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.
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 trial17. Patients with
severe debilitation were excluded from HU use.
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).
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 < 6gm per dl. The
protocol17,33aims 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.
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 109 /L, absolute neutrophil count of less
than 1.5 x109 /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
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.
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.
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.