Thymosin α1 improves the outcomes of patients with hepatitis B virus-related acute-on-chronic liver failure by restoring immune balance.
This open-label randomized controlled trial (NCT03082885) enrolled 73 patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF), randomizing them to standard medical therapy (SMT, n=38) or SMT plus Thymosin α1 (Tα1, n=35), with a primary endpoint of 90-day transplant-free survival. Using flow cytometry and ELISA, researchers characterized peripheral immune cell subsets and serum cytokines at baseline and over follow-up. The study found that 90-day survivors had higher baseline effector T (TE) cell proportions, lower regulatory T cells (Tregs), and higher pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) compared to non-survivors. Non-survivors developed a progressive hyperinflammatory trajectory over time. Tα1 treatment was associated with improved 90-day transplant-free survival, reduced Treg frequencies (including CD226 low/- Treg subsets) at weeks 4–8, and moderation of late-stage hyperinflammation without suppressing early immune activation. The authors conclude Tα1 may rebalance immune responses in ACLF. Key limitations include the open-label design, relatively small sample size, and a single-center context, which may limit generalizability.
Why this grade: This is a registered, randomized controlled trial in human patients with a clinically meaningful endpoint, but its open-label design, modest sample size (n=73), and single indication limit the strength of evidence to moderate.
Background Thymosin α1 (Tα1) has been shown to improve survival in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF), but its immunomodulatory mechanisms remain unclear. This study investigated how Tα1 restores immune homeostasis to confer a survival benefit in these patients. Methods In this open-label, randomized controlled trial (NCT03082885), 73 patients with HBV-ACLF received either standard medical therapy (SMT, n = 38) or SMT plus Tα1 (n = 35). Peripheral blood immune cell subsets were analyzed by flow cytometry and serum cytokine levels were measured by ELISA. Patients were stratified by 90-day transplant-free survival. Results Patients who survived at 90 days exhibited a higher proportion of effector T (TE) cells and lower levels of regulatory T cells (Tregs) at baseline compared to non-survivors. Survivors also had significantly higher initial levels of pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) and lower levels of TGF-β. Over time, survivors showed a gradual decline in inflammatory markers, whereas non-survivors developed a progressive inflammatory storm. Tα1 treatment significantly increased 90-day transplant-free survival and was associated with reduced frequencies of Tregs and CD226 low/- Treg subsets at weeks 4-8. Tα1 also moderated the late-stage hyperinflammatory response without compromising early immune activation. Conclusions Tα1 improves clinical outcomes in HBV-ACLF by rebalancing the immune response-mitigating excessive inflammation and preventing immune paralysis by modulating T-cell differentiation and cytokine production, thereby breaking the cycle of hyperinflammation and immunosuppression that characterizes ACLF progression.
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