Sahel Medical Journal

ORIGINAL ARTICLE
Year
: 2018  |  Volume : 21  |  Issue : 4  |  Page : 189--193

The use of hydroxycarbamide in children with sickle cell anemia


Hafsat Rufai Ahmad, Jamilu Abdullahi Faruk, Adekunle Matthew Sobowale, Amos Solomon, Adebiyi Niyi Mustapha, Olufemi Gboye Ogunrinde 
 Paediatric Haematology/Oncology Unit, Department Of Paediatrics, Ahmadu Bello University/Teaching Hospital, Zaria, Nigeria

Correspondence Address:
Dr. Hafsat Rufai Ahmad
Department of Paediatrics, Paediatrics Haematology/Oncology Unit, Ahmadu Bello University Teaching Hospital, Zaria
Nigeria

Abstract

Background: Although hydroxycarbamide (hydroxyurea [HU]) has been in use for decades in both adults and child populations with sickle cell disease (SCD), its reported use has remained low in Africa and Nigeria where the largest number of SCD patients reside. Availability, cost, and concerns about safety and efficacy are some of the challenges to its use. Objectives: This study highlights the experience of using HU for children with sickle cell anemia in Ahmadu Bello University Teaching Hospital, Zaria. Materials and Methods: A descriptive, retrospective observational study of children is presented. Demographic, clinical, and laboratory features of children on HU, the indications for therapy and adverse clinical events encountered were analyzed. Results: A total of 165 children were treated with HU over a 4-year period, their ages ranging between 0.9 and 17 years. A total of 85 (47.5%) had HU for >12 months, while 61 (34.1%) were on treatment <11 months, while 19 (10.2%) were lost to follow-up. There was a significant increase in the weight, height, fetal hemoglobin, mean corpuscular volume, and a significant reduction in white cell counts; with no differences in the packed cell volume, hemoglobin concentration, creatinine, alanine transaminase, and bilirubin levels. Adverse events and/or comorbidities were reported in 48 (56.5%) patients, while one patient discontinued treatment because of skin rash. Conclusion: This study highlights the increased utilization of HU among children in an African region, the observed clinical events, and laboratory parameters. The benefits are demonstrable, and the drug-related organ toxicities appear minimal.



How to cite this article:
Ahmad HR, Faruk JA, Sobowale AM, Solomon A, Mustapha AN, Ogunrinde OG. The use of hydroxycarbamide in children with sickle cell anemia.Sahel Med J 2018;21:189-193


How to cite this URL:
Ahmad HR, Faruk JA, Sobowale AM, Solomon A, Mustapha AN, Ogunrinde OG. The use of hydroxycarbamide in children with sickle cell anemia. Sahel Med J [serial online] 2018 [cited 2019 Jan 21 ];21:189-193
Available from: http://www.smjonline.org/text.asp?2018/21/4/189/249078


Full Text



 Introduction



Hydroxycarbamide or hydroxyurea (HU) has been in use for decades in adult sickle cell disease (SCD) patients. Of recent, several studies, including the BABY HUG study, have demonstrated the safety and efficacy of HU in preventing severe SCD manifestations in children.[1] The National Institutes of Health's Expert Panel Report 2014 recommends starting infants from 9 months of age and older children and adolescents with SCD, on HU treatment regardless of clinical severity.[2] This is to delay the development and minimize the severity of these complications in the new patient and to reduce their frequency and severity in the patient that has already developed them. Other studies have also shown that the burden of caregivers of patients who did not take HU was significantly higher than those of patients on HU.[3] Despite HU being on the WHO essential medicines list, its availability is far from universal, and there are still concerns as to its safety and efficacy in the African child, prompting several studies from the continent including the REACH trial.[4] Others have opined on the efficacy of low-dose HU in the control of symptoms of SCD.[5] Data from developing countries are beginning to emerge, showing the acceptability,[6] and some of the benefits and adverse effects in these populations.[7],[8]

The Federal Ministry of Health of Nigeria published its guidelines for the management of SCD in 2014, which recommended the use of HU in persons with greater than five severe pains crises per year, acute chest syndrome, or stroke, among other things.[9] However, the use of HU in Nigerian children is not consistent across the centers treating SCD patients in the country. Data from the use of HU in the adult Nigerian population are beginning to emerge and appear promising.[10]

We present a description of the characteristics of patients using HU at Pediatrics Hematology Unit, of Ahmadu Bello University Teaching Hospital, Zaria.

 Materials and Methods



A descriptive, retrospective study, of children taking HU, was undertaken. Case notes and clinic records of patients were reviewed. Demographic data, as well as relevant clinical and laboratory information, were collated and analyzed. Patients' age, weight and height, as well as HU dosage, and duration of treatment were extracted. Indications for HU therapy, adverse events, and clinical events reported during therapy were also extracted. The laboratory parameters obtained at the beginning of therapy, and at the last, hospital visit was computed and expressed as simple differences and means. For anonymity, patients' names were omitted from data entry. Data were stored in passworded file and shared only among the research participants. For all patients starting HU, consent is obtained about sharing their information with other relevant health workers within ABUTH, Zaria and beyond where clinically indicated and for possible publishing. Ethical permission to publish this review was granted by Health Ethics Research Committee of ABUTH Zaria ABUTH/HREC/D32/2018 dated 4th September, 2018.

 Results



Over a 4-year period, from 2014 to 2018, a total of 179 sickle cell anemia patients at Pediatrics Hematology clinic, ABUTH, Zaria, were evaluated and offered HU therapy. Out of this figure, 165 (92.2%) patients accepted and commenced HU therapy, while the remaining 14 (7.8%) rejected the treatment for fear of possible side effects such as infertility and development of secondary cancer. Among the patients on HU, 85 (47.5%) had HU for 12 months or more, while 61 (34.1%) were on treatment for 11 months or less. The remaining 19 (10.2%) were lost to follow-up. Further inquiries revealed that six children had relocated to other parts of the country among which four had continued HU without supervision and two had discontinued due to nonavailability of the drug at their new location; three had died and we could not trace the remaining 10, therefore, their outcomes could not be ascertained. An analysis of the 85 patients on HU for 12 months or more was done. These comprised 48 (56.5%) boys and 37 (43.5%) girls, and a male:female ratio of 1.3:1. Their ages ranged from 0.9 to 17 years, with a mean age of 7.5 ± 4.3 standard deviation (SD). There were two infants, aged 10 months and 1 year, with those aged under-five accounting for 36.9%. Age groups 5–10 years made up 36.9% also, while 11–15 years contributed 23.4%, and the remaining 2.8% being a 16 and 17 years old each.

Duration of hydroxyurea therapy

The minimum duration of HU treatment in the review period was 12 months in nine (10.6%) patients, while the maximum duration was 52 months in one (1.2%) patient. The average duration of therapy was 19.3 (±6.1 SD) months, median 18.5 months, and a mode of 21 months.

Indications for hydroxyurea therapy

Various clinical conditions were encountered in the patients on HU therapy, as summarized in [Table 1].{Table 1}

In five of the patients, there was more than one indication for the commencement of HU therapy. For example, one patient had stroke, and developed avascular necrosis of the femur, and subsequently developed iron-overload from chronic blood transfusion, therefore, opted to switch to HU therapy.

Initiation and maintenance dose of hydroxyurea

Patients were commenced on HU based on their body weight and approximated to the nearest convenient dose formulation. Lower dosages of HU were employed at the commencement of HU and gradually increased as appropriate. The recommended HU dosing in children is between 15 and 35 mg/kg. The child is started at 15 mg/kg, and stepwisely increased until the maximum dose or maximum tolerable dose is reached.

From [Table 2], it can be seen that the minimum dosing employed was 7.4 mg/kg body weight, while the highest dose used for maintenance was 30.4 mg/kg body weight.{Table 2}

Adverse events and comorbidities reported during hydroxyurea therapy

Among the 85 patients on HU for ≥12 months, 48 (56.5%) patients reported at least one or more complaints or were assessed to have a morbid condition directly or indirectly related to SCD or HU therapy. In total, 155 episodes or events were documented in the participants on HU therapy, as shown in [Table 3].{Table 3}

In [Table 3], the 17 episodes with sepsis/infections comprised two measles infections, four malaria infections, one patient had chicken pox, two were treated for hepatitis, one case each of conjunctivitis, impetigo and candidiasis, one patient with lymphadenitis, a case with urinary tract infection, and three patients managed as sepsis.

The one case of body rash was suspected to be an adverse reaction from the HU, which prompted discontinuation of the drug.

Anthropometry and laboratory parameters of subjects on hydroxyurea

A comparison of the anthropometry and laboratory parameters of the patients before the commencement of HU and during HU therapy, as at the time of the last visit was performed. Only paired results were included for this analysis, as shown in [Table 4].{Table 4}

As can be seen from [Table 4], there were apparent increases in the weight, height, packed cell volume (PCV), hemoglobin concentration, fetal hemoglobin, mean corpuscular volume (MCV), creatinine, alanine transaminase (ALT), and bilirubin levels. However, only the changes in weight, height, hemoglobin F (HbF), and MCV were of statistical significance. On the other hand, there was a statistically significant reduction in the white cell count (WBC) during the treatment with HU.

On further analysis, the parameters of patients who had HU for <12 months were done, as shown in [Table 5].{Table 5}

The patients on HU for <12 months also had an increase in their weight, height, PCV, and reduction in WBC, as well as a reduction in creatinine and statistically significant reduction in ALT.

 Discussions



This review has summarized the experience with HU use from pediatrics hematology of ABUTH, Zaria. There has been an escalation in the use of HU in recent years, owing to the availability of child-friendly dosage formulations, increased advocacy, and awareness among caregivers. It is noteworthy that the infants on HU, in this review, were already manifesting severe features of SCD with recurrent anemias and multiple hospitalizations. Similarly, the adolescents aged 16 and 17 years were having frequent crises; hence, the need to offer them HU therapy. Interestingly, a sizeable proportion of the participants requested to start HU, in the absence of severe manifestations of SCD in the affected children; or accepted to commence HU following voluntary counseling.

Although most of the patients were on HU for at least 12 months, two of the patients had been on HU for 42 months or more, and had significant reduction of symptoms, to the extent that one had a surgical intervention for the avascular necrotic hip, without additional comorbidity or need for blood transfusion. Majority of caregivers reported increased level of energy and well-being in the children on HU, although this was not objectively quantified.

Lower doses of HU were used in the present patients, due to previous concerns as to the safety of HU in an infection-ridden environment. Consequently, low-dose HU (10 mg/kg) is thought to be equally effective, less toxic, and ideal in resource-poor settings.[5]

The spectrum of comorbid conditions and episodes encountered reflect commonly seen illnesses in children with or without SCD. The vaso-occlusive episodes (VOE) recorded may appear high but were considerably lower than the number of VOE before the commencement of HU, although poor record keeping before HU commencement prevented objective quantification of these changes. The total number of VOE recorded in this review, as well as the other comorbidities are similar but lower than the numbers reported from the BABY HUG trials.[1] This may just be a reflection of the differences in study design and methodology, rather than a claim to improved efficacy in this review.

The stroke episodes were recorded in patients whom had commenced HU few months earlier, before HU dose escalation could be achieved. Gastroenteritis and respiratory tract infections are commonly encountered in HU patients, as was the case in this study.[1],[8] However, for a malaria-endemic region, there were few malaria infections to consider it excessive at the moment. Although looking at all the episodes of fever without focus and sepsis/infections altogether, there is still some basis to be worried about the increased frequency of infections in HU patients, as previously echoed in studies from the region.[7],[8]

HU exerts its beneficial effects through the induction of HbF, and there was a marginal, although statistically significant rise in its levels in the present study. This mirrored the marginal rise in PCV and Hb as well. This is not in keeping with findings from previous studies, which showed statistically significant increases in hemoglobin concentrations and HbF levels.[1],[10] A possible explanation here is the fact that the present study utilized lower doses of HU. The other laboratory parameters were equally interesting. There were no significant differences in the creatinine or liver functions, which suggest an absence of damage to the kidneys or liver in these participants. Comparing [Table 4] and [Table 5], the parameters in patients on HU for <12 months showed a similar change in direction and statistical significance, with those of the patients taking HU of course, these are weighty conclusions to derive from such a small review as this; however, it will serve as an impetus for more robust use of HU, and diligent data collation to amass the necessary evidence in support or against HU therapy in the subcontinent.

Finally, while adherence to HU was quite high, many participants relied heavily on goodwill and charity to be able to sustain a regular supply of HU. In a few instances, drug stock-outs were also encountered. This reechoes the concerns of lack of universal accessibility and availability of HU particularly in the most SCD afflicted areas. It could potentially negate any perceived benefits of newborn screening programs and other core SCD control initiatives in these resource-poor regions.

 Conclusion



This study has described the utilization of HU in a tertiary center on the African subcontinent, the relative lower dosing regimen employed, as well as the profile of clinical manifestations encountered before and during HU therapy. It is apparent that there are potential benefits, as well as tolerable adverse events. This work should serve as a fulcrum for more robust and focused studies on the use of HU in the control of SCD in the most afflicted impoverished regions.

Acknowledgments

The authors would like to thank Dr. Farruck Shah of Whittington Hospital NHS, London, UK, for reviewing the HU protocol. The authors greatly appreciate the effort of all the doctors and nursing staff of Pediatric Consultant Specialist Clinic of ABUTH, Zaria, for assisting in the management of these children.

Financial support and sponsorship

HU support for some patients was funded by Hafsat Rufai Ahmad.

Conflicts of interest

There are no conflicts of interest.

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