End-of-treatment HBsAg, HBcrAg and HBV RNA predict the risk of off-treatment ALT flares in chronic hepatitis B patients

Sylvia M Brakenhoff; Robert J de Knegt; Margo J H van Campenhout; Annemiek A van der Eijk; Willem P Brouwer; Florian van Bömmel; André Boonstra; Bettina E Hansen; Thomas Berg; Harry L A Janssen; Robert A de Man; Milan J Sonneveld

doi:10.1016/j.jmii.2022.06.002

End-of-treatment HBsAg, HBcrAg and HBV RNA predict the risk of off-treatment ALT flares in chronic hepatitis B patients

J Microbiol Immunol Infect. 2023 Feb;56(1):31-39. doi: 10.1016/j.jmii.2022.06.002. Epub 2022 Jul 2.

Affiliations

¹ Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. Electronic address: s.brakenhoff@erasmusmc.nl.
² Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
³ Department of Viroscience, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
⁴ Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.
⁵ Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.
⁶ Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada.

PMID: 35941076
DOI: 10.1016/j.jmii.2022.06.002

Abstract

Background/purpose(s): Since ALT flares after therapy withdrawal are associated with adverse outcomes, risk stratification is of major importance. We aimed to study whether off-treatment flares are related with virological outcomes, and if serum levels of novel biomarkers at end-of-treatment (EOT) can predict flares.

Methods: Chronic hepatitis B patients who participated in three global randomised trials of peginterferon-based therapy were studied (99-01, PARC, ARES). HBV RNA, HBsAg and HBcrAg were quantified at EOT. Associations between EOT biomarker levels and flares were assessed as continuous data and after categorisation. Flares were defined as ALT ≥5xULN during six months after therapy cessation.

Results: We included 344 patients; 230 HBeAg-positive and 114 HBeAg-negative. Patients were predominantly Caucasian (77.0%) and had genotype A/B/C/D in 23.3/7.3/13.4/52.3%. Flares were observed in 122 patients (35.5%). Flares were associated with lower rates of sustained response (3.5% vs 26.8% among patients with and without a flare; p < 0.001). Higher HBsAg (OR 1.586, 95%CI 1.231-2.043), HBV RNA (OR 1.695, 95%CI 1.371-2.094) and HBcrAg (OR 1.518, 95%CI 1.324-1.740) levels were associated with higher risk of flares (p < 0.001). Combinations of biomarkers further improved risk stratification, especially HBsAg + HBV RNA. Findings were consistent in multivariate analysis adjusted for potential predictors including HBeAg-status and EOT-response (HBV DNA <200 IU/mL).

Conclusion: Off-treatment ALT flares were not associated with favourable virological outcomes. Higher EOT serum HBsAg, HBcrAg and HBV RNA were associated with a higher risk of flares after therapy withdrawal. These findings can be used to guide decision-making regarding therapy discontinuation and off-treatment follow-up.

Trial registration: ClinicalTrials.gov: NCT00114361, NCT00146705, NCT00877760.

Keywords: Flare; HBV; Hepatitis B virus; Hepatology; Liver; Serum biomarkers.

Publication types

Clinical Trial

MeSH terms

Antiviral Agents / therapeutic use
Biomarkers
DNA, Viral
Hepatitis B Core Antigens / therapeutic use
Hepatitis B Surface Antigens
Hepatitis B e Antigens / therapeutic use
Hepatitis B virus / genetics
Hepatitis B, Chronic* / drug therapy
Humans
RNA

Substances

Antiviral Agents
Biomarkers
DNA, Viral
Hepatitis B Core Antigens
Hepatitis B e Antigens
Hepatitis B Surface Antigens
RNA

Associated data

ClinicalTrials.gov/NCT00114361
ClinicalTrials.gov/NCT00877760
ClinicalTrials.gov/NCT00146705