Differential HBV RNA and HBcrAg patterns in untreated patients with chronic hepatitis delta

Abstract

Background and aim

Serum HBV RNA and HBcrAg levels have been proposed as useful biomarkers in the management of HBV patients, however their role in chronic hepatitis Delta (CHD) is currently unknown.

Methods

Consecutive untreated CHD patients were enrolled in a cross-sectional study in three EU centers. Clinical and virological characteristics were collected. Serum HBV RNA and HBcrAg levels were quantified by an automated real-time investigational assay (Cobas® 6800, Roche Diagnostics, Pleasanton, Ca, USA) and by LUMIPULSE® G HBcrAg assay (Fujirebio Europe), respectively. In 18 patients with available liver biopsies, intrahepatic analyses were performed.

Results

Overall, 240 HDV patients were enrolled: median age 46 years, 62% males, 53% cirrhotics, 57% NUC-treated, median ALT 70 U/L, HBsAg 3.8 log₁₀ IU/mL, 88% HBeAg-negative, median HDV RNA 4.9 log₁₀ IU/mL. HBV RNA tested positive (>10 cp/mL) in only 8% of the patients [median 40 (13-82,000) cp/mL], whereas HBcrAg was ≥3 log₁₀ U/mL in 77% [median 4.2 (3.0-8.0) log₁₀ U/mL]. By combining these biomarkers, 3 categories were identified: 23% double negative (HBV RNA neg/HBcrAg neg), 9% double positive (HBV RNA pos/HBcrAg pos) and 68% HBV RNA negative/HBcrAg positive. HBV RNA levels positively correlated with male sex and detectable HBV DNA, while positive HBcrAg correlated with higher HBsAg levels. Double positive patients were younger, non-European, with elevated ALT and HDV RNA levels and detectable HBV DNA. Intrahepatic HDV RNA and HBV RNA were positive in most samples, while intrahepatic levels of covalently closed circular (ccc)DNA were low.

Conclusions

In untreated CHD, most patients had undetectable HBV RNA but quantifiable HBcrAg (“divergent pattern”) in the absence of HBeAg. Additional studies aimed to unravel the molecular mechanisms underlying these findings are warranted.