Funder: National Institute of Mental Health
Project period: 07/17/2025 - 07/17/2027
Grant Type: Research
Abstract Text:
Sub-Saharan Africa (SSA) bears the highest numbers of persons living with HIV (PLHIV), a group for whom holistic treatment also necessitates careful monitoring for noncommunicable diseases. SSA also bears the bulk of the malaria burden, and this pressure has led to the selection for alleles conferring G6PD deficiency (G6PDdef) which protect against malaria. Previous work by our group and others have found the presence of at least a single A- allele, the most common G6PDdef variant in Africa, to be as high as 20% among Ugandan children, though rates of other low activity alleles have been poorly documented. Recent work has revealed a surprising consequence of this adaptive selection. Hemoglobin A1C (HbA1c), a widely used measure to both diagnose and monitor treatment of diabetes, is unreliable in people with G6PDdef.1 In conditions where RBC turnover is increased, like G6PDdef, HbA1c is inaccurate. Consequently, there is a significant underestimation of chronic glucose burden in overlapping G6PDdef and HIV endemic populations. Thus, in order to most effectively manage HIV in areas with the highest rates of G6PDdef (SSA), an alternate measure of glucose metabolism must be investigated and applied. The impact of G6PDdef on diabetes management in malaria endemic regions has been poorly studied, possibly due to the difficulty in establishing a feasible experimental design. The proposed study will leverage our recently funded R01 investigating therapeutic interactions between HIV and malaria (OPTIMAH trial), where metabolic assessments are already planned to evaluate for metabolic effects of dolutegravir in HIV-infected children. Within the context of this trial, we are ideally poised to explore the impact of G6PDdef on glucose measurements. The OPTIMAH trial has longitudinal assessment of HbA1c and other measures of glucose handling over a 2-year period. Funds from the CIRA/YIGH award will allow us to test participants for G6PDdef using quantitative pectrophotometric analysis, the gold-standard method for measuring enzyme activity, alongside next-generation amplicon sequencing to determine allele composition. In participants with G6PDdef, it is theorized that there will be a discordance between the HbA1c and other glucose measurements. Ultimately, we hope to elucidate which glycemic metric is optimal in HIVinfected and HIV-uninfected children with G6PDdef in a malaria-endemic region. We will achieve this by conducting the following aims. In Aim 1, we will determine prevalence of G6PDdef in children enrolled in the OPTIMAH Trial. We will obtain G6PD phenotype, using spectrophotometric assays, and genotype, using amplicon sequencing, to determine the prevalence of G6PDdef in n=160 HIV-infected and n=220 HIV uninfected children in two sites in Uganda. In Aim 2, we will determine the degree of concordance between HbA1c and CGM based glycemic metrics in children with G6PDdef in the OPTIMAH trial. These data will assist in implementing better ways to screen for diabetes in the sizable G6PDdef population residing in the highest HIV endemic region on the world.
