Hydroxyurea Adherence By Personal Best HbF and the 2-Site “HABIT” Intervention Trial for Pediatric Sickle Cell Disease
Authors: Green Nancy S. , Manwani Deepa , Soto Luisa , Karen Ireland , Castillo Yina , Smaldone Arlene M. 
Published: October 2019

Abstract
Introduction: Hydroxyurea (HU) induction of fetal hemoglobin (HbF) is a major therapeutic effect for sickle cell disease (SCD) HbSS or HbSB0thalassemia. Non-adherence to a HU daily regimen is a barrier to its full effect. As no uniform level of HbF induction exists, we hypothesized that a child’s historical “personal best” (PB) HbF level at maximum clinical dose can be used as a marker for HU adherence. The NIH-funded “HABIT” study is a two-site randomized trial to improve patient-centered HU adherence in adolescents age 10-18 years. Eligibility is determined by fall-off from PB HbF over the previous year. Adherence measures include tracking HbF, pharmacy refill data and self-report.
Methods: In a cross-sectional analysis of the entire 2-site clinic-based sample of 95 youth with SCD on HU, ages 10-18 years, and from the subset enrolled in HABIT to date, we assessed demographics, HU use and HbF at pre-treatment, PB and a recent time point. Here, HU non-adherence was defined as ≥20% deviation from PB HbF. Data were analyzed using descriptive statistics and Pearson correlation; groups were stratified by site and participation in HABIT, and were compared using chi-square and student’s t-tests.
Results: Only ethnicity and mean HU dosing significantly differed by site (more Latinos/other and lower HU dosing at Columbia vs. Einstein). Only 39 (41%) youth remained within 20% of their PB HbF, with no significant differences in deviation from PB HbF by: site, gender; ethnicity; age (< or ≥14 years); higher induced PB (HbF of ≥20%); or time to PB (≤ or >1 year). For the 39 adherent to HU, mean deviation from PB HbF was 7.3±8.4% (median 7.2); for the 56 non-adherent, mean deviation was 40.5±16.4% (median 36.8; p<0.001). Greater deviation from PB was associated with: 1) Younger age at HU initiation (r = -0.24, p = 0.03); and 2) Longer duration of HU use (r = 0.28, p=0.009). For the 13 HABIT subjects, significant differences from the other 82 patients were limited to the greater proportion of Latinos/other and slightly older ages. Analyses will be performed to examine relationships between deviation from PB HbF, alterations in MCV, acute clinical events and use of urgent medical services (ER use/admissions).
Conclusion: Our definition of HU non-adherence as ≥20% deviation from Personal Best HbF identified two non-overlapping patient groups ages 10-18 years, with the majority found to be non-adherent. These findings also suggest that HU initiation at younger ages may increase risk of under-adherence during adolescence. PB HbF appears to be a useful marker for HU adherence, and may aid in clinical and patient-centered assessment and intervention. These results underscore the need to assess HU adherence in adolescent patients and for intervention trials such as HABIT.
Abstract 1383. Table: Characteristics of the 2-site sample on hydroxyurea and subjects enrolled in the HABIT study Total(N =95) Columbia (N=39) Einstein (N=56) P value HABIT (N=13) P1 value N % N % N % N % Female gender 43 45.3 18 46.2 25 44.6 0.88 5 38.5 0.60 Ethnicity Hispanic/other2 African Amer 25 59 26.3 62.1 22 17 56.4 43.6 14 42 25.0 75.0 0.002 9 4 69.2 30.8 0.03 Age group 10-13 years 14-18 years 44 51 46.3 53.7 21 18 53.9 46.1 23 33 41.1 58.9 0.22 3 10 23.1 76.9 0.07 Mean SD Mean SD Mean SD Mean SD Current age (years) 14.3 2.6 14.1 2.7 14.4 2.5 0.63 15.7 2.3 0.03 Age at HU initiation (years) 9.2 3.7 8.8 4.3 9.5 3.7 0.44 9.1 4.8 0.91 Age at Personal Best (years) 11.9 3.3 11.2 3.7 12.3 3.0 0.14 13.2 3.7 0.12 HU duration (years) 4.6 3.2 4.9 3.5 4.3 2.9 0.36 6.0 4.2 0.10 Pre-HU HbF HU 7.7 4.8 7.2 4.6 8.1 4.9 0.41 6.6 2.0 0.42 Time to Personal Best (years) 2.5 2.3 2.5 2.7 2.4 2.1 0.96 4.0 3.3 0.09 Personal Best HbF 18.7 6.6 18.5 6.6 18.7 6.7 0.87 18.0 5.8 0.72 HU dose at Personal Best (mg/kg/day) 24.1 3.8 22.6 4.1 25.1 3.3 0.002 25.0 3.8 0.32 Recent HbF 13.6 6.3 13.2 6.4 13.8 6.3 0.62 12.1 5.9 0.36 HbF increase from pre-HU to PB 10.8 6.0 11.6 4.7 10.2 6.8 0.29 11.0 7.2 0.92 Recent HU dose (mg/kg/day) 23.9 4.0 21.9 4.5 25.4 2.7 <0.001 23.5 3.6 0.74 Deviation from PB HbF 28.8 21.7 28.8 21.7 26.2 20.5 0.57 34.1 21.5 0.21 N % N % N % N % Proportion Who Deviate from PB 0.67 0.16 Adherent (≤20% deviation) 39 41.1 15 38.5 24 42.9 3 23.1 Non-adherent (>20% deviation) 56 58.9 24 61.5 32 57.1 10 76.9
1Comparing HABIT subjects to the remaining 82 patients in the sample.
2Designation of “other” includes multi-racial
HABIT: Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment Funding: 5R21NR013745 (PIs NSG and AMS)

Disclosures
Off Label Use: Hydroxyurea is not FDA approved for use in children..