Small Study Group C Report from Benin Workshop
Hydroxyurea Therapy in Africa and other Developing Regions
Co-Chairs: Rajagopal Krishnamoorthy (France) and Richard Lottenberg (USA)
Previous and current major clinical trials of hydroxyurea (HU) therapy in SCD were discussed.
- Multicentre Study of Hydroxyurea in Sickle Cell Anemia (MSH) was the landmark RCT that led to FDA approval of HU for treatment of adults in USA
- BABY HUG is an ongoing study examining the role of HU in infants with primary endpoints addressing the prevention of organ damage.
- SWiTCH is addressing the use of chronic transfusion versus HU for secondary stroke prevention in children
- HEMORIO Medical Centre in Rio de Janeiro, Brazil has evaluated the effectiveness of HU in over 200 patients with encouraging results. However there has been variability in the use of HU therapy in populations outside of major medical centers
There is infrequent use of HU therapy in sub-Saharan Africa. However, certain medical centres in Africa have considerable interest in conducting formal studies e.g.
- Group in Lagos, Nigeria in collaboration with counterparts in the UK have planned to examine HU therapy in primary stroke prevention and the treatment of leg ulcers
- The Muhimbili (Tanzania) group led by Julie Makani have plans for a clinical study of HU involving a large SCD cohort managed in Dar es Salaam
The clinical investigation of HU therapy in Africa would be of high interest to the countries represented. Even if cost issues can be effectively dealt with, an effort simply focused on implementation guidelines would not be appropriate at this time.
Given the absence, or limited availability, of disease modifying interventions, such as hematopoietic stem cell transplantation and chronic red cell transfusions, HU therapy really represents the viable option across practice settings in low- and mid-income countries and is worthy of appropriate clinical investigation.
Barriers to HU therapy were addressed according to the following categories:
- Health care systems: Brazil has a publicly-funded national health care system and SCD has received consideration as a public health priority. Although drug cost is not a major obstacle, the difficulty of obtaining HU registration specifically for SCD indications represents a barrier for health care providers (e.g. legal coverage for physicians).
- In Africa, limited funding creates a scenario of competing priorities for health care financing. In recent years HIV and immunizations have received attention. The cost of HU constitutes a major barrier for its use in Africa. Also, the lack of health care workers in general and in particular the lack of providers with the necessary skills to manage patients with SCD is a major impediment.
- Physician: In Brazil, there has been substantial adoption of HU therapy by hematologists.
- In Africa, there is concern for carcinogenicity associated with HU; less so for altered spermatogenesis or teratogenic risks with pregnancy. In addition, physicians do not have adequate information pertaining to the use of HU therapy in SCD. Misinformation, therefore, may play a role in bias leading to aversion in prescribing the drug. There is an identified need for physician education and training programs.
- Patient/Family: Patients and families are often “on their own”, without adequate information on HU therapy, particularly its risks versus benefits. Patient education, clearly presenting benefits versus harms, should be a priority. Other major barriers include: variable attendance at clinics (making it a challenge to have appropriate follow-up) and apprehension for the risk of cancer associated with HU therapy.
There are major concerns about using results from clinical trials in developed countries to guide therapy recommendations for less developed settings such as Africa. More areas of uncertainty include the impact of infections (e.g. malaria, tuberculosis) and differences in local environment (e.g. diet, lifestyle) on HU efficacy, risks and outcomes.
It is necessary to enroll patients in developing countries in clinical research. The question remains whether a placebo-controlled trial in Africa is necessary considering the results from the MSH trial in the USA and the challenges of conducting such a study.
The need for efficacy research (clinical trials in “ideal” settings) was differentiated from effectiveness research (studies in “real world“settings). There was enthusiasm for pursuing studies of effectiveness.
SCD must be recognized and pursued as a public health priority in order to pursue adequate funding for SCD-related health care including infrastructure support for HU therapy.
Cost-effectiveness studies of HU therapy (possibly in comparison with chronic red cell transfusion) as well as studies demonstrating improvement in patient/family quality of life (particularly alleviation of pain) will strengthen the case for governments and funding agencies to support programs to implement HU therapy.