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.