Comparison of HBV RNA and Hepatitis B Core Related Antigen With Conventional HBV Markers Among Untreated Adults With Chronic Hepatitis B in North America

Abstract

Background and aims: The clinical utility of two biomarkers, hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg), as compared to conventional markers of HBV replication and disease activity, is unclear.

Approach and results: Untreated participants in the North American Hepatitis B Research Network Adult Cohort Study were categorized by chronic hepatitis B (CHB) phases based on HBsAg and HBeAg status and HBV DNA and alanine aminotransferase (ALT) levels. HBV RNA and HBcrAg were measured (Abbott HBV pgRNA Research Assay and Fujirebio Lumipulse Immunoassay, respectively), and cross-sectional associations with conventional CHB markers were tested. Among 1,409 participants across all CHB phases, median HBV DNA was 3.8 log₁₀ IU/mL and ALT was 34 U/L. HBV RNA was quantifiable in 99% of HBeAg⁺ and 58% of HBeAg^- participants; HBcrAg was quantifiable in 20% of HBeAg⁺ (above linear range in the other 80%) and 51% of HBeAg^- participants. Both markers differed across CHB phases (P < 0.001), with higher levels in the HBeAg⁺ and HBeAg^- immune active phases. HBV RNA and HBcrAg correlated moderately strongly with HBV DNA in both HBeAg⁺ and HBeAg^- phases (HBV RNA: e⁺ ρ = 0.84; e^- ρ = 0.78; HBcrAg: e⁺ ρ = 0.66; e^- ρ = 0.56; P for all, <0.001), but with HBsAg levels among HBeAg⁺ phases only (HBV RNA: e⁺ ρ = 0.71; P < 0.001; e^- ρ = 0.18; P = 0.56; HBcrAg: e⁺ ρ = 0.51; P < 0.001; e^- ρ = 0.27; P < 0.001). Associations of higher HBV RNA and HBcrAg levels with higher ALT, APRI, and Fibrosis-4 levels were consistent in HBeAg^- , but not HBeAg⁺ , phases.

Conclusions: Despite clear relationships between HBV RNA and HBcrAg levels and CHB phases, these markers have limited additional value in differentiating CHB phases because of their strong association with HBV DNA and, to a lesser extent, with clinical disease indicators.

FIG. 1

HBV RNA and HBcrAg categories by CHB phase. (A) HBV RNA by CHB phase. (B) HBcrAg categories by CHB phase. (A) HBeAg‐positive participants depicted by red boxes and HBeAg‐negative participants by blue boxes. In box‐whisker plots, upper and lower ends of the boxes = upper and lower quartiles, horizontal line = median, and upper and lower whiskers = highest and lowest observations. n = numbers of participants in each CHB phase. (B) Green bars = HBcrAg below lower limit of detection, brown bars = HBcrAg 3‐<4 U/L, blue bars = HBcrAg 4‐<6.8 U/L, and red bars = HBcrAg ≥6.8 U/L. Abbreviations: LLQ, lower limit of quantification; ULQ, upper limit of quantification.

FIG. 2

HBV DNA (log₁₀ IU/mL) by HBV RNA (log₁₀ U/mL) and HBcrAg (log₁₀ U/mL) categories, respectively. (A) HBV DNA by RNA. HBV DNA by HBcrAg categories. (A) HBeAg‐positive participants represented by red triangles and HBeAg‐negative participants represented by blue circles. (B) HBeAg‐positive participants depicted by red boxes and HBeAg‐negative participants by blue boxes. In box‐whisker plots, upper and lower ends of the boxes = upper and lower quartiles, horizontal line = median, and upper and lower whiskers = highest and lowest observations. Abbreviations: LLQ, lower limit of quantification; ULQ, upper limit of quantification.

FIG. 3

HBsAg (log₁₀ IU/mL) by HBV RNA (log₁₀ U/mL) and HBcrAg (log₁₀ U/mL), respectively. (A) HBsAg by HBV RNA. HBsAg by HBcrAg categories. (A) HBeAg‐positive participants represented by red triangles and HBeAg‐negative participants represented by blue circles. (B) HBeAg‐positive participants depicted by red boxes and HBeAg‐negative participants by blue boxes. In box‐whisker plots, upper and lower ends of the boxes = upper and lower quartiles, horizontal line = median, and upper and lower whiskers = highest and lowest observations. ^*The lowest value of −3.0 HBsAg (log₁₀ IU/mL) corresponds to 0.001 HBsAg (IU/mL). Abbreviations: LLQ, lower limit of quantification; ULQ, upper limit of quantification.

FIG. 4

HBV RNA (log₁₀ U/mL) by ALT (ULN), APRI, and FIB‐4 categories. (A) HBV RNA by ALT. (B) HBV RNA by APRI. HBV RNA by FIB‐4. (A,B,C) HBeAg‐positive particpants represented by red boxes and HBeAg‐negative participants by blue boxes. In box‐whisker plots, upper and lower ends of the boxes = upper and lower quartiles, horizontal line = median, and upper and lower whiskers = highest and lowest observations.