Empirical Antifungal Therapy Improves Survival in Patients With Acute-on-Chronic Liver Failure With Suspected Invasive Fungal Infections: A Pragmatic Randomized Trial

INTRODUCTION: Invasive fungal infections (IFIs) in acute-on-chronic liver failure (ACLF) are associated with transplant delistings, high morbidity, and mortality. An optimal strategy of antifungal therapy in this setting remains uncertain. We compared suspicion-based (empirical) with investigation-driven (diagnostic/biomarker-driven-pre-emptive) antifungal therapy among patients with ACLF in a high-burden setting. METHODS: In this parallel-group, pragmatic, randomized trial with blinded endpoint adjudication (NCT04157465), 216 hospitalized ACLF patients with predefined host and clinical factors for IFI were randomized (1:1) to empirical antifungal therapy at enrolment or diagnostic/biomarker-driven-pre-emptive therapy on laboratory, radiological, or mycological confirmation. Biomarker-guided and culture-guided antifungal stewardship protocols were implemented in both groups. The primary outcome was 28-day overall survival. Secondary outcomes included in-hospital mortality, changes in severity scores, adverse events, and cost-effectiveness. Heterogeneous treatment effects were explored through causal tree analysis. RESULTS: Empirical antifungal therapy significantly improved 28-day survival compared with diagnostic/biomarker-driven-pre-emptive therapy (35% vs 13%; hazard ratio: 0.64, 95% confidence interval: 0.47–0.88; P = 0.005). Treatment success (37.4% vs 16.9%; P = 0.002) and IFI resolution (45.8% vs 22.5%, P = 0.001) were higher; in-hospital and IFI-attributable mortality (55.6% vs 75.9%; P = 0.003) was lower in the empirical group. Fewer adverse events with greater quality-of-life years gains (29.9 vs 10.1) and an incremental cost-effectiveness ratio of international normalized ratio 1,42,737 were observed with empirical therapy. The survival benefit was maximum among patients aged 40 years or older with cardiovascular failure but without respiratory failure. DISCUSSION: Early empirical antifungal therapy within a structured stewardship framework improves survival in patients with ACLF and IFIs. Timely recognition, rapid diagnostics, and individualized antifungal strategies are essential to bridge these high-risk patients toward recovery or definitive therapies.