Trends in Incidence and Risk Factors of HIV-Associated Disseminated Histoplasmosis in the Americas: An Observational Cohort Study

Introduction: Histoplasmosis remains a significant cause of morbidity and mortality in people with HIV. We examined disseminated histoplasmosis incidence, risk factors, and outcomes from North and South American HIV clinical sites. Methods: Cohorts from Brazil, Chile, Honduras, Mexico, Peru and the United States (Tennessee) contributed data on PLWH ≥18 years old from 2000 to 2021. Stratifying by US and Latin American cohorts, we examined diagnosed disseminated histoplasmosis incidence and risk factors with modified Poisson regression models. Cox proportional hazard models examined factors associated with mortality after histoplasmosis. Results: Of 26,672 people with HIV (Latin America n = 19,836; United States n = 6836), 214 had incident histoplasmosis(Latin America n = 140; United States n = 74). From 2000 to 2021, histoplasmosis incidence decreased from 16.08 to 0.93 in Latin America and 13.4 to 0.67 per 1000 person-years in the United States. In Latin America, histoplasmosis risk was higher for males (aRR = 2.50 [95% CI: 1.62−3.86]), pre-antiretroviral therapy initiation (aRR = 7.76 [95% CI: 5.05−11.90]) and those who had migrated from a histoplasma-endemic country (aRR = 6.12 [95% CI: 1.81−20.69]). Risk was also higher for older people with HIV, those with low CD4, earlier calendar year and differed by site. In the United States, risk was higher in people with HIV with low CD4, higher HIV viral load, earlier calendar year and pre-antiretroviral therapy initiation (aRR = 2.65 [95% CI: 1.11−6.36]). Mortality after histoplasmosis was higher in people with HIV with an earlier year of histoplasmosis 2000 versus 2010 (aHR = 2.00 [95% CI: 1.26−3.17]) and among those who developed histoplasmosis after antiretroviral therapy initiation compared to before antiretroviral therapy (aHR = 2.66 [95% CI: 1.43−4.95]). Conclusions: Despite concern for underdiagnosis of disseminated histoplasmosis in Latin America, its incidence in people with HIV decreased, as it did in the United States. Low CD4 cell count and time before antiretroviral therapy initiation remain strongly associated with histoplasmosis risk. Further attention to early HIV diagnosis and treatment is needed.