Hydroxyurea is the only safe and efficacious medication to prevent complications of sickle cell disease (SCD) in children. Unfortunately, hydroxyurea requires daily dosing and frequent drug monitoring. Our objectives were to assess adherence to hydroxyurea, the impact of adherence on hematologic response, and whether we could identify those children at greatest risk for non-adherence for a future intervention. Between 2006 and 2008 children with SCD who had been taking hydroxyurea for ≥5 months were enrolled in an IRB-approved study of treatment adherence. Because adherence is difficult to measure, we used multiple estimates: attendance at clinic visits (visit within 0.5 month of recommended time frame indicating good adherence); caregiver-report with a previously validated instrument (the Modified Morisky Scale; range 0–4; ≤1 indicating good adherence) and with a visual analog scale (VAS) developed for this project (>75% of doses within the last 3–4 weeks indicating good adherence); provider estimates of adherence completed by the physician or physician extender seeing the patient in clinic (“often” or “always” adherent indicating good adherence); and pharmacy prescription refills (≥5 month-supply refills in the six months prior to enrollment indicating good adherence). Caregivers also completed a written survey regarding hydroxyurea utilization. Eighty-three children with SCD enrolled in the study (46 males and 37 females, ages 3.5–17.8 years). The average duration of hydroxyurea therapy at study entry was 4.6 years (range 0.4–11.3). The mean dose at the time of the study was 24.2 mg/kg/day (range 16.6–31.6). Between hydroxyurea initiation and enrollment in this study hemoglobin increased by 1.3 g/dL (95% CI: 1.1–1.5; p<0.0001); mean corpuscular volume increased by 14 fL (95% CI: 10–17; p<0.0001); and %HbF increased by 7.7% (95% CI: 6.0–9.4; p<0.0001). Eighty-nine percent of caregivers rated hydroxyurea as very valuable. More than 90% of parents agreed that hydroxyurea prevents pain and helps their child be more active, lead a more normal life and go to school. Good adherence was estimated at 82% by VAS; 85% by Morisky score; 84% by medical provider report; 77% by clinic visits; and 46% based on pharmacy refills. Increase in hemoglobin was significantly associated with good adherence as measured by the parent/proxy Morisky score (r= −.26; p=0.02) and prescription refills (r =0.30; p<0.01) when adjusting for dose, age at enrollment and length of treatment. The number of pharmacy refills and the Morisky score explained approximately 29% of the variation in hemoglobin response. In summary, families value hydroxyurea and believe that hydroxyurea provides significant benefits. The estimate of adherence was >75% by 4 out of 5 measures. However, the estimate based on pharmacy refills was <50%. Pharmacy refills may underestimate adherence due to extra stock of drug at home or drug dispensed during hospitalization. Alternatively, patients may not fill prescriptions even though they attend clinic visits and report adherence. Although there was an overall significant hematologic response to hydroxyurea, the response was variable. Given that only 29% of the hematologic response was explained by adherence, there are likely multiple pharmacodynamic factors which contribute to response variability. Pharmacy refills and Modified Morisky Scale may be used to identify: children at high risk for poor response due to non-adherence and children with good adherence with poor response due to individual pharmacodynamics. Future hydroxyurea effectiveness research should include improvements in disease specific adherence measures, clinical measures of effectiveness and methods to improve treatment adherence.

Disclosures: Off Label Use: off-label use of hydroxyurea in children.

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