Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy

Tingyan Wang; Cori Campbell; Alexander J Stockdale; Stacy Todd; Karl McIntyre; Andrew Frankland; Jakub Jaworski; Ben Glampson; Dimitri Papadimitriou; Luca Mercuri; Erik Mayer; Christopher R Jones; Hizni Salih; Gail Roadknight; Stephanie Little; Theresa Noble; Kinga A Várnai; Cai Davis; Ashley I Heinson; Michael George; Florina Borca; Louise English; Luis Romão; David Ramlakhan; NIHR HIC Viral Hepatitis and Liver Disease Consortium; Kerrie Woods; Jim Davies; Eleni Nastouli; Salim I Khakoo; William Gelson; Graham S Cooke; Eleanor Barnes; Philippa C Matthews

doi:10.1016/j.jhepr.2024.101229

Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy

JHEP Rep. 2024 Oct 9;7(1):101229. doi: 10.1016/j.jhepr.2024.101229. eCollection 2025 Jan.

Authors

Tingyan Wang^{1

2}, Cori Campbell^{1

2}, Alexander J Stockdale^{3

4}, Stacy Todd⁴, Karl McIntyre⁵, Andrew Frankland⁵, Jakub Jaworski⁶, Ben Glampson^{7

8}, Dimitri Papadimitriou^{7

8}, Luca Mercuri^{7

8}, Erik Mayer^{7

8}, Christopher R Jones^{8

9}, Hizni Salih^{1

10}, Gail Roadknight^{1

10}, Stephanie Little^{1

10}, Theresa Noble^{1

10}, Kinga A Várnai^{1

10}, Cai Davis^{11

12}, Ashley I Heinson^{11

12}, Michael George^{11

12}, Florina Borca^{11

12}, Louise English¹³, Luis Romão¹³, David Ramlakhan¹³; NIHR HIC Viral Hepatitis and Liver Disease Consortium; Kerrie Woods^{1

10}, Jim Davies^{1

14}, Eleni Nastouli^{15

16}, Salim I Khakoo¹⁷, William Gelson¹⁸, Graham S Cooke^{7

8

19}, Eleanor Barnes^{1

2

10}, Philippa C Matthews^{2

10

20

21

22}

Collaborators

NIHR HIC Viral Hepatitis and Liver Disease Consortium:
Eleanor Barnes, Philippa C Matthews, William Gelson, Graham S Cooke, Salim I Khakoo, Eleni Nastouli, Jim Davies, Kerrie Woods, Alexander J Stockdale, Stephen Ryder, Ahmed Elsharkawy, Nicholas Easom, William Bernal, Shazaad Ahmad, Douglas Macdonald, Tingyan Wang, Cori Campbell, Simon Stanworth, Suzanne Maynard, Gail Roadknight, Stephanie Little, Kinga A Várnai, Ben Glampson, Dimitri Papadimitriou, Luca Mercuri, Christopher R Jones, Jakub Jaworski, Cai Davis, Florina Borca, Ashley Heinson, Michael George, Heidi MacNaughton, Yun Kim, Josune Olza Meneses, Louise English, Timothy Roberts, Luis Romão, David Ramlakhan, Stacy Todd, Heather Rogers, Karl McIntyre, Andrew Frankland, Hizni Salih, Theresa Noble, Lara Roberts, Finola Higgins, Javier Vilar, Ruth Norris, George Tilston, Ilina Serafimova, Sarah Montague, Juliette Verheyden, Irene Juurlink, Kathryn Jack, Alex Waldren-Glenn, Lizzie Poole, Victoria Day, Berit Reglar

Affiliations

¹ NIHR Oxford Biomedical Research Centre, Oxford, UK.
² Nuffield Department of Medicine, University of Oxford, Oxford, UK.
³ Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
⁴ Tropical Infectious Diseases Unit, Royal Liverpool Hospital, Liverpool University Hospitals NHS Trust, Liverpool, UK.
⁵ Liverpool Clinical Laboratories, Liverpool University Hospitals NHS Trust, Liverpool, UK.
⁶ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁷ iCARE Secure Data Environment, Digital Collaboration Space, Imperial College Healthcare NHS Trust, London, UK.
⁸ Department of Surgery and Cancer, Imperial College London, London, UK.
⁹ Department of Infectious Disease, Imperial College London, London, UK.
¹⁰ NIHR Health Informatics Collaborative, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹¹ Southampton Emerging Therapies and Technologies Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
¹² Clinical Informatics Research Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
¹³ NIHR University College London Hospitals Biomedical Research Centre, London, UK.
¹⁴ Department of Computer Science, University of Oxford, Oxford, UK.
¹⁵ Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, London, UK.
¹⁶ Department of Virology, UCLH, London, UK.
¹⁷ School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
¹⁸ Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁹ Faculty of Medicine, Department of Infectious Disease, Imperial College London, UK.
²⁰ The Francis Crick Institute, London, UK.
²¹ Division of Infection and Immunity, University College London, London, UK.
²² Department of Infectious Diseases, University College London Hospital, London, UK.

Abstract

Background & aims: The dynamics of HBV viral load (VL) in patients with chronic hepatitis B (CHB) on nucleos(t)ide analogue (NA) treatment and its relationship with liver disease are poorly understood. We aimed to study longitudinal VL patterns and their associations with CHB clinical outcomes.

Methods: Utilising large scale, routinely collected electronic health records from six centres in England, collated by the National Institute for Health and Care Research Health Informatics Collaborative (NIHR HIC), we applied latent class mixed models to investigate VL trajectory patterns in adults receiving NA treatment. We assessed associations of VL trajectory with alanine transaminase, and with liver fibrosis/cirrhosis.

Results: We retrieved data from 1,885 adults on NA treatment (median follow-up 6.2 years, IQR 3.7-9.3 years), with 21,691 VL measurements (median 10 per patient, IQR 5-17). Five VL classes were identified from the derivation cohort (n = 1,367, discrimination: 0.93, entropy: 0.90): class 1 'long term suppression' (n = 827, 60.5%), class 2 'timely virological suppression' (n = 254, 18.6%), class 3 'persistent moderate viraemia' (n = 140, 10.2%), class 4 'persistent high-level viraemia' (n = 44, 3.2%), and class 5 'slow virological suppression' (n = 102, 7.5%). The model demonstrated a discrimination of 0.93 and entropy of 0.88 for the validation cohort (n = 518). Alanine transaminase decreased variably over time in VL-suppressed groups (classes 1, 2, 5; all p <0.001), but did not significantly improve in those with persistent viraemia (classes 3, 4). Patients in class 5 had twofold increased hazards of fibrosis/cirrhosis compared with class 1 (adjusted hazard ratio, 2.00; 95% CI, 1.33-3.02).

Conclusions: Heterogeneity exists in virological response to NA therapy in CHB patients, with over 20% showing potentially suboptimal responses. Slow virological suppression is associated with liver disease progression.

Impact and implications: Treatment recommendations for people living with chronic hepatitis B virus (HBV) infection are becoming less stringent, meaning that more of the population will be eligible to receive therapy with nucleos(t)ide analogue agents. We explored outcomes of HBV treatment in a large UK dataset, describing different responses to treatment, and showing that the viral load is not completely suppressed after 1 year in about one in five cases, associated with an increased risk of liver complications. As treatment is rolled out more widely, patients and clinicians need to be aware of the potential for incomplete virologic responses. The findings can support the identification of high-risk individuals, improve early fibrosis and cirrhosis prediction, guide monitoring and preventive interventions, and support public health elimination goals.

Keywords: Antiviral treatment; Cirrhosis; HBV; Health Informatics Collaborative (HIC); Latent class mixed models; Liver fibrosis; Longitudinal; Nucleotide analogue; Viral load.

Associated data

figshare/10.6084/m9.figshare.27094348