Classification of virologic trajectories during nucleos/tide analogue treatment of hepatitis B virus (HBV) infection

Tingyan Wang, Cori Campbell, Alexander J Stockdale, Stacy Todd, Karl McIntyre, Andrew Frankland, Jakub Jaworski, Ben Glampson, Dimitri Papadimitriou, Luca Mercuri, Christopher R Jones, Hizni Salih, Gail Roadknight, Stephanie Little, Theresa Noble, Kinga A Várnai, Cai Davis, Ashley I Heinson, Michael George, Florina BorcaLouise 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

Research output: Working paperPreprintAcademic

Abstract

Background & Aims The dynamics of HBV viral load (VL) in patients with chronic hepatitis B (CHB) on nucleos/tide 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 (ALT), and with liver fibrosis/cirrhosis.Results We retrieved data from 1885 adults on NA treatment (median follow-up 6.2 years, interquartile range (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=1367, 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). ALT 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 2-fold increased hazards of fibrosis/cirrhosis compared to 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.Competing Interest StatementG.C. reports personal fees from Gilead and Merck Sharp & Dohme, outside the submitted work. E.N. reports grants from ViiV healthcare, grants from GlaxoSmithKline (GSK), grants from Gilead, outside the submitted work. S.T. reports she has previously received Gilead Investigator-led grant for a viral hepatitis project. W.G. reports personal fees from GSK outside the submitted work. E.B. and P.C.M. have academic collaborative partnerships with GSK. Other authors have no conflict of interest. EB has consulted for, and received research grants from Roche and GSK.Funding StatementThis work has been conducted using National Institute for Health and Care Research Health Informatics Collaborative (NIHR HIC) data resources and funded by the NIHR HIC and has been supported by NIHR Biomedical Research Centres at Cambridge, Imperial, Oxford, Southampton, and University College London Hospitals. G.S.C. is an NIHR research professor, E.B. is an NIHR senior investigator. P.C.M. is funded by the Wellcome Trust (ref. 110110), the Francis Crick Institute, and UCLH NIHR Biomedical Research Centre. C.C. is a doctoral student who receives partial doctoral funding from GlaxoSmithKline (GSK). A.J.S. is supported by a Senior Clinical Lectureship from the National Institute for Health and Care Research at the University of Liverpool. The views expressed in this article are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The research database for the NIHR HIC Viral Hepatitis and Liver Disease theme was approved by South Central - Oxford C Research Ethics Committee (REF Number: 21/SC/0060). All methods for data collection, transmission, and management for this study were carried out in accordance with relevant guidelines and regulations. The requirement for written informed consent was waived by South Central - Oxford C Research Ethics Committee, because data have been in effect anonymised before transfer to the research database.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present work are contained in the manuscript.
Original languageEnglish
Pages2023.12.01.23299288
DOIs
Publication statusPublished - 1 Jan 2023
Externally publishedYes

Publication series

NamemedRxiv
PublisherCold Spring Harbor Laboratory Press

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