1. Hydroxyurea For the Management of Childhood SCD in Kenyan County Hospitals Hydroxyurea for SCD Panel

2. Objectives To understand the background to the emergence of hydroxyurea as a therapy for SCD and review the evidence available to inform decision making – Should Hydroxyurea be promoted for prophylactic treatment of SCD in children aged <5 years being managed in County hospitals At what stage of disease might introduction be considered Are there any specific conditions for using the drug To provide preliminary recommendations to MoH on use of HU

3. Outline Background Evidence Summary on quality of evidence (as per panel discussions) Panel deliberations

4. Burden of SCD It is estimated 312 000 neonates globally are born yearly with SCD (HbS) homozygous type (Piel FB 2013). 75% of the burden is in sub-Saharan Africa (WHO 2006) Mortality is high in children aged between 6 months and 3 years (Leikin SL 1998,Rogers DW 1978) High mortality rate of 7.3 (4.8-11.0)per 100 Patient years Of Observation in <5 years in Tanzania (Makani J 2011)

5. Existing guidelines GOK Clinical Guidelines 2009 (expert meeting): – Hydroxyurea only for (adult) patients with more than 3 painful crises in a year – Supportive care (analgesics, supplementary folic, malaria prophylaxis when travelling to malaria endemic zone, penicillin prophylaxis)

6. Guideline relevant question populationInterventionControlOutcomes Children( <5 years) with Severe SCD OR Children (<5 years) with SCD at first presentation in the clinics HydroxyureaConventional care Critical; Mortality, Hospitalizations PlaceboImportant; Pain episodes, Toxicity

7. Study selection IDENTIFICATION (Pubmed,clinical trials web, Cochrane Lib.) SCREENING (Titles and abstracts) ELIGIBILITY (full articles assessment) INCLUDED (Studies included for analysis) N=98 N=44 N=19 1 Syst. review 2 RCT 14 observational studies 2 NIH reports

8. BABY-HUG TRIAL 2011 PopulationIntervention (n=96) Comparator (n=97) Outcomes Children aged 9-18months irrespective of clinical severity Hydroxyurea (Fixed dose of 20mg/kg) PlaceboPrimary Outcomes Splenic function Renal function Secondary Outcomes Adverse clinical events Hematological Toxic effects

9. Results (secondary outcomes) Outcome (total events) HU Group (n=96)Placebo Group (n=97) Hazard Ratio (95% CI) Pain1773750.59(0.42-0.83) Dactylitis241230.27(0.15-0.50) Acute Chest Syndrome 8270.36(0.15-0.87) Hospitalizations2323240.73(0.53-1.00) Transfusion35630.55(0.32-0.96) Mild-Moderate Neutropenia 107 times in 45 children 34 times in 18 children 3.0(1.7-5.1)

10. Summary OutcomeHazard ratio(95% CI)Quality Of Evidence MortalityLimited evidence- Hospitalizations0.73(0.53-1.00) Low Toxicity (Mild-Moderate Neutropenia ) 3.0(1.7-5.1)Low Pain Episodes0.59(0.42-0.83)Moderate

11. Consensus on balance of benefits versus harms: Hydroxyurea vs no HU Mild form of diseaseSevere form of disease Monitoring availableHarms outweigh benefits (Majority) Benefits outweigh harms (Unanimous) Monitoring not availableHarms outweigh benefits (Unanimous) Benefits outweigh harms (Considerable number) Benefits balances harms (Half of the Panel)

12. Panel proposed definition of severe disease as possible indication for initiating HU Pain crises ( >3 /year) Primary stroke Transfusions( ≥2/year) Acute chest syndrome Hospitalizations which are Sickle cell Disease related(to be specified further) Splenic sequestration

13. Panel proposed Monitoring Requirement Where monitoring comprises: Monthly monitoring at the minimum Monitoring includes: Complete blood count Hemoglobin White blood cell count especially the neutrophils Platelet counts

14. Panel view on formulations of HU Currently 500mg available Recommendation: Appropriate capsules should be procured of different strengths (200mg, 300mg, 400mg) prior to widespread implementation of HU in GoK hospitals able to provide minimum monitoring.

15. Areas for research Need to get better data on the burden of SCD in the country Studies on effect of Hydroxyurea on morbidity and mortality (including harms) are required Data on long term effects of HU are required

16. Draft Recommendation ‘Hydroxyurea at a standard dose of 20mg/kg/day should be considered for use in children below 5 years for management of severe form of sickle cell disease where minimum monitoring conditions and appropriate formulation are available’