Implementation of the therapeutic use of hydroxyurea for sickle cell disease management in resource-constrained settings: a systematic review of adoption, cost and acceptability.

OBJECTIVES: Mortality associated with sickle cell disease (SCD) is high in many low- and middle-income countries (LMICs). Hydroxyurea, a medicine to effectively manage SCD, is not widely available in resource-constrained settings. We identified and synthesised the reported implementation outcomes for the therapeutic use of hydroxyurea for SCD in these settings. DESIGN: Systematic review. DATA SOURCES: PubMed, Embase, Cochrane, Web of Science Plus, Global Health, CINAHL, and PsycINFO were searched February through May 2019 without any restrictions on publication date. ELIGIBILITY CRITERIA: We included empirical studies of hydroxyurea for management of SCD that were carried out in LMICs and reported on implementation outcomes. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently assessed studies for inclusion, carried out data extraction using Proctor et al.'s implementation and health service outcomes, and assessed the risk of bias using ROBINS-I (Risk Of Bias In Non-randomised Studies - of Interventions). RESULTS: Two cross-sectional surveys (n=2) and one cohort study (n=1) reported implementation of hydroxyurea for SCD management, namely regarding outcomes of adoption (n=3), cost (n=3) and acceptability (n=1). These studies were conducted exclusively among paediatric and adults populations in clinical settings in Nigeria (n=2) or Jamaica (n=1). Adoption is low, as observed through reported provider practices and patient adherence, in part shaped by misinformation and fear of side effects among patients, provider beliefs regarding affordability and organisational challenges with procuring the medicine. There was no difference in the cost of hydroxyurea therapy compared with blood transfusion in the paediatric population in urban Jamaica. Risk of bias was low or moderate across the included studies. CONCLUSIONS: This review rigorously and systematically assessed the evidence on implementation of hydroxyurea in resource-constrained settings such as LMICs. Findings suggest that knowledge regarding implementation is low. To address the know-do gap and guide clinical practice, implementation research is needed. Integrating effective interventions into existing health systems to improve hydroxyurea uptake is essential to reducing SCD-associated mortality. PROSPERO REGISTRATION NUMBER: CRD42020155953.

Pancreatic enzyme therapy and clinical outcomes in patients with cystic fibrosis.

OBJECTIVE: To assess the relationship between pancreatic enzyme therapy (PET) and the clinical outcomes of growth, abdominal pain, constipation, gassiness, and number of stools in cystic fibrosis (CF). STUDY DESIGN: Patients (n = 1215) >4 weeks of age from 33 Cystic Fibrosis Foundation accredited sites who had a sweat chloride >60 mmol/L or two CF-causing mutations were enrolled using a proportionate sampling strategy in a nonblinded study. Patients submitted a stool sample and completed a questionnaire. The study coordinator also completed a questionnaire for each patient. Enzyme dosing and growth, abdominal pain, gassiness, constipation, and number of stools were compared. RESULTS: Of the 1215 enrolled patients, 1131 (93.1%) were prescribed PET. Only 14.9% had pancreatic function assessed before enrolling in this study. Stool elastase-1 analysis identified 1074 (89%) patients as pancreatic insufficient (PI). There was no association between PET and the outcomes: growth, abdominal pain, gassiness, constipation, and number of stools. CONCLUSION: PET dose is not correlated with growth or gastrointestinal symptoms. More sensitive outcome measures of the effectiveness of PET in patients with CF are needed to guide treatment of PI.

Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis.

OBJECTIVE: To test the hypothesis that some patients with cystic fibrosis (CF) are misclassified as pancreatic insufficient, using fecal elastase-1 (FE-1) to define pancreatic status. STUDY DESIGN: Subjects with CF at 33 CF centers filled out questionnaires and submitted a stool specimen that was analyzed for FE-1. Subjects taking pancreatic enzyme supplements (PES) were asked to discontinue them and perform a 3-day fecal fat balance study if their FE-1 was >200 microg/g stool and they had never had pancreatitis. RESULTS: The median value for FE-1 in 1215 subjects was 0 microg/g stool (range, 0-867). There was a significant difference between patients who had been prescribed PES (n=1131) and those who had FE-1 <200 microg/g stool (n=1074; P<.0001). Sixty-seven subjects met criteria for discontinuation of PES. The mean coefficient of fat absorption for these subjects was 96.1%. CONCLUSIONS: FE-1 is an accurate, easily obtained screening test to classify pancreatic status in patients with CF. This information is important for prognostication, treatment, and to avoid misclassification in clinical research. Measurement of FE-1 should become a standard of care for patients with CF.