Empirical Antifungal Therapy Improves Survival in patients with Acute-on-Chronic Liver Failure with Suspected Invasive Fungal Infections: A Pragmatic Randomised Trial

Background: Invasive fungal infections (IFIs) in acute-on-chronic liver failure (ACLF) are associated with transplant de-listings, high morbidity, and mortality. 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 ACLF patients 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 upon laboratory, radiological, or mycological confirmation. Biomarker- 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 to diagnostic/biomarker-driven-pre-emptive therapy (35% vs. 13%; HR: 0.64, 95%CI: 0.47-0.88; p=0.005). Treatment success (37.4% vs. 16.9%; p=0.002), 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 empirical group. Fewer adverse events with greater QALY gains (29.9 vs. 10.1) and an ICER of INR 1,42,737 were observed with empirical therapy. The survival benefit was maximum among patients ≥40 years with cardiovascular failure but without respiratory failure. Conclusion: 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 towards recovery or definitive therapies.