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. 2025 May 16;9(6):e0708.
doi: 10.1097/HC9.0000000000000708. eCollection 2025 Jun 1.

Dynamics of HBV biomarkers during nucleos(t)ide analog treatment: A 14-year study

Florian van Bömmel  1 , Elisabetta Degasperi  2 , Alena van Bömmel  3 , Floriana Facchetti  2 , Dana Sambarino  2 , Danilo Deichsel  1 , Jessica Brehm  4 , Rodrigue Kamga Wouambo  1 , Melanie Maier  5 , Maria Pfefferkorn  1 , Thomas Berg  1 , Pietro Lampertico  2   6
Affiliations

Dynamics of HBV biomarkers during nucleos(t)ide analog treatment: A 14-year study

Florian van Bömmel et al. Hepatol Commun. .

Abstract

Background: Circulating HBsAg, HBV RNA, and hepatitis B core-related antigen (HBcrAg) are potential biomarkers for the response to nucleos(t)ide analog (NA) treatment discontinuation in patients with chronic hepatitis B (CHB). We retrospectively investigated the long-term kinetics of HBsAg, HBV RNA, and HBcrAg in HBeAg-negative patients treated with NA for up to 14 years in a prospective cohort study.

Methods: Ninety-six patients (mean age 65 y, 77% male, 52% with cirrhosis, all HBV genotype D) who were undergoing first (n=33, group A) or second-line (n=63, group B) treatment with tenofovir disoproxil fumarate were included. HBV biomarkers collected during tenofovir disoproxil fumarate treatment were measured in 384 serum samples stored at -20 °C. The combined biomarker endpoints associated with functional cure following NA discontinuation included HBsAg <1000 IU/mL, HBV RNA <54 copies/mL, and HBcrAg <2 log U/mL.

Results: Before NA treatment, HBV RNA and HBcrAg were detectable in 85% (mean 3.9±2.3 [range, 0-9.2] log10 copies/mL) and 80% (mean 4.3±1.9 [2-8.9] log10 U/mL), respectively, of the patients in group A. In groups A and B, the percentages of patients with detectable HBV RNA levels decreased to 53% and 34%, respectively, during years 8-10 of NA treatment, and to 29% in group B during years 11-14 to 29%. HBcrAg could be quantified in 2% of patients in group B NA treatment years 8-10. Combined biomarker endpoints were met at baseline and at years 1-4, 5-7, 8-10, and 11-14 of treatment by 3.3%, 12% and 14%, 13% and 38%, 26% and 29%, and 41% of patients, respectively.

Conclusions: HBV biomarker endpoints are associated with functional cure after the discontinuation of NA increase during long-term NA treatment.

Keywords: HBV biomarkers; HBcrAg; functional cure; stop NUC; treatment discontinuation.

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Conflict of interest statement

Florian van Bömmel has served as a speaker for and provided consulting services to Gilead, Roche, Janssen, Ipsen, ADVANZ, Norgine, MSD, Esai, and AstraZeneca, and has served as an advisory board member of Janssen, Eisai, AstraZeneca, and Roche. He has received travel support from AstraZeneca, ADVANZ, and Gilead Sciences. He has received research funding from Gilead Sciences, Roche, VIR, Janssen, Ipsen, and Fujirebio. Pietro Lampertico: Advisory Board/Speaker Bureau for BMS, Roche, Gilead Sciences, GSK, Abbvie, MSD, Arrowhead, Alnylam, Janssen, Spring Bank, MYR, Eiger, Antios, Aligos, and Vir. Thomas Berg received grants from Abbvie, BMS, Gilead, MSD/Merck, Humedics, Intercept, Merz, Norgine, Novartis, Orphalan, and Sequana Medical and provided consulting services to Abbvie, Alexion, Bayer, Gilead, GSK, Eisai, Enyo Pharma, HepaRegeniX GmbH, Humedics, Intercept, Ipsen, Janssen, MSD/Merck, Novartis, Orphalan, Roche, Sequana Medical, SIRTEX, SOBI, and Shionogi. Thomas Berg has served as a speaker for Abbvie, Alexion, Bayer, Gilead, Eisai, Falk Foundation, Intercept, Ipsen, Janssen, MedUpdate GmbH, MSD/Merck, Novartis, Orphalan, Sequana Medica, SIRTEX, and SOBI and serves as an advisory board member for Gilead, Assembly, and GSK. All other authors disclose any conflicts of interest related to the present work.

Figures

FIGURE 1
FIGURE 1
Study design and time points of HBV biomarker measurements. Before treatment with TDF, patients were either naïve to NA treatment (group A) or treated with LMV (group B). Abbreviations: NA, nucleos(t)ide analog; LMV, lamivudine; TDF, tenofovir disoproxil fumarate.
FIGURE 2
FIGURE 2
Kinetics of the circulating HBV biomarkers HBV DNA (A), HBsAg (B), HBV RNA (C), and HBcrAg (D), and the ALT levels (E) during up to 10 years of TDF treatment in HBeAg-negative patients. The values of patients receiving first-line TDF treatment (group A) are displayed in blue, and the values of patients receiving TDF as second-line treatment after lamivudine (group B) are displayed in red. Abbreviations: HBcrAg, hepatitis B core-related antigen; TDF, tenofovir disoproxil fumarate.
FIGURE 3
FIGURE 3
Categories of different circulating HBV biomarkers during long-term NA treatment. Biomarker categories of HBV DNA (A), HBsAg (B), HBV RNA (C), and HBcrAg (D) are shown for patients treated with TDF as first-line treatment (group A, n=33) or second-line treatment (group B, n=63). Abbreviations: NA, nucleos(t)ide analog; HBcrAg, hepatitis B core-related antigen; TDF, tenofovir disoproxil fumarate.
FIGURE 4
FIGURE 4
HBV biomarker endpoints are favorable for the response to treatment discontinuation during long-term NA therapy. A combination endpoint of HBsAg <1000 IU/mL, HBcrAg <2 log U/mL, and HBV RNA <54  copies/mL was rare during the first 4 years, though it continuously increased during the following treatment period (A). The achievement of combined endpoints in group A (B) and group B (C) was driven mostly by the kinetics of HBsAg and HBV RNA, as HBcrAg was less than 2 log in most patients. Abbreviations: NA, nucleos(t)ide analog; HBcrAg, hepatitis B core-related antigen; LOD, lower limit of detection; LOQ, lower limit of quantification.
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References

    1. Lok AS. Chronic hepatitis B. N Engl J Med. 2002;346:1682–1683. - PubMed
    1. Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: A modelling study. Lancet Gastroenterol Hepatol. 2018;3:383–403. - PubMed
    1. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–398. - PubMed
    1. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. . Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–1599. - PMC - PubMed
    1. Jeng WJ, Lok AS. Should treatment indications for chronic hepatitis B be expanded? Clin Gastroenterol Hepatol. 2021;19:2006–2014. - PubMed

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