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, 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
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.
Conflict of interest statement
Declaration of competing interest SB received an unrestricted research grant from Gilead. AB has been received research grants from Roche, Gilead Sciences, Fujirebio, and Janssen. RdK has received honoraria for consulting/speaking from Gilead, Janssen, AbbVie, and Norgine and received research grants form Gilead and Janssen. FvB has received research support and provided consultancy for Roche. TB has received research support, consulting and/or speaking fees Gilead, Roche, Merck, AbbVie, Bristol-Myers Squibb, and Janssen. BH has received research support and consultancy fees from Intercept, Cymabay, Genfit, Mirum, Albireo, Calliditas and Chemomab. HJ has received research support, consulting and/or speaking fees from Gilead, Roche, Merck, AbbVie, Bristol-Myers Squibb, Arbutus, Janssen and MedImmune. MS has received speaker’s fees and research support from Roche, Innogenetics, BMS, Gilead and Fujirebio. The other authors report no disclosures.
Copyright © 2022. Published by Elsevier B.V.
Source: PubMed