduce the number of bleeds suggests an interesting approach for the treatment of hemophilia in the context of limited access to factor concentrates.

Prophylaxis for the Developing World: A Dream or Possible Reality?

The second portion of the webinar—Prophylaxis for the Developing World: A Dream or Possible Reality?—was presented by Professor Johnny Mahlangu, an adult hematologist from Johannesburg, South Africa.

Professor Mahlangu explained that one of the most important benefits of prophylaxis was the reduction (up to 7-fold) of the annualized number of bleeding episodes per patient. He went on to outline some other important benefits, including significant reduction in clinical and radiological measures of joint deterioration. These benefits translate to fewer days lost from school or work, increased physical activity, and preserved bone mass density (which can enable patients to lead more active lives).

Although prophylaxis provides many benefits, there are also many barriers to its use, globally. Professor Mahlangu categorized these barriers as those which concern patients, physicians, and clotting factor concentrates. While patient-related barriers (e.g. venous access and adherence) and physician-related barriers (e.g. lack of randomized clinical trials and failure rate) exist everywhere, the key differentiators between developed and developing countries are the cost of, and access to, clotting factor concentrates.

The cost of effective hemophilia care increases as treatment strategies progress from addressing episodic bleeds to the ultimate goal of primary prophylaxis enabling normal life. Professor Mahlangu explained that in developed countries, the classical treatment approach involves relatively high doses (25–50 IU/kg/dose) administered between one and three times per week, depending on whether the patient has hemophilia A or B. He illustrated that the annual cost for this approach could reach as high as US$200,000 to $400,000 per patient, costs that are prohibitive for many developing countries.

Professor Mahlangu described a goal of easing the cost burden of prophylaxis in developing countries while improving quality of life for the patient. Real-world experience suggests that low-dose prophylaxis might be an effective approach for attaining this goal. He cited a number of studies including one conducted in China by Wu et al as proof of concept that low doses (10 IU/kg/dose) of factor administered twice weekly can reduce the frequency of joint bleeds in patients with moderate and severe hemophilia [1]. Subsequently, Professor Mahlangu—using as an example of the factor IX with a prolonged half-life—explained the impact that such products would have on the frequency of administration and, consequently, the cost of prophylaxis. This would therefore be a benefit for the implementation of prophylaxis. Professor Mahlangu concluded that prophylaxis in the developing world is not just a dream, but a reality that can be realized by reductions in dose and/or dosing frequency combined with the use of extended half-life products.

Laboratory Diagnosis of Bleeding Disorders: Challenges in the Developing World

The final presentation of the webinar, Laboratory Diagnosis of Bleeding Disorders: Challenges in the Developing World, was given by Professor Sukesh Nair of Christian Medical College, Vellore, India. Professor Nair discussed the minimal requirements for laboratory diagnosis of patients with an increased bleeding tendency—specifically, the identification of factor deficiencies or inhibitors, confirmation by assay, and assurance of the precision and accuracy of the laboratory results.

Professor Nair presented the major challenges to laboratory diagnosis of bleeding disorders as they have been identified by the WFH International External Quality Assessment Scheme (WFH-IEQAS). Most often, issues relate to the lack of availability, or deterioration, of reagents for screening tests and factor VIII assays, or the lack of funds to purchase these reagents. Professor Nair proposes that in such cases reference plasma and factor VIII-deficient plasma may be prepared locally. He described how factor VIII-deficient plasma can be obtained from a consenting patient with severe hemophilia, and how plasma can be pooled from 20 consenting individuals who do not have a bleeding disorder.

In addition to challenges securing predictable supplies of reagents from manufacturers, WFH-IEQAS data also reveal issues concerning skilled personnel, procedural errors (mixing studies), and the nature of the coagulation laboratory (low sample numbers and short shelf-life of reagents). Professor Nair expressed concerns about the inadequacies in diagnostic capabilities of many laboratories revealed by the WFH-IEQAS data. In one specific example, of 36 laboratories assessed fewer than 50% included mixing studies in their algorithm for factor deficiency while fewer than 10% screened for inhibitors. This means that the risk of missing an inhibitor was high. The ability to reliably screen for inhibitors is an important requirement for the establishment of a prophylaxis program.

Professor Nair made several recommendations, including leveraging the International Society on Thrombosis and Haemostasis (ISTH) and WFH programs that train laboratory personnel, and enrolling laboratories in an accredited proficiency testing or external quality assessment scheme. He also highlighted a need for the development of simple and reproducible laboratory tests that capitalize upon reagents that can be prepared in-house. Professor Nair concluded by proposing a strategy to develop coagulation laboratories in collaboration with transfusion centres to help raise the priority level of tests conducted by these labs, thus greatly improving the services available to the bleeding disorders community.

This first ever live interactive WFH webinar was very well attended with people logging in from 68 different cities in over 30 countries. In just one hour the international experts provided a clear and insightful discussion of the promise and challenges of wide-spread prophylaxis as a treatment option for hemophilia in developing world. The webinar recording, accompanied by. a PDF of the speakers’ slides, constitutes a highly impactful enduring resource, and is available here for all to watch and rewatch at their convenience.

1. Wu et al, Haemophilia. 2011;17(1):70-4.