ACE Score Identifies HBeAg-negative Inactive Carriers at a Single-point Evaluation, Regardless of HBV Genotype

Abstract

Background and aims: Hepatitis B virus (HBV) biomarkers have been used for a better categorization of patients, even though the lack of simple algorithms and the impact of genotypes limit their application. Our aim was to assess the usefulness of noninvasive markers for the identification of HBV inactive carriers (ICs) in a single-point evaluation and to design a predictive model for their identification.

Methods: This retrospective-prospective study included 343 consecutive HBeAg-negative individuals. Clinical, analytical, and virological data were collected, and a liver biopsy was performed if needed. Subjects were classified at the end of follow-up as ICs, chronic hepatitis B and gray zone.A predictive model was constructed, and validated by 1000-bootstrap samples.

Results: After 39 months of follow-up, 298 subjects were ICs, 36 were chronic hepatitis B CHB, and nine were gray zone. Eighty-nine (25.9%) individuals required a liver biopsy. Baseline HBV DNA hazard ratio (HR) 6.0, p<0.001), HBV core-related antigen (HBcrAg) (HR 6.5, p<0.001), and elastography (HR 4.6, p<0.001) were independently associated with the IC stage. The ACE score (HBV DNA, HBcrAg, elastography), obtained by bootstrapping, yielded an area under the receiver operating characteristics (AUROC) of 0.925 (95% CI: 0.880-0.970, p<0.001) for identification of ICs. The AUROC for genotype D was 0.95, 0.96 for A, 0.90 for E, and 0.88 for H/F. An ACE score of <1 had a positive predictive value of 99.5%, and a score ≤12 points had a diagnostic accuracy of 93.8%.

Conclusions: Low baseline HBV DNA, HBcrAg, and liver stiffness were independently associated with the IC phase. A score including those variables identified ICs at a single-point evaluation, and might be applied to implement less intensive follow-up strategies.

Keywords: Core-related antigen; HBV DNA; Hepatitis B virus; Inactive carrier; Liver stiffness; Quantitative HBsAg.

Fig. 1. Country of origin and most prevalent HBV genotype of immigrants in the overall cohort (by relative frequency).

HBV, hepatitis B virus.

Fig. 2. HBV infection phase evolution and liver biopsy performance during follow-up.

*Liver biopsy indication was established by normal ALT plus HBV DNA persistently above 2,000 IU/mL, or ALT <2-fold ULN plus viral load above 2,000 IU/mL during follow-up. **Final classification was carried out according to European Association for the Study of the Liver 2017 Clinical Practice Guidelines. Chronic HBeAg-negative infection-inactive carriers had persistently normal ALT plus HBV DNA <2,000 IU/mL or HBV DNA between 2,000 and 20,000 IU/mL in the absence of significant fibrosis in liver biopsy. Chronic HBeAg negative hepatitis required elevated ALT and HBV DNA >2,000 IU/mL and/or significant fibrosis at liver biopsy. Gray zone required persistently normal ALT and HBV DNA >20,000 IU/mL in the absence of fibrosis in liver biopsy. ALT, alanine aminotransferase; HBV, hepatitis B virus; ULN, upper limit of normal.

Fig. 3. Area under the receiver operating characteristic (AUROC) of the model for identification of HBeAg-negative chronic infection-inactive carriers subjects.