IL-37 and IL-36 Cytokine Profiles in Chronic Hepatitis Delta During Bulevirtide Therapy

Chronic hepatitis delta is the most severe form of viral hepatitis and is associated with rapid progression to cirrhosis and hepatocellular carcinoma. Although bulevirtide (BLV) effectively inhibits hepatitis D virus (HDV) entry, immunological biomarkers reflecting treatment response and residual viral activity remain poorly defined. This study investigated the serum profiles of interleukin-37 (IL-37) and IL-36 isoforms (IL-36α, IL-36β, and IL-36γ) in 22 HBV/HDV-coinfected patients receiving BLV monotherapy (2 mg/day). Serum cytokine levels were measured by ELISA at baseline (BL) and after 48 weeks of BLV treatment (TW48) and compared with HBV-monoinfected patients under nucleos(t)ide-analogue therapy and healthy donors. Patients were stratified according to virological, biochemical, and combined responses. At both BL and TW48, serum IL-37, IL-36α, and IL-36β levels were significantly higher in HBV/HDV-coinfected patients than in comparison groups (all <i>p</i> < 0.05), independent of treatment response, indicating a persistent cytokine signature during BLV therapy. IL-36β levels significantly decreased over time, particularly in biochemical non-responders (<i>p</i> = 0.0469), whereas IL-36α remained elevated and differed at TW48 between combined responders and non-responders (<i>p</i> = 0.0400). IL-36γ was detectable only in a small subset of patients. Notably, in a subgroup of patients evaluated at week 96, baseline IL-37 levels were significantly lower in those achieving virological response compared with non-responders (<i>p</i> = 0.0275). Moreover, IL-37 was the only cytokine showing a significant positive correlation with HDV RNA levels at TW48 when quantified by the AltoStar^® assay (<i>p</i> = 0.033; R² = 0.7563). Overall, HBV/HDV-coinfected patients display a distinct IL-37/IL-36 cytokine profile during BLV therapy. The association between IL-37 and residual viremia supports further investigation of this cytokine as a complementary biomarker for monitoring low-level viral activity during treatment.