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 p < 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 (p = 0.0469), whereas IL-36α remained elevated and differed at TW48 between combined responders and non-responders (p = 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 (p = 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 (p = 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.

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