Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis

Milan J. Sonneveld; Willem P. Brouwer; Bettina E. Hansen; Henry L.Y. Chan; Teerha Piratvisuth; Ji Dong Jia; Stefan Zeuzem; Rong Nan Chien; Hannah Choi; Robert J. de Knegt; Cynthia Wat; Vedran Pavlovic; Anuj Gaggar; Qing Xie; Maria Buti; Robert A. de Man; Harry L.A. Janssen

doi:10.1111/apt.16067

Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis

Milan J. Sonneveld^*
, Willem P. Brouwer
, Bettina E. Hansen^*
, Henry L.Y. Chan
, Teerha Piratvisuth
, Ji Dong Jia
, Stefan Zeuzem
, Rong Nan Chien
, Hannah Choi
, Robert J. de Knegt
, Cynthia Wat
, Vedran Pavlovic
, Anuj Gaggar
, Qing Xie
, Maria Buti
, Robert A. de Man
, Harry L.A. Janssen

^*Corresponding author for this work

Gastroenterology & Hepatology

Welwyn Garden City

Research output: Contribution to journal › Article › Academic › peer-review

40 Citations (Scopus)

Abstract

Background: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment. Aim: To study rates and determinants of clinically significant liver inflammation. Methods: We selected patients with HBV DNA > 2000 IU/mL from the SONIC-B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2). Results: The cohort included 2991 patients; 1672 were HBeAg-positive. ALT was < ULN in 270 (9%), 1-2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1-2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis. Conclusions: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non-invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.

Original language	English
Pages (from-to)	1399-1406
Number of pages	8
Journal	Alimentary Pharmacology and Therapeutics
Volume	52
Issue number	8
DOIs	https://doi.org/10.1111/apt.16067
Publication status	Published - 1 Oct 2020

Bibliographical note

Funding Information:
Data were shared by Roche and Gilead for the purposes of this analysis. Financial support was provided by the Foundation for Liver and Gastrointestinal Research, Rotterdam, the Netherlands. None had any influence on study design, data collection, analysis and interpretation of the data, writing of the report nor the decision to submit for publication.

Funding Information:
MJS has received speaker's fees and research support from Roche, Innogenetics, Fujirebio, Gilead and BMS. HLAJ received grants from and is a consultant for: Bristol Myers Squibb, Gilead Sciences, Novartis, Roche, Merck, Innogenetics. SZ reports consultancy and lecture honoraria from Abbvie, Gilead, Intercept, Janssen, Merck/MSD. HLYC is an advisor of AbbVie, Altimmune, Aptorum, Arbutus, Gilead, GRAIL, MedImmune, Intellia, Janssen, Roche, Vir Biotechnology, and a speaker for AbbVie, Gilead and Roche. TP serves on advisory boards and speakers bureaus for Bayer, BMS, Gilead, Eisai and received research support from Fibrogen, Gilead, Janssen, Roche and VIR. AG is an employee of Gilead Sciences. RdK is a consultant and speaker for AbbVie, BMS, Gilead, Janssen, Merck, Norgine and received grants from Abbvie, Gilead, Janssen and BMS. MB reports consultancy and lecture honoraria from Abbvie, Arbutus, Gilead, Janssen, Merck/MSD, Spring‐Bank. The other authors report no relevant conflicts. Declaration of personal interests:

Funding Information:
Data were shared by Roche and Gilead for the purposes of this analysis. Financial support was provided by the Foundation for Liver and Gastrointestinal Research, Rotterdam, the Netherlands. None had any influence on study design, data collection, analysis and interpretation of the data, writing of the report nor the decision to submit for publication. Declaration of personal interests: MJS has received speaker's fees and research support from Roche, Innogenetics, Fujirebio, Gilead and BMS. HLAJ received grants from and is a consultant for: Bristol Myers Squibb, Gilead Sciences, Novartis, Roche, Merck, Innogenetics. SZ reports consultancy and lecture honoraria from Abbvie, Gilead, Intercept, Janssen, Merck/MSD. HLYC is an advisor of AbbVie, Altimmune, Aptorum, Arbutus, Gilead, GRAIL, MedImmune, Intellia, Janssen, Roche, Vir Biotechnology, and a speaker for AbbVie, Gilead and Roche. TP serves on advisory boards and speakers bureaus for Bayer, BMS, Gilead, Eisai and received research support from Fibrogen, Gilead, Janssen, Roche and VIR. AG is an employee of Gilead Sciences. RdK is a consultant and speaker for AbbVie, BMS, Gilead, Janssen, Merck, Norgine and received grants from Abbvie, Gilead, Janssen and BMS. MB reports consultancy and lecture honoraria from Abbvie, Arbutus, Gilead, Janssen, Merck/MSD, Spring-Bank. The other authors report no relevant conflicts.

Publisher Copyright:
© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd

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10.1111/apt.16067Licence: CC BY-NC-ND

Cite this

Sonneveld, M. J., Brouwer, W. P., Hansen, B. E., Chan, H. L. Y., Piratvisuth, T., Jia, J. D., Zeuzem, S., Chien, R. N., Choi, H., de Knegt, R. J., Wat, C., Pavlovic, V., Gaggar, A., Xie, Q., Buti, M., de Man, R. A., & Janssen, H. L. A. (2020). Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis. Alimentary Pharmacology and Therapeutics, 52(8), 1399-1406. https://doi.org/10.1111/apt.16067

@article{442b88fe751147bbb55cf41e0bcdd5c9,

title = "Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis",

abstract = "Background: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment. Aim: To study rates and determinants of clinically significant liver inflammation. Methods: We selected patients with HBV DNA > 2000 IU/mL from the SONIC-B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2). Results: The cohort included 2991 patients; 1672 were HBeAg-positive. ALT was < ULN in 270 (9\%), 1-2 times ULN in 852 (29\%) and > 2 times ULN in 1869 (63\%). Significant fibrosis was found in 1419 (47\%) and significant inflammatory activity in 630 (21\%). Significant inflammatory activity was found in 34\% of patients with liver fibrosis, compared to 9.5\% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6\% of those with normal ALT, 5.0\% of those with ALT 1-2 times ULN and in 13\% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95\% for ruling out significant inflammatory activity among patients without liver fibrosis. Conclusions: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5\% probability of significant inflammatory activity. If fibrosis can be ruled out using non-invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.",

author = "Sonneveld, \{Milan J.\} and Brouwer, \{Willem P.\} and Hansen, \{Bettina E.\} and Chan, \{Henry L.Y.\} and Teerha Piratvisuth and Jia, \{Ji Dong\} and Stefan Zeuzem and Chien, \{Rong Nan\} and Hannah Choi and \{de Knegt\}, \{Robert J.\} and Cynthia Wat and Vedran Pavlovic and Anuj Gaggar and Qing Xie and Maria Buti and \{de Man\}, \{Robert A.\} and Janssen, \{Harry L.A.\}",

note = "Funding Information: Data were shared by Roche and Gilead for the purposes of this analysis. Financial support was provided by the Foundation for Liver and Gastrointestinal Research, Rotterdam, the Netherlands. None had any influence on study design, data collection, analysis and interpretation of the data, writing of the report nor the decision to submit for publication. Funding Information: MJS has received speaker's fees and research support from Roche, Innogenetics, Fujirebio, Gilead and BMS. HLAJ received grants from and is a consultant for: Bristol Myers Squibb, Gilead Sciences, Novartis, Roche, Merck, Innogenetics. SZ reports consultancy and lecture honoraria from Abbvie, Gilead, Intercept, Janssen, Merck/MSD. HLYC is an advisor of AbbVie, Altimmune, Aptorum, Arbutus, Gilead, GRAIL, MedImmune, Intellia, Janssen, Roche, Vir Biotechnology, and a speaker for AbbVie, Gilead and Roche. TP serves on advisory boards and speakers bureaus for Bayer, BMS, Gilead, Eisai and received research support from Fibrogen, Gilead, Janssen, Roche and VIR. AG is an employee of Gilead Sciences. RdK is a consultant and speaker for AbbVie, BMS, Gilead, Janssen, Merck, Norgine and received grants from Abbvie, Gilead, Janssen and BMS. MB reports consultancy and lecture honoraria from Abbvie, Arbutus, Gilead, Janssen, Merck/MSD, Spring‐Bank. The other authors report no relevant conflicts. Declaration of personal interests: Funding Information: Data were shared by Roche and Gilead for the purposes of this analysis. Financial support was provided by the Foundation for Liver and Gastrointestinal Research, Rotterdam, the Netherlands. None had any influence on study design, data collection, analysis and interpretation of the data, writing of the report nor the decision to submit for publication. Declaration of personal interests: MJS has received speaker's fees and research support from Roche, Innogenetics, Fujirebio, Gilead and BMS. HLAJ received grants from and is a consultant for: Bristol Myers Squibb, Gilead Sciences, Novartis, Roche, Merck, Innogenetics. SZ reports consultancy and lecture honoraria from Abbvie, Gilead, Intercept, Janssen, Merck/MSD. HLYC is an advisor of AbbVie, Altimmune, Aptorum, Arbutus, Gilead, GRAIL, MedImmune, Intellia, Janssen, Roche, Vir Biotechnology, and a speaker for AbbVie, Gilead and Roche. TP serves on advisory boards and speakers bureaus for Bayer, BMS, Gilead, Eisai and received research support from Fibrogen, Gilead, Janssen, Roche and VIR. AG is an employee of Gilead Sciences. RdK is a consultant and speaker for AbbVie, BMS, Gilead, Janssen, Merck, Norgine and received grants from Abbvie, Gilead, Janssen and BMS. MB reports consultancy and lecture honoraria from Abbvie, Arbutus, Gilead, Janssen, Merck/MSD, Spring-Bank. The other authors report no relevant conflicts. Publisher Copyright: {\textcopyright} 2020 The Authors. Alimentary Pharmacology \& Therapeutics published by John Wiley \& Sons Ltd",

year = "2020",

month = oct,

day = "1",

doi = "10.1111/apt.16067",

language = "English",

volume = "52",

pages = "1399--1406",

journal = "Alimentary Pharmacology and Therapeutics",

issn = "0269-2813",

publisher = "John Wiley \& Sons Inc.",

number = "8",

}

Sonneveld, MJ , Brouwer, WP, Hansen, BE, Chan, HLY, Piratvisuth, T, Jia, JD, Zeuzem, S, Chien, RN, Choi, H, de Knegt, RJ, Wat, C, Pavlovic, V, Gaggar, A, Xie, Q, Buti, M, de Man, RA & Janssen, HLA 2020, 'Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis', Alimentary Pharmacology and Therapeutics, vol. 52, no. 8, pp. 1399-1406. https://doi.org/10.1111/apt.16067

Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis. / Sonneveld, Milan J.; Brouwer, Willem P.; Hansen, Bettina E. et al.
In: Alimentary Pharmacology and Therapeutics, Vol. 52, No. 8, 01.10.2020, p. 1399-1406.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis

AU - Sonneveld, Milan J.

AU - Brouwer, Willem P.

AU - Hansen, Bettina E.

AU - Chan, Henry L.Y.

AU - Piratvisuth, Teerha

AU - Jia, Ji Dong

AU - Zeuzem, Stefan

AU - Chien, Rong Nan

AU - Choi, Hannah

AU - de Knegt, Robert J.

AU - Wat, Cynthia

AU - Pavlovic, Vedran

AU - Gaggar, Anuj

AU - Xie, Qing

AU - Buti, Maria

AU - de Man, Robert A.

AU - Janssen, Harry L.A.

N1 - Funding Information: Data were shared by Roche and Gilead for the purposes of this analysis. Financial support was provided by the Foundation for Liver and Gastrointestinal Research, Rotterdam, the Netherlands. None had any influence on study design, data collection, analysis and interpretation of the data, writing of the report nor the decision to submit for publication. Funding Information: MJS has received speaker's fees and research support from Roche, Innogenetics, Fujirebio, Gilead and BMS. HLAJ received grants from and is a consultant for: Bristol Myers Squibb, Gilead Sciences, Novartis, Roche, Merck, Innogenetics. SZ reports consultancy and lecture honoraria from Abbvie, Gilead, Intercept, Janssen, Merck/MSD. HLYC is an advisor of AbbVie, Altimmune, Aptorum, Arbutus, Gilead, GRAIL, MedImmune, Intellia, Janssen, Roche, Vir Biotechnology, and a speaker for AbbVie, Gilead and Roche. TP serves on advisory boards and speakers bureaus for Bayer, BMS, Gilead, Eisai and received research support from Fibrogen, Gilead, Janssen, Roche and VIR. AG is an employee of Gilead Sciences. RdK is a consultant and speaker for AbbVie, BMS, Gilead, Janssen, Merck, Norgine and received grants from Abbvie, Gilead, Janssen and BMS. MB reports consultancy and lecture honoraria from Abbvie, Arbutus, Gilead, Janssen, Merck/MSD, Spring‐Bank. The other authors report no relevant conflicts. Declaration of personal interests: Funding Information: Data were shared by Roche and Gilead for the purposes of this analysis. Financial support was provided by the Foundation for Liver and Gastrointestinal Research, Rotterdam, the Netherlands. None had any influence on study design, data collection, analysis and interpretation of the data, writing of the report nor the decision to submit for publication. Declaration of personal interests: MJS has received speaker's fees and research support from Roche, Innogenetics, Fujirebio, Gilead and BMS. HLAJ received grants from and is a consultant for: Bristol Myers Squibb, Gilead Sciences, Novartis, Roche, Merck, Innogenetics. SZ reports consultancy and lecture honoraria from Abbvie, Gilead, Intercept, Janssen, Merck/MSD. HLYC is an advisor of AbbVie, Altimmune, Aptorum, Arbutus, Gilead, GRAIL, MedImmune, Intellia, Janssen, Roche, Vir Biotechnology, and a speaker for AbbVie, Gilead and Roche. TP serves on advisory boards and speakers bureaus for Bayer, BMS, Gilead, Eisai and received research support from Fibrogen, Gilead, Janssen, Roche and VIR. AG is an employee of Gilead Sciences. RdK is a consultant and speaker for AbbVie, BMS, Gilead, Janssen, Merck, Norgine and received grants from Abbvie, Gilead, Janssen and BMS. MB reports consultancy and lecture honoraria from Abbvie, Arbutus, Gilead, Janssen, Merck/MSD, Spring-Bank. The other authors report no relevant conflicts. Publisher Copyright: © 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd

PY - 2020/10/1

Y1 - 2020/10/1

N2 - Background: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment. Aim: To study rates and determinants of clinically significant liver inflammation. Methods: We selected patients with HBV DNA > 2000 IU/mL from the SONIC-B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2). Results: The cohort included 2991 patients; 1672 were HBeAg-positive. ALT was < ULN in 270 (9%), 1-2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1-2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis. Conclusions: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non-invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.

AB - Background: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment. Aim: To study rates and determinants of clinically significant liver inflammation. Methods: We selected patients with HBV DNA > 2000 IU/mL from the SONIC-B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2). Results: The cohort included 2991 patients; 1672 were HBeAg-positive. ALT was < ULN in 270 (9%), 1-2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1-2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis. Conclusions: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non-invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.

UR - https://www.scopus.com/pages/publications/85090160697

U2 - 10.1111/apt.16067

DO - 10.1111/apt.16067

M3 - Article

C2 - 32886813

AN - SCOPUS:85090160697

SN - 0269-2813

VL - 52

SP - 1399

EP - 1406

JO - Alimentary Pharmacology and Therapeutics

JF - Alimentary Pharmacology and Therapeutics

IS - 8

ER -

Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis

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