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\begin{document}

\title{Hydroxyurea in children with sickle cell disease in a resource-poor
setting: Monitoring and effects of therapy. A practical perspective}



\author[1]{Uche Nnebe-Agumadu}%
\author[2]{Innocent Adebayo}%
\author[2]{Ifeanyi Erigbuem}%
\author[2]{Esther James}%
\author[2]{Evelyn Kumode}%
\author[3]{Obiageli Nnodu}%
\author[4,4]{Adekunle Adekile}%
\affil[1]{University of Abuja}%
\affil[2]{University of Abuja Teaching Hospital}%
\affil[3]{University of Abuja College of Health Sciences}%
\affil[4]{Kuwait University}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\selectlanguage{english}
\begin{abstract}
Abstract Background: Effectiveness of hydroxyurea (HU) in SCD is well
established. Unanswered questions persist about use in African children
in terms of acceptability and monitoring. We determined real-life
user-barriers, safety and effects of therapy among children using HU in
Nigeria. Methods: We retrieved and reviewed case notes of children on
hydroxyurea (10-15mg/kg/day followed by dose escalation) from January
2017 to June 2019, checked for adherence to drugs, clinics and
laboratory tests; starting dose, toxicity and benefits (hematologic,
clinical, parental satisfaction). A questionnaire complemented case note
findings. Results 116 patients received hydroxyurea (mean dose of 18
mg/kg/ day). Improvement in general well-being was 91.25\%, reduction in
bone pain 83.3\%, hospital admissions 71.9\%, abdominal pain 62.3\%,
blood transfusion 56.1\%. Sixteen percent voluntarily stopped HU because
of cost and side effects. Sixty-seven percent of parents complained
about daily drug use, frequency and cost of monitoring. Adherence to
daily HU was 88.8\%, doctor's appointments 22.8\%, hematology tests
17.5\%, organ function 32.5\%. Five patients had mild neutropenia. No
significant hepatic or renal toxicity occurred. Common side effects were
abdominal pain (18.4\%) and headache (13.2\%). Significant increase in
hemoglobin, fetal hemoglobin, MCV and reduction in absolute neutrophil
counts occurred. Conclusion: Hydroxyurea at 10-15mg/kg/day is safe,
effective and acceptable to parents. Monitoring is challenging.
Care-giver education, support services, staff training, HU clinics may
improve utilization. HU protocols that reduce monitoring and yet provide
good clinical and laboratory benefits are necessary. This study adds to
the implementation science strategies that is needed to increase HU use
in Nigeria.%
\end{abstract}%



\sloppy




\textbf{INTRODUCTION}

Sickle cell disease (SCD) is a chronic debilitating genetic disorder
with significant global public health implications\textsuperscript{1}.
Progress made so far in understanding of the molecular and
clinico-pathological basis of the disorder has not been matched with
corresponding treatment
modalities\textsuperscript{2}'\textsuperscript{3}. Effective and
accessible treatment globally is based on use of blood transfusions,
antibiotics, analgesics and hydroxyurea in the context of a
comprehensive approach to care\textsuperscript{4}'\textsuperscript{5}.
Bone marrow transplant and gene therapy offer tangible hope of cure but
are very expensive and inaccessible to many patients. Comprehensive care
is reported as largely responsible for the improved quality of life and
survival in people with SCD in resource rich
countries\textsuperscript{1}'\textsuperscript{6}. With improved
diagnosis and management, over 98\% of children with SCD in resource
-rich countries survive to adulthood with a life-expectancy of 53 years
for men and 58.5 years for women\textsuperscript{7}'\textsuperscript{8}.
On the contrary, SCD remains a huge economic and psychosocial burden in
sub-Saharan Africa (SSA) and for most families in Nigeria, partly
because of absence of accessible quality health care and public health
interventions\textsuperscript{2}'\textsuperscript{4}'\textsuperscript{9}.

In Nigeria, with an estimated disease prevalence of 2\% , a carrier rate
of 21\%(NDHS 2019) and a projected global increase in annual delivery of
infants with SCD to 400,000\textsuperscript{10}, the scourge of the
disease will increase if interventions are not put in place. The
benefits and safety of hydroxyurea as a disease-modifying agent in the
treatment of SCD in children and adults, is well documented and is in
common use in resource-rich
countries\textsuperscript{11}'\textsuperscript{12}'\textsuperscript{13}'\textsuperscript{14}As
part of a comprehensive care for SCD that incorporates early detection
through neonatal screening, penicillin prophylaxis, immuno-prophylaxis
and caregiver education on health maintenance and splenic palpation,
hydroxyurea has been shown to significantly reduce acute painful
episodes, hospitalization, transfusions, and protect organs with
consequent improvement in quality of life and ultimately,
survival\textsuperscript{12,15,16} . In 2014, the National Heart, Lung
and Blood Institute recommended offering children hydroxyurea from 9
months of age irrespective of their clinical
symptoms\textsuperscript{17}.

Although Nigeria has the highest global burden of the disease with over
150, 000 SCD deliveries annually and 50-90\% dying before their fifth
birthday, as reported for most parts of SSA\textsuperscript{4,18} many
centers still lack the full complement of a comprehensive care that
includes hydroxyurea
therapy\textsuperscript{19}'\textsuperscript{20}'\textsuperscript{21,22}.
Reasons adduced for paucity of use include inadequate knowledge and
experience on the part of healthcare providers, lack of appropriate
treatment guidelines( including paediatric guidelines), lack of data on
the impact and magnitude of SCD in resource-poor settings, concerns
about response to hydroxyurea in children as influenced by issues of
geography, poverty, health literacy, nutrition, infestations, underlying
host disease and immunological
response\textsuperscript{5}'\textsuperscript{19}'\textsuperscript{23,24}.
There are also concerns about affordability (including multiple
laboratory tests and hospital visits) and sustainability of hydroxyurea
within the weak health system that characterizes most health
institutions in Nigeria\textsuperscript{19,21,22}. These issues raise
questions about adopting results of hydroxyurea use in resource-rich
countries to Nigeria or SSA as a whole.

In 2016, the NOHARM clinical trial in Ugandan children with SCD reported
extensively on the safety and effectiveness of hydroxyurea in
malaria-endemic Uganda even though optimum dosing and monitoring
regimens were not explored\textsuperscript{25}. In 2018, a larger
African-based study on hydroxyurea, involving children with SCD in four
countries in SSA (Angola, Democratic Republic of Congo, Kenya and
Uganda) showed that hydroxyurea treatment was feasible, reasonably safe,
and had both laboratory and clinical benefits\textsuperscript{23}.

Some recent studies about hydroxyurea uptake in
Nigeria\textsuperscript{19}'\textsuperscript{26}'\textsuperscript{27}have
demonstrated the clinical effects of hydroxyurea that may be comparable
to that observed in resource-rich countries and other African countries.
Lagunju et al, while working on Nigerian children with SCD reported the
benefits of hydroxyurea in primary and secondary prevention of
stroke\textsuperscript{28}'\textsuperscript{29}. Focus of research is
consequently on increasing HU uptake. Adeyemo\textsuperscript{24} and
other Nigerian researchers\textsuperscript{5,30,31} have reported
extensively on provider-related barriers to HU use but little is, known
about user- related barriers like feasibility (adherence to drug use,
regular hospital visits, laboratory tests and sustainability of
affordable hydroxyurea). As Nigeria and other SSA countries begin to
devote more resources to the care of patients with SCD, survivors would
be on the increase with a corresponding increase in morbidity making it
compelling that hydroxyurea, an affordable and cost-effective treatment
option, be used to boost their quality of life and
survival\textsuperscript{32}

This retrospective review deals with issues of acceptability,
availability, monitoring, safety and efficacy of hydroxyurea that
constitute barriers to HU uptake from the user perspective. The study
seeks to answer the following research questions: Can patients comply
with daily use of hydroxyurea? Is monitoring of therapy and dose
escalation possible? Is 15 mg/kg/day a safe starting dose of hydroxyurea
for children? Does HU produce adverse effects? Will daily use of
hydroxyurea produce clinical and laboratory benefits? Are parents
satisfied with the use of hydroxyurea? The study may identify modifiable
factors that hamper use of hydroxyurea among paediatric sickle cell
population in Nigeria.

\textbf{Patients, Materials and Methods}

This study is retrospective in design and involves the first set of
patients to use hydroxyurea in the pediatric hematology unit of the
University of Abuja Teaching Hospital from January 2017 to June 2019.
The unit offers comprehensive care to patients with SCD that includes
structured health education, prophylaxis for malaria and pneumococcal
infection with proguanil and penicillin V respectively. Everyone
received daily folic acid and/or non-iron containing multivitamins. All
patients had childhood immunizations according to the National Program
on Immunization but less than 25\% of the patients could afford the
extra immunization recommended for SCD (pneumococcal, meningococcal and
typhoid vaccines). The unit does not have a newborn screening program
and patients do not have access to routine transcranial doppler
screening. Diagnosis of SCD was by hemoglobin electrophoresis and High
Performance Liquid Chromatography.

\textbf{Indications for hydroxyurea therapy:} All the patients aged 1
year to 18 years who had Hb F values of less than 10\% or had a severe
manifestation of SCD such as stroke, acute chest syndrome, repeated
admissions/transfusions as well as patients who expressed interest in HU
were eligible for this pilot trial\textsuperscript{17}. Patients with
severe debilitation were excluded from HU use.

\textbf{Pre-HU Evaluation} : An initial sampling of parental opinion
about HU revealed unfamiliarity with the drug while a few were concerned
about side effects, affordability, and sustainability. Consequently,
patients and families had 2 awareness programs that focused on effects
of HU and dispelling myths. Patient information leaflets were provided.
Families who indicated interest in using HU returned for another session
that allowed them to learn more about monitoring and ask questions
emanating from the leaflet. Those who expressed commitment to follow-ups
were offered therapy. They did baseline evaluations: Hb F levels,
complete blood count, liver function tests (serum bilirubin, alanine
transaminase, aspartate transaminase and alkaline phosphatase), renal
function tests (serum urea nitrogen and creatinine).

\textbf{Dosing of HU/escalation:} Hydroxyurea (Oxyurea) was locally
sourced and patients started on 15mg/kg/day or 10mg/kg/day for steady
state Hb of \textless{} 6gm per dl. The
protocol\textsuperscript{17,33}aims to achieve symptomatic relief and
hematologic response (Hb of 10gm/dl) with the lowest dose of HU that is
sustainable over 12weeks (therapeutic dose). Dose escalation was 3 to 6
monthly to a maximum of 25mg/kg/day as appropriate. HU was available in
capsules of 100mg, 250mg and 500mg and the hospital pharmacy compounded
suspensions fortnightly for infants and toddlers. HU was affordable at
an initial cost of Naira 600=\$1.70 for 100mg pack of 30 capsules; Naira
800= \$2.25 for 250mg pack of 30 capsules; Naira 1100= \$3.07 for 500mg
pack of 30 capsules. Cost of drug increased by 45\% to 62.5\% during
study period because of hospital logistics but some patients could
access a health insurance with annual premium of Naira 15000 (\$41.00)
that covered most laboratory tests and HU.

\textbf{Monitoring and Toxicity} : Patients were seen in the clinic
biweekly for one month (for complete blood counts) and then monthly.
Liver and renal function tests were done 3 monthly for 6 months, then 6
monthly for evidence of toxicity (13 doctor's appointments and 15
laboratory tests in a year). Hb F quantification was repeated at 1 and 2
years of therapy due to cost. During each monitoring visit, patients
were asked about HU acceptability, adherence, side effects and
occurrence of acute events. A physical exam was done every 3 months.
Toxicity was defined as hemoglobin of [?]5g or 20\% decline from baseline
(in the absence of any other cause for the decline), platelets of less
than 80 x 10\textsuperscript{9} /L, absolute neutrophil count of less
than 1.5 x10\textsuperscript{9} /L, alanine transaminase of twice the
upper limit of normal for age or double the baseline value, creatinine
of 2 times baseline value or more than 1 mg/dl. For toxicity, HU was
either reduced by 5mg/kg/day or stopped for 1 to 2 weeks for values to
normalize

\textbf{Data Collection:} Outcome variables for the study are user
barriers (adherence to monthly clinic visits, completion of laboratory
tests, adherence to daily HU), safety (safe starting dose/escalation,
reported and observed side effects), benefits: hematologic (Hb F, Hb,
white cells, platelets, mean corpuscular volume), clinical ( reduction
in acute painful episodes, hospitalization, transfusion, improved
general wellbeing) and parental/patient satisfaction.

Data were initially recorded in patients' case files and later
transferred to a proforma before extraction for analysis.

\textbf{Tracking patients/Missed visits:} The unit relied on case note
documentations and nurses' appointment registers which were often
incomplete or missing. We developed a questionnaire to capture
information on compliance to clinic visits, laboratory tests, HU use and
parental satisfaction with HU therapy. The questionnaire, which was
administered by a trained research assistant, consisted of 12 items and
took about 5 to 8 minutes to complete (appendix1). Patients' responses
were matched with available information in the case notes.

Ethical approval was given by the UATH ethical review board
(UATH/HREC/PR/2019/057) and parents gave consent to provide extra
information to collaborate the case note documentations.

\textbf{Statistical Analysis:}Analysis was with statistical package for
social sciences IBM {[}SPSS{]} version 21 (Armonk, NY 2012). Initial
descriptive analysis of all variables was done using means and standard
deviations for continuous variables (laboratory data) and frequencies
and percentages for categorical variables (user barriers, safety,
clinical benefits and parental satisfaction). The annual mean values of
the laboratory variables were compared with patients' baseline values
pre-HU using the paired Student's t-test. Statistical significance was
set at 0.05.

\textbf{Results}

\textbf{Patient characteristics:} There were 66 males and 50 females.
Most of the patients were HbSS (96.5\%), 3 were
HbS\selectlanguage{greek}β\selectlanguage{english}\textsuperscript{0}thal (2.6\%) and 1HbSC (0.9\%). The median age at
initiation of HU was 9.5 years. Average duration of HU therapy was 18
months (range 12 months- 33months) with an average HU dose of 18.5
mg/kg/day (range of 10 mg-32mg/kg/day). Only 1 patient with persistent
pain received HU dose at 32 mg/kg/day and 3 patients with stroke
received 25 mg/kg/day.

\textbf{Patient retention:} 116 patients were offered HU from January
2017 to September 2019. Eighteen patients (15.6\%) dropped out within 12
months for: lack of funds (50\%), family issues (22\%), drug not working
(16.7\%), bleeding gums (5.6\%), splenic sequestration (5.6\%).
Seventeen other patients (14.7\%) stopped because of family logistics
and lack of funds but resumed therapy after counselling. Three patients
(2.6\%) relocated to other states and another three had missing baseline
data. Only patients who had baseline laboratory data and who had used
hydroxyurea for at least 6 months were used for statistical analysis (N=
89). Patients who had missing data at various stages of the analysis
were analyzed for their available data. Questionnaire was administered
to 114 families (66 Males, 48 Females) including those who stopped
hydroxyurea. Two patients who relocated could not be reached. Response
rate was 100\%.

\textbf{User barriers: Table 1}

\textbf{Adherence to therapy:} Ninety-five (88.8\%) patients reported
taking hydroxyurea daily. Among defaulters, six (50\%) reported failing
to take for 3 months (poor compliance). Table 1 summarizes
c\textbf{ompliance with doctor's appointments and laboratory tests.}Only
26 patients (22.8\%) complied with 13 doctor's appointments in 1 year.
Twenty patients (17.5\%) and 37 patients (32.5\%) completed expected
hematologic and organ function tests respectively.

\textbf{Safety} : \textbf{Starting dose} : Most patients (96.5\%)
received 15 mg/kg /day of HU. Four patients (3.5\%) with Hb
\textless{}6gm/dl received 10 mg/kg/day. \textbf{Dose escalation:}
Escalation of dose was not consistent for logistic reasons and many
patients were on the starting dose for over 6 months. Routine escalation
did not go above 20 mg/kg/day for about 90\% of the patients.
\textbf{Side effects:}Reported side effects are shown in Table 2.
Therapy was stopped for 3 months in a patient with persistent abdominal
pain and was later resumed at a lower dose and gradually escalated. One
child had accidental overdosage of HU suspension (about 105mg/kg/dose)
and therapy was suspended because of transient marrow suppression.
Changes in mean serum alanine transaminase and serum creatinine at
baseline and 18 months are not statistically significant (p=0.312;
p=0.122) respectively. Table 3. No patient had dose-limiting toxic
effects regarding thrombocytopenia, alanine transaminase or serum
creatinine. Mild, transient neutropenia (ANC of 1.34 to 1.5x
10\textsuperscript{9}/l) occurred in 5 patients (5.6\%) that resolved
with dose adjustment.

\textbf{Hematologic} : Baseline values showed anemia (mean of
7.1\selectlanguage{ngerman}±1.3g/dl), low Hb F (mean of 8.2±0.6\%) and leukocytosis (mean of
13.7±0.5 x10\textsuperscript{9}/l). After 24 months of therapy (n=40),
there was significant increase from baseline in Hb (1.6g/dl, 95\% CI 1.1
to 1.7), the mean corpuscular volume (9 fl, 95\% CI 5.2 to 11.4), foetal
hemoglobin (5.3\%, 95\% CI 2.4 to 8.2). Significant increases were also
documented at 6 months, 12 months and 18 months of therapy (Table 3).
There was a progressive and significant reduction in white cell count (
-4.1x10\textsuperscript{9}/l, 95\% CI -4.8 to-2.4), absolute neutrophil
count ( -2.3 x 10\textsuperscript{9}/l, 95\% CI -2.1 to -2.9) from
baseline through 24 months. Table 4. There was a progressive decline in
total bilirubin (TB) over the 2-year period.

\textbf{Clinical effects:} Majority 104 (91.2\%) of the patients
reported an improved general well-being and symptomatic relief Table
2.\textbf{Parental satisfaction:} Most 102 (89.5\%) of the parents
expressed satisfaction with use of hydroxyurea and would like to
continue its use. Table 5 summarizes parental concerns about hydroxyurea
which includes cost of laboratory tests, availability and cost of drugs.

\textbf{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 REACH\textsuperscript{23} and the NOHARM\textsuperscript{25}studies,
as well as some Nigerian studies\textsuperscript{26--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.
Adewoyin\textsuperscript{19} and Aliyu\textsuperscript{31} 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
al\textsuperscript{26} reported 6 monthly monitoring of his paediatric
patients on HU because of cost. Ofakunri et al\textsuperscript{27} 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
Nigeria\textsuperscript{26},\textsuperscript{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 SCD\textsuperscript{21,27,34} 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 India\textsuperscript{35} 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 effect\textsuperscript{36,37,38} 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 escalation\textsuperscript{39}. Researchers in Africa and
Asia are reporting effectiveness of intermittent\textsuperscript{40} or
low-fixed dosing\textsuperscript{35,41} of HU in SCD subjects. In
Nigeria, Titilola\textsuperscript{42} 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

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\verb`TABLE 2.docx`  available at \url{https://authorea.com/users/324442/articles/456983-hydroxyurea-in-children-with-sickle-cell-disease-in-a-resource-poor-setting-monitoring-and-effects-of-therapy-a-practical-perspective}

\textbf{Hosted file}

\verb`TABLE 3.docx`  available at \url{https://authorea.com/users/324442/articles/456983-hydroxyurea-in-children-with-sickle-cell-disease-in-a-resource-poor-setting-monitoring-and-effects-of-therapy-a-practical-perspective}

\textbf{Hosted file}

\verb`TABLE 4.docx`  available at \url{https://authorea.com/users/324442/articles/456983-hydroxyurea-in-children-with-sickle-cell-disease-in-a-resource-poor-setting-monitoring-and-effects-of-therapy-a-practical-perspective}

\textbf{Hosted file}

\verb`TABLE 5.docx`  available at \url{https://authorea.com/users/324442/articles/456983-hydroxyurea-in-children-with-sickle-cell-disease-in-a-resource-poor-setting-monitoring-and-effects-of-therapy-a-practical-perspective}

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