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