Discussion
In this retrospective review of a short-term use of HU in children with SCD, we found that a starting dose of HU of 10-15 mg per kilogram body weight per day is safe, effective and feasible except for challenges posed by monitoring and dose escalation. Majority of the patients reported compliance to daily use of HU but were unable to keep all doctor’s appointments and laboratory tests. Most patients reported improvement in well-being and sickle-related symptoms but expressed concerns about cost of drugs, frequent laboratory tests and hospital appointments. Common side effects reported were headaches and abdominal pains. Few parents either wanted to discontinue use of HU or were undecided about future use. There was good hematologic response to HU even among children with very low stable state hemoglobin.
The REACH23 and the NOHARM25studies, as well as some Nigerian studies26–28, have reported on the safety, laboratory and clinical response of African children to HU that compares to the results of this retrospective study. Our study, in addition, reports on user-related barriers to a sustainable HU use from the paediatric point of view.
Our data show that contrary to concerns about feasibility of a sustainable HU use in Nigeria and Africa in general, many care givers welcome the use of HU in their patients and made concerted efforts to comply with drug use. The increasing mean MCV reported in this study corroborates the good drug compliance reported by parents even though many complained about the stress of daily consumption of HU. Some local studies that provided free HU for patients observed that many patients stopped HU after the study because of cost and unavailability and opined that offering free HU to patients would improve uptake in resource-poor settings (oral communication). Our study showed that an affordable and sustainable drug supply, anchored on proper health education enhanced uptake of HU. A hike in drug price during the study resulted in patient protest and only patients with an insurance policy afforded it with ease. This underscores the importance of sourcing affordable HU for sustainability of therapy.
Worse challenges to a sustainable HU uptake were frequent laboratory tests and doctor’s appointments. In this study, patients were subjected to monthly doctor’s appointments and laboratory tests because of the poor health-seeking behavior of most families. Parents who accept HU but do not come for follow-up expose their children to risk of drug toxicities. With steady and intensive health education given at each visit, obvious clinical response to HU and the unit 24-hour phone access to patients for appointment reminders, many families appreciated the reason for the frequent monitoring and showed willingness to improve compliance. Most standard HU protocols require frequent monitoring especially at the onset until patient is on a stable dose. Adewoyin19 and Aliyu31 in separate reports attributed low HU uptake in Nigeria partly to cost of drug and follow-up visits in their adult and non HU using patients. Akinshete et al26 reported 6 monthly monitoring of his paediatric patients on HU because of cost. Ofakunri et al27 in Jos monitored laboratory tests monthly under a protected research environment with good compliance. There is no consensus on frequency of monitoring for the African user that will reduce cost without exposing users to toxicity. Cost of HU and follow-up visits remain common barriers for both adult and paediatric patients who use HU in real-life situations
In keeping with reports from resourceful centers with many years of experience HU, no major side effects were reported from patients within the 2-year period. In our study, headache was commonly reported at onset of therapy but improved with use. Patients with recurrent abdominal pain were advised to take medication at bedtime and many subsequently did well. This observation adds to other reports from Nigeria26,27 that showed no worsening safety margins of HU in Africa because of host and environmental factors and calls for a wider use of HU in African children with SCD21,27,34 Doses at 10-15mg/kg of HU was a safe starting dose that resulted in significant clinical and laboratory effects even with minimal dose escalation. Jain and co-workers in India35 reported good response of patients to 10mg/kg/day of HU even though many had higher baseline Hb F values compared to patients in our study. These observations may be an indication of good hematologic response to moderate doses of HU and underscores the use of therapeutic dose rather than a maximum tolerable dose that may expose patients in resource poor countries to toxicity where monitoring may be suboptimal. HU dosing in our study failed to produce a mean Hb of 9-10g/dl and HbF level of at least 20% or marrow depression with ANC of 2 to 4000 which is associated with sustainable clinical effect36,37,38 even though most of our patients had good clinical response within the short duration of therapy. Our focus is on achieving good clinical response without overly intensive dose escalation39. Researchers in Africa and Asia are reporting effectiveness of intermittent40 or low-fixed dosing35,41 of HU in SCD subjects. In Nigeria, Titilola42 reported clinical and laboratory response to a low fixed dose of HU in adult patients with SCD. This approach may ameliorate the challenges of HU monitoring. Reduced frequency of HU use will reduce cost, ensure better compliance and may represent a viable option for improving HU uptake in Nigeria and sub-Sahara Africa.
The limitation of this study lies in its retrospective nature and the use of manual documentation of patient medical records which made retrieval of source documents laborious. The hospital, however, is in the process of migrating to electronic medical information system which will make future studies easier. The strength, nonetheless, lies in the real-life circumstances of the review which provides practical and real-time insights and possible solutions compared to the protected circumstances of a structured research.
In conclusion, there is a compelling need for the adoption of HU as an integral part of the standard of care for children with SCD in Nigeria. Challenges of sustaining HU use are many but can be improved by on-going patient and parental health education, provision of affordable and sustainable supply of HU and subsidized laboratory tests through affordable health insurance schemes. This study joins others to attest to the good clinical efficacy and safety of HU while highlighting some user- barriers to a sustainable HU use. It will add to the implementation science strategies and training that is needed to increase HU uptake among children with SCD in Nigeria.
Future research may focus on determining effective intermittent and fixed- dosing protocols that would reduce monitoring and cost of HU and still provide good clinical and laboratory benefits to users.
Conflict of Interest Statement: None
Data Availability Statement: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions