Health status of Ugandan children born with sickle cell anemia and congenital HIV identified through newborn screening Free

Introduction. In 2014-2015, the Uganda Sickle Surveillance Study (US3) tested almost 100,000 dried blood spots that were originally collected from infants born to HIV+ mothers, documenting a high prevalence and broad geographical distribution of sickle cell anemia (SCA) throughout the Republic of Uganda. Subsequent screening in the highest burden districts confirmed >1% prevalence of SCA births in the central regions. Due to the unique study design of US3, an additional key observation was the identification of infants born with both SCA and vertically transmitted HIV. The consequences of SCA and congenital HIV together are poorly understood, although both likely contribute to morbidity and early mortality in affected children.

Methods. Using all available US3 and post-US3 screening sample results collected between 2014-2020, we designed a retrospective case-control study (Sickle Evaluation and Assessment of Risks: Co-morbidity with HIV, SEARCH, NCT06301893), to evaluate the clinical effects of concurrent SCA and HIV in Ugandan children diagnosed as newborns, comparing cases (children with SCA+ HIV+) versus controls (children with only one or neither condition). Only infants with SCA (HbSS) or normal Hb (AA) were eligible; those born with sickle cell trait were excluded due to their known malaria survival advantage, and hemoglobin variants or equivocal results were also excluded. For each SCA+ HIV+ case, a novel database algorithm identified 3-6 age-matched control children from each additional category (SCA+ HIV-, SCA- HIV+, and SCA- HIV-) within the same geographical region, to improve the likelihood of successful contact. Telephone communication with healthcare facilities and families was first attempted to confirm vital status, clinical complications, and medications for all accessible cases and controls within 150km of Kampala, the capital city. An in-person visit was also offered to complete these questions, and to perform a limited physical exam with limited laboratory studies.

Results. Over this six-year period 258,690 infants were screened for SCA, of whom 2544 were documented to have SCA (1.0%) and 24,923 (9.6%) with HIV. A total of 103 children with both SCA and HIV were identified, average age 5.9 ± 2.8 years, along with appropriately matched controls. Direct communication was attempted for 41 identified cases along with 41 controls from each additional category. Contact was successful for 26 cases, of whom 14 (53.8%) had already died; similar rates of contact were made with 72 controls, of whom 10 (13.9%) had died, p=0.0001 for comparison of proportions. Among children still alive with SCA and HIV, clinical morbidity was documented including malnutrition and sickle-related clinical events. Point-of-care testing documented that SCA+ HIV+ children had an average hemoglobin (Hb) concentration of 9.3 ± 1.9 g/dL, while SCA+ HIV- children had Hb = 7.9 ± 1.8 g/dL. These were lower average values than SCA- HIV+ children with Hb = 12.4 ± 1.7 g/dL or SCA- HIV- children with Hb = 12.0 ± 1.4 g/dL. Almost every HIV+ child was taking antiretroviral therapy, but only one child with SCA was taking hydroxyurea.

Conclusions. Using national screening data, SEARCH has confirmed poor clinical outcomes and high mortality in Ugandan children born with both SCA and congenital HIV, compared to either condition alone. SEARCH documents health disparities for children with concurrent SCA and HIV, and provides insight into key health infrastructure and capacity opportunities within this resource-limited setting. These data support the crucial need for the implementation of clinical guidelines and strategies for the management of both conditions in affected children, particularly to provide disease-modifying and potentially life-saving therapy with hydroxyurea in addition to antiretroviral therapy. Ongoing expansion of well-structured education and training related to SCA diagnosis and care, coupled with wider access to hydroxyurea, represents major steps toward building capacity and improving outcomes for children with SCA in Uganda.