Hydroxyurea Treatment Reduces Infection Rates in African Children with Sickle Cell Anemia

Introduction: Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is a multicenter prospective clinical trial using open-label hydroxyurea to treat children with sickle cell anemia in sub-Saharan Africa. We previously reported that hydroxyurea treatment is safe and effective in this cohort, and when used at maximum tolerated dose (MTD) leads to significant decreases in the rates of acute vaso-occlusive events, transfusions, stroke, malaria, non-malarial infections, and death. However, the beneficial effects of hydroxyurea at MTD on non-malarial infections, and whether treatment reduces the rate of all infections or just certain types of infections, are poorly understood. In addition, potentially deleterious effects of hydroxyurea during unusual or life-threatening infections have not been investigated. Methods: REACH is a Phase 1/2 open-label trial of hydroxyurea in Angola, Democratic Republic of Congo, Kenya, and Uganda. After a 3-month screening phase, 606 children between age 1-10 years received fixed-dose hydroxyurea at 17.5±2.5 mg/kg/day for 6 months then dose escalation to MTD by Month 24. Thereafter, dosing has been optimized with periodic dose adjustments to maintain mild myelosuppression. Clinical Adverse Events (AE) of grade 2 and above were collected prospectively at all scheduled and unscheduled (sick) visits. Infectious AE were classified by anatomical location, likely etiology, and severity grade. Serious Adverse Events (SAE) were recorded similarly. Rates were calculated based on hydroxyurea exposure in 6-month intervals and by dosing phase. The incident rate ratio (IRR) and 95% confidence intervals (CI) were calculated between Screening and MTD. Unusual infections including tuberculosis (TB), human immunodeficiency virus (HIV), parvovirus, varicella, measles, and mumps were recorded with further details about treatment and outcomes. Results: Clinical AE were analyzed during 4,766 patient-years of observation (111 in screening, 4,655 in treatment). A total of 4,568 infections were recorded (0.96 per patient-year), including 590 (12.9%) Grade 3 or above, and 98 (2.1%) SAE. The overall infection rate significantly decreased from the Screening to Fixed-Dose Phases, and further decreased in the MTD Phase (IRR =0.43, 0.37 - 0.50, p<0.0001). Non-malarial infections (N=3,540) were similarly decreased (IRR =0.43, 0.36 - 0.50, p<0.0001). Infection rates decreased significantly for several categories including upper respiratory tract (N=1101, IRR =0.59, 0.42 - 0.82, p=0.0017), oropharyngeal (N=480, IRR =0.50, 0.32 - 0.78, p=0.0022), lower respiratory tract (N=175, IRR =0.27, 0.14 - 0.53, p=0.0001), and skin infections (N=363, IRR =0.38, 0.23 - 0.63, p=0.0002); other categories were also reduced but not to statistical significance including gastrointestinal (N=208, IRR =0.69, 0.29 - 1.62, p=0.39) and urinary infections (N=65, IRR =0.52, 0.16 - 1.66, p=0.27). Several notable infections were also recorded. Three children developed TB (two pulmonary, one pulmonary plus bone), all of whom continued hydroxyurea at MTD while completing 6-9 months of treatment with rifampin/isoniazid, pyrazinamide, and ethambutol. Two children contracted transfusion-acquired HIV, both of whom have continued hydroxyurea at MTD while concurrently receiving highly active antiretroviral treatment. A total of 35 children had documented varicella infections (32 Grade 2, 3 Grade 3) without sequelae or dose adjustments. Similarly, 6 children acquired mumps, 2 acquired measles infections, and 5 had documented parvovirus infections, none of which became SAE or incurred sequelae. Conclusions: Infections were common in REACH but the majority were minor and without sequelae. Hydroxyurea at MTD led to significantly lower overall rates of non-malarial infections. Specific categories including oropharyngeal, upper respiratory tract, lower respiratory tract, and skin infections were significantly reduced on hydroxyurea, while others (gastrointestinal, urinary) were also reduced but not to statistical significance. Notable infections including TB, HIV, and varicella were documented but the clinical course was unaffected by concomitant hydroxyurea at MTD. These salutary effects of hydroxyurea on overall and specific infection rates provide further evidence for safety and a rationale for wider access across sub-Saharan Africa.

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