The Impact of Cognitive Function on Adherence to Hydroxyurea Therapy in Patients with Sickle Cell Disease
Authors: Merkhofer Cristina , Sylvester Susan , Zmuda Michelle , Jonassaint Jude , De Castro Laura M. , Kato Gregory J , Butters Meryl A. , Novelli Enrico M. 
Published: October 2019

Abstract
Introduction:
Cognitive impairment is a serious complication of sickle cell disease (SCD) that affects both children and adults. While it is known to adversely affect school performance and overall development in children, its functional impact in adults is not known. Importantly, poor disease self-management and adherence to hydroxyurea are major problems in SCD and are likely to be impacted by cognitive impairment. In the study presented herein, we hypothesized that lower cognitive function in areas of memory and executive function would be associated with worse adherence to hydroxyurea therapy in adults with SCD.
Methods:
We designed a cross-sectional study of patients with SCD from the University of Pittsburgh Medical Center Adult Sickle Cell Clinic. Patients who underwent neurocognitive testing between 2011 and 2016 as part of an ongoing neurocognitive study and whose adherence to hydroxyurea therapy has been monitored by a dedicated clinical nurse were included. Performance on four neurocognitive tests of verbal learning, memory and executive function - the Hopkins Verbal Learning Test-Revised (HVLT-R) retention, HVLT-R total recall, Delis-Kaplan Executive Function System Trail Making Condition 4 vs. 5, and Color Word Condition 3 - were selected a priori as explanatory variables. We explored the association between the four test scores and the most recent adherence data at the time of the study. Adherence measures included the laboratory biomarkers red blood cell corpuscular volume (MCV) and percentage of fetal hemoglobin (HbF) - whose values are expected to rise with hydroxyurea therapy - and the patient's self-report of adherence categorized as "good" (≥ 80% adherence) or "less-than-good" (< 80% adherence). Differences between groups were compared by 2-sided t-test or chi-square tests where indicated.
Results:
Study participants (n=48) had a mean age of 35.2 years (range 22-60) and were predominantly female (58.3%). Fifty-two percent had higher than high-school level education, and 72.9% had a HbSS or HbS/β0 thalassemia phenotype. There were no statistically significant differences between the "good" adherence and "less-than-good" adherence groups with regard to these baseline characteristics. As expected, the mean MCV, an objective marker of hydroxyurea adherence, was significantly higher in the "good" adherence group (102.3 ± 15.0 vs. 89.1 ± 11.5 fL, p=0.005), corroborating the patients' self-report. We observed a statistically significant positive correlation between the HVLT-R retention score and MCV that remained significant after adjustment for demographic characteristics (Pearson r=0.309, p=0.033) and a similar correlation with HVLT-R total recall (Pearson r=0.269, p=0.065). A similar trend between HVLT-R retention and HbF percentage was observed (Pearson r=0.260, p=0.081). The mean HVLT-R retention and HVLT-R total recall scores were higher in the "good" adherence group (80.1% ± 27% vs. 64.9% ± 33%, and 41.9% ± 14% vs.34.1% ± 13%, respectively), although the difference between the two groups did not reach statistical significance. There was no significant difference in performance on the Trail Making Condition 4 vs. 5 or the Color Word Condition 3 tests.
Discussion:
Our study suggests that adherence to hydroxyurea therapy in adult patients with SCD might be affected by impairment in episodic memory, as measured in our study through HVLT-R retention, with qualitatively similar patterns by HVLT-R total recall. Although more extensive investigation is warranted, these results suggest that a brief, targeted neurocognitive assessment should be considered as a component of any strategy aimed at improving adherence to hydroxyurea and other therapeutic interventions in patients with SCD.

Disclosures
Jonassaint: Sicklesoft: Other: officer of Sicklesoft. Kato:Mast Therapeutics: Consultancy; Bayer: Research Funding.