Impact of humanitarian aid linked prophylaxis in Côte d'Ivoire (Ivory Coast)

Access to health care is a global challenge particularly exaggerated in low and low-middle income countries (LIC, LMIC). Treatment of haemophilia is no exception, with high morbidity and mortality due to lack of case-finding, comprehensive care and treatment products.1 While the benefits of prophylactic treatment of haemophilia are well established in high-income countries,2 lower income countries have developed several protocols using lower-dose prophylaxis in an effort to decrease bleeding episodes in children and adults with haemophilia. Initial reports from Wu (China), Gouider (Tunisia) and Verma (India) and their colleagues3-5 use different doses and regimens and show partial benefit in reduction in bleed rates compared to on-demand, or episodic treatment of bleeding. It is important to note low-dose prophylaxis is not a replacement for full prophylaxis, and the joint bleeds that occur will inevitably lead to arthropathy, albeit perhaps at a slower rate. The publication from Lambert and colleagues points to the benefits of a concerted effort to establish a prophylactic regimen in children for managing haemophilia in a single country, Côte d'Ivoire (Ivory Coast).6 The authors designed a study to determine the effects of low-dose prophylaxis with extended half life (EHL) factor VIII and IX products delivered via the World Federation of Hemophilia (WFH) humanitarian aid programme.7 The WFH humanitarian aid programme, consisting of prospective donations from six pharmaceutical companies, enables predictable quantities of products delivered to countries, enabling essential planning for prophylactic treatment regimens. Presently, ~250 million IU/year of conventional and EHL products is being delivered to ~20,000 people with haemophilia in over 70 countries. Of these, approximately 1000 children under 10 years are receiving a low-dose prophylaxis regimen. The prophylactic programme in Côte d'Ivoire has not been without significant challenges, including temporary interruption in supply of the humanitarian aid products, need to establish home-based infusions, and need for education level-appropriate training. The results, however, are unequivocal, despite some limitations in delivery of therapy. Dramatic reductions in bleeding rates, and evidence of improvement in joint health over up to 2 years, as assessed by the Hemophilia Joint Health Score (HJHS). In contrast to earlier low-dose prophylactic studies,3-5 the present study utilized a defined weekly regimen for haemophilia A and every 10 days for haemophilia B, due to the benefits of the extended half life products, providing a lower treatment burden for the families, compared to conventional FVIII and FIX products. The study provides for three overarching conclusions. First, the humanitarian aid programme is a stopgap, with the intention for governments to eventually provide clotting factors. While the programme is reasonably reliable, long term advocacy efforts are essential to improving the care provided by governments in most resource limited countries. The humanitarian aid programme can be used, as in this case, to demonstrate the long term quality of life benefits and cost effectiveness of a prophylactic programme in children, and the benefits of an adequately resourced comprehensive care haemophilia treatment centre programme. These are vital criteria to establish for purposes advocacy efforts with governments. Second, low-dose prophylaxis results in coverage gaps- times when circulating factor levels will fall below 1–3 IU/dl, resulting in increased bleeding risk. As expected, this was seen in the Lambert et al study with resultant breakthrough bleeding, including intracranial haemorrhage. However, imperfect coverage established here and elsewhere provides significant reduction in bleeding risk, thus has been encouraged where treatment quantities are limited.2-5 Poon and Lee recently summarized numerous variables in optimizing prophylactic regimens in lower and higher resourced countries.8 Bleeding triggers (activity levels, extent of arthropathies), coupled with required trough levels to maintain an agreed upon breakthrough bleed rate are the primary factors that determine the compliance required for an acceptable prophylactic dosing regimen. Some of these initial variables were first encountered by Manco-Johnson et al9 in their primary prophylaxis vs on-demand therapy clinical trial. And the third conclusion is the critical need for culturally sensitive training, which may be underappreciated but is essential to convincing the parents and children (and their healthcare providers) of the benefits of 100% compliance with prophylactic regimens. WFH programmes such as Hemophilia Treatment Center Twinning (which occurred in this case between Belgium and Côte d'Ivoire,10 the World Bleeding Disorders Registry (WBDR), which establishes the importance of prospective tracking and management of bleeding and treatment regimens in patient populations,11 and regionally oriented haemophilia management training programmes to reinforce the principles of comprehensive care to healthcare providers form a more inclusive approach towards advancing prophylactic regimens in lower resource countries.7 This includes reinforcing the need among physicians to develop home care therapy programmes, as initiated in Côte d'Ivoire6 to obviate the noncompliance intrinsic to hospital-based prophylactic programmes. In countries where there are great distances and inadequate transportation, hospital-based prophylactic infusion programmes should not be the first choice. It should be noted, education for providers and patients is not a trivial task, as exemplified by the many contributors that result in the lack of adherence in higher income countries where conventional prophylactic programmes sometimes targeting troughs of 3–5% are undertaken (Table 3 in12, 13). There is no doubt, imperfect adherence leads to breakthrough bleeding, which ultimately leads to progressive arthropathies and other bleeding risks.14 Less burdensome therapies, such as EHL products and subcutaneously delivered non-factor products (e.g. emicizumab), may positively impact compliance rates, and therefore decrease breakthrough bleeding if product specific educational initiatives are employed. In fact, the EHL FVIII and FIX likely had a positive impact on the long interval treatment regimen in the present study. The challenges may at times feel insurmountable, but as the study in Côte d'Ivoire shows, progress occurs via one study, one country at a time. The WFH vision remains ‘Treatment for All’, with positive incremental progress measured year over year, both globally and within countries.1, 15-18 Over the long term, some form of genetic therapy may be a likely successor to the humanitarian aid programme,19 and may result in a cure or partial cure to alleviate the misery and death of severe and severely moderate haemophilia in resource constrained countries. Much work is required on the technology and advocacy fronts before this vision becomes reality. For instance, the commonly used viral vector, adeno-associated virus (AAV), may have a seroprevalence rate of 50% or more in some countries, making those individuals ineligible for the therapy at present. In the meantime, optimal use of prophylaxis utilizing humanitarian aid and increasing amounts of government purchased products are viable tactics to improve morbidity and mortality globally. GFP, Director and vice president, medical, WFH; member US National Hemophilia Foundation Medical and Scientific Advisory Council. AH and DC are both employees of the WFH. No new data were generated, nor are available.

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