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

Area of Science:

• Hepatology
• Immunology
• Virology

Background:

• Chronic hepatitis delta (CHD) is the most severe viral hepatitis form, rapidly progressing to cirrhosis and hepatocellular carcinoma.
• Bulevirtide (BLV) inhibits hepatitis D virus (HDV) entry, but immunological biomarkers for treatment response and residual activity are needed.
• Interleukin-37 (IL-37) and IL-36 isoforms (IL-36α, IL-36β, IL-36γ) are key immune modulators, but their role during BLV therapy for HBV/HDV coinfection is unclear.

Purpose of the Study:

• To investigate serum profiles of IL-37 and IL-36 isoforms in patients with chronic hepatitis B virus/hepatitis D virus (HBV/HDV) coinfection receiving BLV monotherapy.
• To identify potential immunological biomarkers reflecting treatment response and residual viral activity during BLV therapy.
• To compare cytokine levels between treated patients, HBV-monoinfected patients, and healthy donors.

Main Methods:

• Serum IL-37 and IL-36 isoform levels were measured using ELISA in 22 HBV/HDV-coinfected patients on BLV monotherapy (2 mg/day).
• Measurements were taken at baseline (BL) and 48 weeks post-treatment (TW48).
• Patients were stratified by virological, biochemical, and combined response; comparisons were made with HBV-monoinfected patients and healthy controls.

Main Results:

• HBV/HDV-coinfected patients consistently showed higher serum IL-37, IL-36α, and IL-36β levels than controls, irrespective of treatment response.
• IL-36β decreased over time, especially in biochemical non-responders, while IL-36α remained elevated and differentiated combined responders from non-responders at TW48.
• Baseline IL-37 was lower in virological responders at week 96, and IL-37 positively correlated with HDV RNA levels at TW48, suggesting a link to residual viremia.

Conclusions:

• Patients with HBV/HDV coinfection exhibit a distinct IL-37/IL-36 cytokine signature during BLV therapy.
• The correlation between IL-37 and residual HDV RNA suggests its potential as a complementary biomarker for monitoring low-level viral activity.
• Further investigation into IL-37 is warranted for optimizing treatment monitoring in chronic hepatitis delta.