Outcomes After Antifungal Discontinuation in Immunocompromised Patients Treated for Histoplasmosis

Abstract Background Histoplasmosis is an important opportunistic infection. Current guidelines recommend prolonged antifungal therapy, typically 12 months of therapy. However, antifungal therapy is occasionally discontinued earlier in clinical practice due to medication intolerance, drug interactions, or adherence challenges. Data describing outcomes after antifungal discontinuation in immunocompromised patients remain limited. Methods We conducted a retrospective cohort study of immunocompromised adults treated for histoplasmosis within a large healthcare system between 2005 and 2025. Patients who discontinued antifungal therapy and had clinical follow-up were included. Patients were categorized according to treatment duration (<12 months vs ≥12 months). The primary outcome was a composite of histoplasmosis-related adverse events after antifungal discontinuation, including relapse, hospitalization attributed to histoplasmosis, or histoplasmosis-related death. Secondary outcomes included all-cause adverse events. Cox proportional hazards models with inverse probability of treatment weighting (IPTW). Results 106 patient met inclusion criteria and 75% presented with disseminated disease. Histoplasmosis-related adverse events were uncommon. Relapse occurred in 7/106 (6.6%), including 3/28 (11%) treated for <12 months and 4/78 (5.1%) treated for ≥12 months. No deaths were attributed to histoplasmosis. Shorter treatment duration was not associated with a higher hazard of histoplasmosis-related outcomes (HR 2.34, 95% CI 0.52–10.62). Lower antigen burden at diagnosis was associated with reduced risk of adverse outcomes. Conclusions Relapse after antifungal discontinuation was uncommon. Baseline disease burden, reflected by antigen levels and timing of diagnosis, appeared to influence post-treatment outcomes. These findings suggest further investigation is warranted into individualized antifungal treatment duration based on disease severity and fungal burden.