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

Serum HBV RNA and hepatitis B core-related antigen (HBcrAg) levels have been proposed as useful biomarkers in the management of patients with HBV; however, their role in chronic hepatitis delta (CHD) is currently unknown.

Consecutive untreated patients with CHD 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.

Overall, 240 patients with HDV were enrolled: median age 46 years, 62% male, 53% with cirrhosis, 57% nucleos(t)ide analogue treated, median ALT 70 U/L, median HBsAg 3.8 log₁₀ IU/ml, 88% HBeAg negative, and median HDV RNA 4.9 log₁₀ IU/ml. HBV RNA was positive (>10 copies/ml) in only 8% of patients (median 40 [13-82,000] copies/ml), whereas HBcrAg was ≥3 log₁₀ U/ml in 77% (median 4.2 [3.0-8.0] log₁₀ U/ml). By combining these biomarkers, three categories were identified: 23% double negative (HBV RNA/HBcrAg), 9% double positive (HBV RNA/HBcrAg) 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 DNA were low.

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

Serum HBV RNA and HBcrAg (hepatitis B core-related antigen) are promising biomarkers of the transcriptional activity of covalently closed circular DNA in chronic HBV infection; however, their role in patients with HBV-HDV coinfection is unknown. At variance with what is commonly observed in HBV-monoinfected patients, HBV RNA was undetectable and HBcrAg detectable in the serum of most patients with HDV ("divergent pattern"). The understanding of the viral interplay between HBV and HDV is crucial to dissect the pathogenic mechanisms associated with the distinct phenotypes of patients with HDV.