Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy
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 outcom...
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2025-01-01
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| author | 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 Kerrie Woods Jim Davies Eleni Nastouli Salim I. Khakoo William Gelson Graham S. Cooke Eleanor Barnes Philippa C. Matthews 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 |
| author_facet | 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 Kerrie Woods Jim Davies Eleni Nastouli Salim I. Khakoo William Gelson Graham S. Cooke Eleanor Barnes Philippa C. Matthews 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 |
| author_sort | Tingyan Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-77072b17de5440f0bb8253ca24d4c200 |
| institution | DOAJ |
| issn | 2589-5559 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj-art-77072b17de5440f0bb8253ca24d4c2002025-08-20T02:46:47ZengElsevierJHEP Reports2589-55592025-01-017110122910.1016/j.jhepr.2024.101229Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapyTingyan Wang0Cori Campbell1Alexander J. Stockdale2Stacy Todd3Karl McIntyre4Andrew Frankland5Jakub Jaworski6Ben Glampson7Dimitri Papadimitriou8Luca Mercuri9Erik Mayer10Christopher R. Jones11Hizni Salih12Gail Roadknight13Stephanie Little14Theresa Noble15Kinga A. Várnai16Cai Davis17Ashley I. Heinson18Michael George19Florina Borca20Louise English21Luis Romão22David Ramlakhan23Kerrie Woods24Jim Davies25Eleni Nastouli26Salim I. Khakoo27William Gelson28Graham S. Cooke29Eleanor Barnes30Philippa C. Matthews31Eleanor BarnesPhilippa C. MatthewsWilliam GelsonGraham S. CookeSalim I. KhakooEleni NastouliJim DaviesKerrie WoodsAlexander J. StockdaleStephen RyderAhmed ElsharkawyNicholas EasomWilliam BernalShazaad AhmadDouglas MacdonaldTingyan WangCori CampbellSimon StanworthSuzanne MaynardGail RoadknightStephanie LittleKinga A. VárnaiBen GlampsonDimitri PapadimitriouLuca MercuriChristopher R. JonesJakub JaworskiCai DavisFlorina BorcaAshley HeinsonMichael GeorgeHeidi MacNaughtonYun KimJosune Olza MenesesLouise EnglishTimothy RobertsLuis RomãoDavid RamlakhanStacy ToddHeather RogersKarl McIntyreAndrew FranklandHizni SalihTheresa NobleLara RobertsFinola HigginsJavier VilarRuth NorrisGeorge TilstonIlina SerafimovaSarah MontagueJuliette VerheydenIrene JuurlinkKathryn JackAlex Waldren-GlennLizzie PooleVictoria DayBerit ReglarNIHR Oxford Biomedical Research Centre, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UKNIHR Oxford Biomedical Research Centre, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UKDepartment of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; Tropical Infectious Diseases Unit, Royal Liverpool Hospital, Liverpool University Hospitals NHS Trust, Liverpool, UKTropical Infectious Diseases Unit, Royal Liverpool Hospital, Liverpool University Hospitals NHS Trust, Liverpool, UKLiverpool Clinical Laboratories, Liverpool University Hospitals NHS Trust, Liverpool, UKLiverpool Clinical Laboratories, Liverpool University Hospitals NHS Trust, Liverpool, UKCambridge University Hospitals NHS Foundation Trust, Cambridge, UKiCARE Secure Data Environment, Digital Collaboration Space, Imperial College Healthcare NHS Trust, London, UK; Department of Surgery and Cancer, Imperial College London, London, UKiCARE Secure Data Environment, Digital Collaboration Space, Imperial College Healthcare NHS Trust, London, UK; Department of Surgery and Cancer, Imperial College London, London, UKiCARE Secure Data Environment, Digital Collaboration Space, Imperial College Healthcare NHS Trust, London, UK; Department of Surgery and Cancer, Imperial College London, London, UKiCARE Secure Data Environment, Digital Collaboration Space, Imperial College Healthcare NHS Trust, London, UK; Department of Surgery and Cancer, Imperial College London, London, UKDepartment of Surgery and Cancer, Imperial College London, London, UK; Department of Infectious Disease, Imperial College London, London, UKNIHR Oxford Biomedical Research Centre, Oxford, UK; NIHR Health Informatics Collaborative, Oxford University Hospitals NHS Foundation Trust, Oxford, UKNIHR Oxford Biomedical Research Centre, Oxford, UK; NIHR Health Informatics Collaborative, Oxford University Hospitals NHS Foundation Trust, Oxford, UKNIHR Oxford Biomedical Research Centre, Oxford, UK; NIHR Health Informatics Collaborative, Oxford University Hospitals NHS Foundation Trust, Oxford, UKNIHR Oxford Biomedical Research Centre, Oxford, UK; NIHR Health Informatics Collaborative, Oxford University Hospitals NHS Foundation Trust, Oxford, UKNIHR Oxford Biomedical Research Centre, Oxford, UK; NIHR Health Informatics Collaborative, Oxford University Hospitals NHS Foundation Trust, Oxford, UKSouthampton Emerging Therapies and Technologies Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Clinical Informatics Research Unit, Faculty of Medicine, University of Southampton, Southampton, UKSouthampton Emerging Therapies and Technologies Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Clinical Informatics Research Unit, Faculty of Medicine, University of Southampton, Southampton, UKSouthampton Emerging Therapies and Technologies Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Clinical Informatics Research Unit, Faculty of Medicine, University of Southampton, Southampton, UKSouthampton Emerging Therapies and Technologies Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Clinical Informatics Research Unit, Faculty of Medicine, University of Southampton, Southampton, UKNIHR University College London Hospitals Biomedical Research Centre, London, UKNIHR University College London Hospitals Biomedical Research Centre, London, UKNIHR University College London Hospitals Biomedical Research Centre, London, UKNIHR Oxford Biomedical Research Centre, Oxford, UK; NIHR Health Informatics Collaborative, Oxford University Hospitals NHS Foundation Trust, Oxford, UKNIHR Oxford Biomedical Research Centre, Oxford, UK; Department of Computer Science, University of Oxford, Oxford, UKDepartment of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Virology, UCLH, London, UKSchool of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UKCambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKiCARE Secure Data Environment, Digital Collaboration Space, Imperial College Healthcare NHS Trust, London, UK; Department of Surgery and Cancer, Imperial College London, London, UK; Faculty of Medicine, Department of Infectious Disease, Imperial College London, UKNIHR Oxford Biomedical Research Centre, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK; NIHR Health Informatics Collaborative, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Corresponding authors. Address: The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, OX1 3SY, UK. Tel.: +44-1865-281547 (E. Barnes); The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK (P.C. Matthews).Nuffield Department of Medicine, University of Oxford, Oxford, UK; NIHR Health Informatics Collaborative, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; The Francis Crick Institute, London, UK; Division of Infection and Immunity, University College London, London, UK; Department of Infectious Diseases, University College London Hospital, London, UK; Corresponding authors. Address: The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, OX1 3SY, UK. Tel.: +44-1865-281547 (E. Barnes); The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK (P.C. Matthews).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.http://www.sciencedirect.com/science/article/pii/S2589555924002337HBVViral loadLongitudinalLiver fibrosisCirrhosisAntiviral treatment |
| spellingShingle | 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 Kerrie Woods Jim Davies Eleni Nastouli Salim I. Khakoo William Gelson Graham S. Cooke Eleanor Barnes Philippa C. Matthews 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 Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy JHEP Reports HBV Viral load Longitudinal Liver fibrosis Cirrhosis Antiviral treatment |
| title | Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy |
| title_full | Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy |
| title_fullStr | Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy |
| title_full_unstemmed | Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy |
| title_short | Distinct virologic trajectories in chronic hepatitis B identify heterogeneity in response to nucleos(t)ide analogue therapy |
| title_sort | distinct virologic trajectories in chronic hepatitis b identify heterogeneity in response to nucleos t ide analogue therapy |
| topic | HBV Viral load Longitudinal Liver fibrosis Cirrhosis Antiviral treatment |
| url | http://www.sciencedirect.com/science/article/pii/S2589555924002337 |
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