(Hydroxy-) Chloroquine, G6PD-deficiency, and sex differences in mortality during the COVID-19 pandemic: An ecological study in Peru

BackgroundPeru implemented a nationwide chloroquine/hydroxychloroquine (CQ/HCQ) treatment policy during the early phase of the COVID-19 pandemic. Whether these drugs trigger hemolytic crises in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd), a genetic condition primarily affecting men, with a relatively high prevalence in certain regions, is a matter of debate. This study investigated whether the CQ/HCQ policy contributed to sex-specific differences in mortality, potentially mediated by regional G6PDd prevalence. MethodsI conducted an ecological analysis using both all-cause excess and COVID-19 mortality data at the state level for adults aged [≥]45 years. Using sex differences in age standardized mortality rates (ASMR) as the outcome in two-way fixed effects (TWFE) models, interaction analyses were performed to examine the influence of regional G6PDd prevalence, CQ/HCQ availability, and elevated healthcare system strain during pandemic waves with the CQ/HCQ recommendation. ResultsMale all-cause excess and COVID-19 mortality consistently exceeded female mortality, with the largest sex differences coinciding with periods with CQ/HCQ treatment recommendations. The TWFE models revealed that states with higher G6PDd prevalence, greater CQ/HCQ availability, and elevated healthcare system strain presented increased male-female mortality gaps. These results are consistent with the hypothesized mechanism in which oxidative stress from both COVID-19 infection and CQ/HCQ exposure contributed to hemolytic crises among (undiagnosed) G6PD-deficient outpatients, potentially misidentified as severe COVID-19 during periods of healthcare strain. ConclusionWhile causality cannot be established owing to the ecological design, these findings suggest that pandemic treatment policies may have unintended, sex-specific consequences if population-specific genetic vulnerabilities are overlooked. They underscore the broader public health implication that drugs considered safe under normal conditions may have unanticipated risks during infectious crises that induce additional oxidative stress, emphasizing the importance of integrating genetic risk awareness into future emergency response frameworks.