. 2025 Nov 7;8(2):101671.

doi: 10.1016/j.jhepr.2025.101671. eCollection 2026 Feb.

Circulating HBV RNA and hepatitis B core-related antigen as determinants of HBsAg loss in persons with HIV in Europe

Lorin Begré^{1

2}, Anders Boyd^{3

4

5}, Marie-Laure Plissonnier^{6

7}, Barbara Testoni^{6

7}, Charles Béguelin¹, Franziska Suter-Riniker⁸, Caroline Scholtès^{6

7

9}, Jürgen K Rockstroh¹⁰, Karine Lacombe^{11

12}, Lars Peters¹³, Marintha Heil¹⁴, Massimo Levrero^{6

7

15}, Andri Rauch¹, Fabien Zoulim^{6

7

15}, Gilles Wandeler^{1

16}; Swiss HIV Cohort Study, EuroSIDA and French HIV/HBV and Biliver cohorts; Members of the EuroSIDA Study Group; Members of the French HIV/HBV and Biliver cohorts

Collaborators, Affiliations

Collaborators

Swiss HIV Cohort Study, EuroSIDA and French HIV/HBV and Biliver cohorts:
Irene A Abela, Karoline Aebi-Popp, Alexia Anagnostopoulos, Manuel Battegay, Enos Bernasconi, Dominique L Braun, Heiner C Bucher, Alexandra Calmy, Matthias Cavassini, Angela Ciuffi, Günter Dollenmaier, Matthias Egger, Luisa Elzi, Jan S Fehr, Jacques Fellay, Hansjakob Furrer, Christoph A Fux, Huldrych F Günthard, Anna Hachfeld, David Hans-Ulrich Haerry, Barbara Hasse, Hans H Hirsch, Matthias Hoffmann, Irene Hösli, Michael Huber, David Jackson-Perry, Christian R Kahlert, Olivia Keiser, Thomas Klimkait, Roger D Kouyos, Helen Kovari, Katharina Kusejko, Niklaus D Labhardt, Karoline Leuzinger, Begoña Martinez de Tejada, Catja Marzolini, Karin J Metzner, Nicolas Müller, Johannes Nemeth, Dunja Nicca, Julia Notter, Paolo Paioni, Giuseppe Pantaleo, Matthieu Perreau, Andri Rauch, Luisa Paola Salazar-Vizcaya, Patrick Schmid, Olivier Segeral, Speck R F, Marcel Stöckle, Philip E Tarr, Alexandra Trkola, Gilles Wandeler, Maja Weisser, Sabine Yerly
Members of the EuroSIDA Study Group:
A Harxhi, M Losso, M Kundro, M Knappik, P Cichon, Klinik Penzing, M Sarcletti, I Karpov, V M Mitsura, D Paduto, N Clumeck, S De Wit, M Delforge, M Frankenhuijsen, M De Scheerder, J Topalovic, J Begovac, D Jilich, L Machala, D Sedlacek, T Benfield, J Gerstoft, A M Lebech, O Kirk, I S Johansen, L Ostergaard, L Wiese, L N Nielsen, K Zilmer, I Aho, J-P Viard, K Lacombe, C Pradier, E Fontas, C Duvivier, J Rockstroh, O Degen, C Hoffmann, C Stefan, J Bogner, C Lehmann, A Abutidze, H Sambatakou, G Adamis, N Paissios, J Szlávik, M Gottfredsson, E Devitt, L Tau, O A Bondarenko, L M Wattad, H Elinav, D Elbirt, G Marchetti, G Guaraldi, C Mussini, A Castagna, A Ridolfo, F Schiavo, V Uzdaviniene, R Matulionyte, T Staub, R Batutu, M Vd Valk, J Trajanovska, D H Reikvam, B Knysz, B Szetela, M Inglot, E Bakowska, M Parczewski, B Aksak-Was, M Beniowski, E Mularska, E Jablonowska, J Kamerys, K Wojcik, I Mozer-Lisewska, B Rozplochowski, A Zagalo, K Mansinho, F Maltez, R Radoi, C Oprea, D Gusev, T Trofimova, E Kuzovatova, E Borodulina, E Vdoushkina, J Ranin, J Tomazic, E Martínez, J M Miró, M Laguno, J L Blanco, M Martinez-Rebollar, J Ambrosioni, B Torres, L de la Mora, A Gonzalez-Cordon, I Chivite, A Foncillas, E de Lazzaari, L Berrocal, P Callau, A Inciarte, J Alcami, J Mallolas, R Paredes, J Puig, J R Santos, C Miranda, P Domingo, G M Mar, M G Gracia, E S De A Arroniz, A Ponz, C Carlander, A Sönnerborg, J Brännström, K Falconer, F Månsson, K Kusejko, D Braun, M Cavassini, A Calmy, H Furrer, M Battegay, P Schmid, E Bernasconi, A Kuznetsova, L Hetman, A Kryshchuk, M Boffito, S Edwards, F Burns, C Orkin, A Winston, A Clarke, C Mackintosh, C Boesecke, C Carlander, C Pradier, C Oprea, E Martinez, G Wandeler, I Aho, I Karpov, J Begovac, J D Kowalska, J Lundgren, L D Rasmussen, L Tau, O Nesterova, R Matulionyte, S Nozza, J D Kowalska, L Peters, L Peters, J F Larsen, M Gardizi, N Jaschinski, A Timiryasova, B Neesgaard, F Roper, D Raben, A H Fischer, A Cozzi-Lepri, W Bannister, T W Elsing, L R Kumar, S Shahi, B Pepa
Members of the French HIV/HBV and Biliver cohorts:
Anders Boyd, Patrick Miailhes, Caroline Lascoux-Combe, Julie Chas, Pierre-Marie Girard, Joël Gozlan, Fabien Zoulim, Constance Delaugerre, Hayette Rougier, Karine Lacombe

Affiliations

¹ Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
² Graduate School for Health Sciences, University of Bern, Bern, Switzerland.
³ Stichting HIV Monitoring, Amsterdam, The Netherlands.
⁴ Department of Infectious Diseases, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
⁵ Department of Infectious Diseases, Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands.
⁶ UMR PaThLiv U1350, Inserm, Université Claude Bernard Lyon 1, Lyon, France.
⁷ Lyon Hepatology Institute, IHU EVEREST, Lyon, France.
⁸ Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
⁹ Department of Virology, Hospices Civils de Lyon, Lyon, France.
¹⁰ HIV-Clinic, Department of Medicine I, University Hospital Bonn, Bonn, Germany.
¹¹ Sorbonne Université, Inserm, Institut Pierre Louis d'Épidémiologie et de Santé Publique, IPLESP, Paris, France.
¹² AP-HP, GH Sorbonne.Université, Hôpital Saint-Antoine, Service de maladies infectieuses et tropicales, Paris, France.
¹³ CHIP, Centre of Excellence for Health, Immunity and Infections, Rigshospitalet, Copenhagen, Denmark.
¹⁴ Roche Molecular Diagnostics, Pleasanton, CA, USA.
¹⁵ Department of Hepatology, Hospices Civils de Lyon, Lyon, France.
¹⁶ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

PMID: 41551412
PMCID: PMC12803887
DOI: 10.1016/j.jhepr.2025.101671

Circulating HBV RNA and hepatitis B core-related antigen as determinants of HBsAg loss in persons with HIV in Europe

Lorin Begré et al. JHEP Rep. 2025.

. 2025 Nov 7;8(2):101671.

doi: 10.1016/j.jhepr.2025.101671. eCollection 2026 Feb.

Authors

Collaborators

Swiss HIV Cohort Study, EuroSIDA and French HIV/HBV and Biliver cohorts:
Irene A Abela, Karoline Aebi-Popp, Alexia Anagnostopoulos, Manuel Battegay, Enos Bernasconi, Dominique L Braun, Heiner C Bucher, Alexandra Calmy, Matthias Cavassini, Angela Ciuffi, Günter Dollenmaier, Matthias Egger, Luisa Elzi, Jan S Fehr, Jacques Fellay, Hansjakob Furrer, Christoph A Fux, Huldrych F Günthard, Anna Hachfeld, David Hans-Ulrich Haerry, Barbara Hasse, Hans H Hirsch, Matthias Hoffmann, Irene Hösli, Michael Huber, David Jackson-Perry, Christian R Kahlert, Olivia Keiser, Thomas Klimkait, Roger D Kouyos, Helen Kovari, Katharina Kusejko, Niklaus D Labhardt, Karoline Leuzinger, Begoña Martinez de Tejada, Catja Marzolini, Karin J Metzner, Nicolas Müller, Johannes Nemeth, Dunja Nicca, Julia Notter, Paolo Paioni, Giuseppe Pantaleo, Matthieu Perreau, Andri Rauch, Luisa Paola Salazar-Vizcaya, Patrick Schmid, Olivier Segeral, Speck R F, Marcel Stöckle, Philip E Tarr, Alexandra Trkola, Gilles Wandeler, Maja Weisser, Sabine Yerly
Members of the EuroSIDA Study Group:
A Harxhi, M Losso, M Kundro, M Knappik, P Cichon, Klinik Penzing, M Sarcletti, I Karpov, V M Mitsura, D Paduto, N Clumeck, S De Wit, M Delforge, M Frankenhuijsen, M De Scheerder, J Topalovic, J Begovac, D Jilich, L Machala, D Sedlacek, T Benfield, J Gerstoft, A M Lebech, O Kirk, I S Johansen, L Ostergaard, L Wiese, L N Nielsen, K Zilmer, I Aho, J-P Viard, K Lacombe, C Pradier, E Fontas, C Duvivier, J Rockstroh, O Degen, C Hoffmann, C Stefan, J Bogner, C Lehmann, A Abutidze, H Sambatakou, G Adamis, N Paissios, J Szlávik, M Gottfredsson, E Devitt, L Tau, O A Bondarenko, L M Wattad, H Elinav, D Elbirt, G Marchetti, G Guaraldi, C Mussini, A Castagna, A Ridolfo, F Schiavo, V Uzdaviniene, R Matulionyte, T Staub, R Batutu, M Vd Valk, J Trajanovska, D H Reikvam, B Knysz, B Szetela, M Inglot, E Bakowska, M Parczewski, B Aksak-Was, M Beniowski, E Mularska, E Jablonowska, J Kamerys, K Wojcik, I Mozer-Lisewska, B Rozplochowski, A Zagalo, K Mansinho, F Maltez, R Radoi, C Oprea, D Gusev, T Trofimova, E Kuzovatova, E Borodulina, E Vdoushkina, J Ranin, J Tomazic, E Martínez, J M Miró, M Laguno, J L Blanco, M Martinez-Rebollar, J Ambrosioni, B Torres, L de la Mora, A Gonzalez-Cordon, I Chivite, A Foncillas, E de Lazzaari, L Berrocal, P Callau, A Inciarte, J Alcami, J Mallolas, R Paredes, J Puig, J R Santos, C Miranda, P Domingo, G M Mar, M G Gracia, E S De A Arroniz, A Ponz, C Carlander, A Sönnerborg, J Brännström, K Falconer, F Månsson, K Kusejko, D Braun, M Cavassini, A Calmy, H Furrer, M Battegay, P Schmid, E Bernasconi, A Kuznetsova, L Hetman, A Kryshchuk, M Boffito, S Edwards, F Burns, C Orkin, A Winston, A Clarke, C Mackintosh, C Boesecke, C Carlander, C Pradier, C Oprea, E Martinez, G Wandeler, I Aho, I Karpov, J Begovac, J D Kowalska, J Lundgren, L D Rasmussen, L Tau, O Nesterova, R Matulionyte, S Nozza, J D Kowalska, L Peters, L Peters, J F Larsen, M Gardizi, N Jaschinski, A Timiryasova, B Neesgaard, F Roper, D Raben, A H Fischer, A Cozzi-Lepri, W Bannister, T W Elsing, L R Kumar, S Shahi, B Pepa
Members of the French HIV/HBV and Biliver cohorts:
Anders Boyd, Patrick Miailhes, Caroline Lascoux-Combe, Julie Chas, Pierre-Marie Girard, Joël Gozlan, Fabien Zoulim, Constance Delaugerre, Hayette Rougier, Karine Lacombe

Affiliations

¹ Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
² Graduate School for Health Sciences, University of Bern, Bern, Switzerland.
³ Stichting HIV Monitoring, Amsterdam, The Netherlands.
⁴ Department of Infectious Diseases, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
⁵ Department of Infectious Diseases, Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands.
⁶ UMR PaThLiv U1350, Inserm, Université Claude Bernard Lyon 1, Lyon, France.
⁷ Lyon Hepatology Institute, IHU EVEREST, Lyon, France.
⁸ Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
⁹ Department of Virology, Hospices Civils de Lyon, Lyon, France.
¹⁰ HIV-Clinic, Department of Medicine I, University Hospital Bonn, Bonn, Germany.
¹¹ Sorbonne Université, Inserm, Institut Pierre Louis d'Épidémiologie et de Santé Publique, IPLESP, Paris, France.
¹² AP-HP, GH Sorbonne.Université, Hôpital Saint-Antoine, Service de maladies infectieuses et tropicales, Paris, France.
¹³ CHIP, Centre of Excellence for Health, Immunity and Infections, Rigshospitalet, Copenhagen, Denmark.
¹⁴ Roche Molecular Diagnostics, Pleasanton, CA, USA.
¹⁵ Department of Hepatology, Hospices Civils de Lyon, Lyon, France.
¹⁶ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

PMID: 41551412
PMCID: PMC12803887
DOI: 10.1016/j.jhepr.2025.101671

Abstract

Background & aims: HBsAg loss improves clinical outcomes in persons with HIV and HBV coinfection. We aimed to evaluate if hepatitis B core-related antigen and circulating HBV RNA levels were associated with HBsAg loss in Euro-B, a multi-cohort collaboration including data from the Swiss HIV Cohort Study, EuroSIDA, and the French HIV/HBV cohort.

Methods: We included persons with HIV, a positive HBsAg, and ≥6 months of follow-up on tenofovir-containing antiretroviral therapy. We evaluated quantitative HBsAg, HBV DNA, hepatitis B core-related antigen, and HBV RNA levels over time and assessed HBsAg loss (i.e. quantitative HBsAg <0.05 IU/ml) during tenofovir therapy.

Results: Among 599 participants median age was 41 years (IQR 35-47), 18.4% were female and 47.3% HBeAg-positive. We observed HBsAg loss in 12.9% of participants after 2 years and in 18.2% during a median follow-up of 8.2 years (IQR 3.6-13.1). Individuals who were HBeAg-negative were more likely to have a negative hepatitis B core-related antigen and HBV RNA below the detection limit than participants who were HBeAg-positive. Quantitative HBsAg ≤1,000 IU/ml at baseline was the strongest predictor of HBsAg loss regardless of HBeAg status. Additionally, HBsAg loss was associated with lower baseline HBV RNA levels (odds ratio 0.66, 95% CI 0.49-0.88) and higher baseline HBV DNA levels in participants who were HBeAg-positive.

Conclusions: In this European cohort of persons with HIV/HBV, 18% experienced HBsAg loss during tenofovir-containing antiretroviral therapy. In addition to low baseline quantitative HBsAg levels, HBV RNA may predict HBsAg loss in individuals who are HBeAg-positive.

Impact and implications: The present study builds on a multi-cohort collaboration including persons with HIV/HBV from Europe. It provides estimates on the probability of HBsAg loss during long-term tenofovir-containing antiretroviral therapy and describes the potential of the novel biomarkers HBV RNA and hepatitis B core-related antigen as its predictors. The discrepancies regarding HBV RNA and HBcrAg levels before and during therapy observed between persons who were HBeAg-negative and HBeAg-positive with HIV/HBV may influence treatment decisions and the development of new treatment strategies.

Clinical trials registration: The study is registered at ClinicalTrials.gov (NCT04984772).

Keywords: Cohort studies; Coinfection; HBV RNA; HIV; Hepatitis B core-related antigen; Hepatitis B virus; Tenofovir.

PubMed Disclaimer

Conflict of interest statement

LB reports unrestricted research grants from Gilead Sciences and Roche Diagnostics, support for travel and conference participation from the CROI Foundation and the SAFE-ID Foundation, and speaker honoraria from Roche, all paid to his institution. AB reports receiving speaker’s fees from Gilead Sciences, Inc. MLP reports support from the French National Research Agency (ANR). BT reports research grants paid to her institution from Aligos, Assembly, BlueJay, AusperBio, and ImCheck, and lecture honoraria from Gilead Sciences France, Hospital Vall d’Hebron and the Belgian Association for the Study of the Liver, and payment for expert testimony and travel support from the International Hepatology Education Program. CB reports travel support from Gilead and participation in the post EASL HDV advisory board 2023. FSR has no conflicts of interest to declare. CS reports honoraria for educational lectures from Abbvie and expert testimony paid to her institution from Roche Diagnostics. JKR reports grants from Gilead, paid to his institution, consulting fees from Boehringer, Gilead, MSD, ViiV, speaker honoraria from Gilead, Janssen, MSD, ViiV, participation in advisory boards from BerlinCure, and being unpaid co-chair of EuroTEST. KL reports grants from MSD, and personal funding for advisory boards and educational activities as well as support for travel and conference participation from Gilead, MSD, ViiV Healthcare. LP reports stock or stock options from Novo Nordisk, Eli Lilly and Company, and Bavarian Nordic. MH reports support from Roche, patents issued, and stock or stock options from Roche as part of employee compensation. ML reports support for travel and conference participation from Gilead, Abbvie, Madrigal, speakers honoraria from Gilead, Abbvie, and support for medical writing from Roche Diagnostics and Gilead (outside of submitted work). AR reports support to his institution for advisory boards and/or travel grants from MSD, Gilead Sciences, Pfizer, and Moderna, and an investigator-initiated trial (IIT) grant from Gilead Sciences. All remuneration went to his home institution and not to AR personally, and all remuneration was provided outside the submitted work. FZ reports research grants from Aligos, Ausperbio, Bluejay, and ImCheck, consulting fees from Aligos, Ausperbio, Bluejay, GSK, nChroma, Precision, and Gilead, and speaker honoraria from Gilead. GW reports unrestricted research grants from Gilead Sciences and Roche Diagnostics, as well as advisory board fees from MSD, ViiV, and Gilead Sciences, all paid to his institution. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

**Fig. 1**
**Alluvial plot showing qHBsAg levels during follow-up on tenofovir-containing antiretroviral therapy among the 456 (76.1%) participants with three available measurements.** Red includes participants with qHBsAg >1,000 IU/ml, yellow those with >10–1,000 IU/ml, green those with 0.05–10 IU/ml, and blue those with HBsAg loss, defined as qHBsAg <0.05 IU/ml. qHBsAg, quantitative hepatitis B surface antigen.

**Fig 2**
qHBsAg (A), HBV DNA (B), HBcrAg (C), and HBV RNA (D) levels in HBeAg-negative and HBeAg-positive participants at start of tenofovir therapy, after 2 years of follow-up and at the last follow-up visit after a median follow-up of 8.2 years (IQR 3.6-13.1). cp/ml, copies per milliliter; FUP, follow-up; HBcrAg, hepatitis B core-related antigen; HBeAg-, hepatitis B e antigen negative; HBeAg+, hepatitis B e antigen positive; Mio, million; qHBsAg, quantitative hepatitis B surface antigen; HBV, hepatitis B virus.

**Fig. 3**
**Proportion of participants with HBV DNA <20 IU/ml, HBcrAg <3 log₁₀ U/ml and HBV RNA below the detection limit at the last follow-up time point, stratified by HBsAg loss and HBeAg status.** HBcrAg, hepatitis B core-related antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.

**Fig. 4**
**Multivariable logistic regression models for HBsAg loss at the last follow-up time point.** (A) with HBcrAg included in the model, (B) with HBV RNA included in the model. Except follow-up time, all parameters included in the models are baseline values. Points represent the odds ratios and bands the 95% CIs. Green refers to the model restricted to participants who were HBeAg-positive and blue to the model restricted to those who were HBeAg-negative. Wald tests were performed to assess statistical significance of individual covariables with significance defined as p <0.05. In the models including HBcrAg (panel A) the following variables were significantly associated with HBsAg loss in at least one sub-group: qHBsAg ≤1,000 IU/ml (HBeAg-negative participants p <0.001; HBeAg-positive participants p = 0.007), being ART-experienced (HBeAg-negative participants p = 0.40; HBeAg-positive participants p = 0.02), and follow-up time (HBeAg-negative participants p = 0.02; HBeAg-positive participants p = 0.04). In the models including HBV RNA (panel B) the following variables were significantly associated with HBsAg loss: qHBsAg ≤1,000 IU/ml (participants who were HBeAg-negative p <0.001; participants who were HBeAg-positive p = 0.006), HBV DNA (participants who were HBeAg-negative p = 0.67; participants who were HBeAg-positive p = 0.003), HBV RNA (participants who were HBeAg-negative p = 0.89; participants who were HBeAg-positive p = 0.005), ALT (participants who were HBeAg-negative p = 0.048; participants who were HBeAg-positive p = 0.71), and follow-up time (participants who were HBeAg-negative p = 0.02; participants who were HBeAg-positive p = 0.12). Actual odds ratios, 95% CIs and p values for all variables are depicted in Tables S3 and S4. ALT, alanine aminotransferase; ART, antiretroviral therapy; cp/ml, copies per milliliter; HBcrAg, hepatitis B core-related antigen; HBeAg, hepatitis B e antigen; qHBsAg, quantitative hepatitis B surface antigen.

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Circulating HBV RNA and hepatitis B core-related antigen as determinants of HBsAg loss in persons with HIV in Europe

Collaborators

Affiliations

Circulating HBV RNA and hepatitis B core-related antigen as determinants of HBsAg loss in persons with HIV in Europe

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Associated data

LinkOut - more resources

Full Text Sources

Medical