Association Between Severe Serum Alanine Aminotransferase Flares and Hepatitis B e Antigen Seroconversion and HBV DNA Decrease in Untreated Patients With Chronic HBV Infection

Hepatitis B Research Network

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Abstract

Background & Aims: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous group of patients in North America. Methods: We collected data from the Hepatitis B Research Network—an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). Results: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th–75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P<.0001), at risk alcohol use (OR, 2.27 vs none or moderate; P=.02), and higher FIB-4 values (OR, 1.85 per log2; P<.0001). Older age was associated with lower odds of an ALT flare (OR, 0.63 per 10 years; P=.004). Rate of decrease in level of HBV DNA by 1 log10 or more (59 vs 23 per 100 person-years for HB e antigen (HBeAg)-positive vs HBeAg-negative patients; P=.003) and HBeAg loss (47 vs 15 per 100 person-years; P=.002) were higher in patients with an ALT flare than in patients without, but the rate of HBsAg loss was similar (4 vs 2 per 100 person-years; P=.26). No hepatic decompensation, liver transplants, or deaths were observed in participants with ALT flares. Conclusion: In a large racially heterogeneous cohort of adults with chronic HBV infection, the cumulative incidence of severe ALT flares was low and associated with greater decreases in HBV DNA and loss of HBeAg, but not with loss of HBsAg.

Original languageEnglish (US)
Pages (from-to)2541-2551.e2
JournalClinical Gastroenterology and Hepatology
Volume17
Issue number12
DOIs
StatePublished - Nov 2019

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Hepatitis B e Antigens
Alanine Transaminase
DNA
Infection
Serum
Odds Ratio
Hepatitis B Surface Antigens
Liver
Incidence
Seroconversion
Sex Ratio
North America
Natural History
Hepatitis B
Bone Marrow Transplantation
Statistical Factor Analysis
Canada
Observational Studies
Antiviral Agents
Hepatocellular Carcinoma

Keywords

  • Biomarker
  • HBRN
  • Immune Response
  • Prognosis

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

@article{253db34450d14d2db79d9f080b6067f8,
title = "Association Between Severe Serum Alanine Aminotransferase Flares and Hepatitis B e Antigen Seroconversion and HBV DNA Decrease in Untreated Patients With Chronic HBV Infection",
abstract = "Background & Aims: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous group of patients in North America. Methods: We collected data from the Hepatitis B Research Network—an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9{\%} male, 73.7{\%} Asian, 35.2{\%} genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). Results: ALT flares occurred in 102 participants (6{\%}), with 31 flares (30{\%}) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7{\%}. The median peak level of ALT was 450 U/L (25th–75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P<.0001), at risk alcohol use (OR, 2.27 vs none or moderate; P=.02), and higher FIB-4 values (OR, 1.85 per log2; P<.0001). Older age was associated with lower odds of an ALT flare (OR, 0.63 per 10 years; P=.004). Rate of decrease in level of HBV DNA by 1 log10 or more (59 vs 23 per 100 person-years for HB e antigen (HBeAg)-positive vs HBeAg-negative patients; P=.003) and HBeAg loss (47 vs 15 per 100 person-years; P=.002) were higher in patients with an ALT flare than in patients without, but the rate of HBsAg loss was similar (4 vs 2 per 100 person-years; P=.26). No hepatic decompensation, liver transplants, or deaths were observed in participants with ALT flares. Conclusion: In a large racially heterogeneous cohort of adults with chronic HBV infection, the cumulative incidence of severe ALT flares was low and associated with greater decreases in HBV DNA and loss of HBeAg, but not with loss of HBsAg.",
keywords = "Biomarker, HBRN, Immune Response, Prognosis",
author = "{Hepatitis B Research Network} and Mayur Brahmania and Manuel Lombardero and Hansen, {Bettina E.} and Terrault, {Norah A.} and Lok, {Anna S.} and Perrillo, {Robert P.} and Belle, {Steven H.} and {Di Bisceglie}, {Adrian M.} and Feld, {Jordan J.} and Lee, {William M.} and Fried, {Michael W.} and Janssen, {Harry L.A.} and Lau, {Daryl T.Y.} and Chung, {Raymond T.} and Roberts, {Lewis R.} and Hassan, {Mohamed A.} and Mauricio Lisker-Melman and Wong, {David K.} and Joshua Juan and Colina Yim and Keyur Patel and Murakami, {Carol S.} and Son Do and Han, {Steven Huy B.} and Tran, {Tram T.} and Mandana Khalili and Cooper, {Stewart L.} and Fontana, {Robert J.} and Naoky Tsai and Barak Younoszai and Andrew Muir and Donna Evon and Darling, {Jama M.} and Carithers, {Robert C.} and Margaret Shuhart and Kowdley, {Kris V.} and Wang, {Chia C.} and Sterling, {Richard K.} and Ghany, {Marc G.} and Liang, {T. Jake} and Hoofnagle, {Jay H.} and Edward Doo and Chang, {Kyong Mi} and Park, {Jang June} and Abdus Wahed and Yona Cloonan and David Kleiner",
year = "2019",
month = "11",
doi = "10.1016/j.cgh.2019.02.005",
language = "English (US)",
volume = "17",
pages = "2541--2551.e2",
journal = "Clinical Gastroenterology and Hepatology",
issn = "1542-3565",
publisher = "W.B. Saunders Ltd",
number = "12",

}

TY - JOUR

T1 - Association Between Severe Serum Alanine Aminotransferase Flares and Hepatitis B e Antigen Seroconversion and HBV DNA Decrease in Untreated Patients With Chronic HBV Infection

AU - Hepatitis B Research Network

AU - Brahmania, Mayur

AU - Lombardero, Manuel

AU - Hansen, Bettina E.

AU - Terrault, Norah A.

AU - Lok, Anna S.

AU - Perrillo, Robert P.

AU - Belle, Steven H.

AU - Di Bisceglie, Adrian M.

AU - Feld, Jordan J.

AU - Lee, William M.

AU - Fried, Michael W.

AU - Janssen, Harry L.A.

AU - Lau, Daryl T.Y.

AU - Chung, Raymond T.

AU - Roberts, Lewis R.

AU - Hassan, Mohamed A.

AU - Lisker-Melman, Mauricio

AU - Wong, David K.

AU - Juan, Joshua

AU - Yim, Colina

AU - Patel, Keyur

AU - Murakami, Carol S.

AU - Do, Son

AU - Han, Steven Huy B.

AU - Tran, Tram T.

AU - Khalili, Mandana

AU - Cooper, Stewart L.

AU - Fontana, Robert J.

AU - Tsai, Naoky

AU - Younoszai, Barak

AU - Muir, Andrew

AU - Evon, Donna

AU - Darling, Jama M.

AU - Carithers, Robert C.

AU - Shuhart, Margaret

AU - Kowdley, Kris V.

AU - Wang, Chia C.

AU - Sterling, Richard K.

AU - Ghany, Marc G.

AU - Liang, T. Jake

AU - Hoofnagle, Jay H.

AU - Doo, Edward

AU - Chang, Kyong Mi

AU - Park, Jang June

AU - Wahed, Abdus

AU - Cloonan, Yona

AU - Kleiner, David

PY - 2019/11

Y1 - 2019/11

N2 - Background & Aims: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous group of patients in North America. Methods: We collected data from the Hepatitis B Research Network—an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). Results: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th–75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P<.0001), at risk alcohol use (OR, 2.27 vs none or moderate; P=.02), and higher FIB-4 values (OR, 1.85 per log2; P<.0001). Older age was associated with lower odds of an ALT flare (OR, 0.63 per 10 years; P=.004). Rate of decrease in level of HBV DNA by 1 log10 or more (59 vs 23 per 100 person-years for HB e antigen (HBeAg)-positive vs HBeAg-negative patients; P=.003) and HBeAg loss (47 vs 15 per 100 person-years; P=.002) were higher in patients with an ALT flare than in patients without, but the rate of HBsAg loss was similar (4 vs 2 per 100 person-years; P=.26). No hepatic decompensation, liver transplants, or deaths were observed in participants with ALT flares. Conclusion: In a large racially heterogeneous cohort of adults with chronic HBV infection, the cumulative incidence of severe ALT flares was low and associated with greater decreases in HBV DNA and loss of HBeAg, but not with loss of HBsAg.

AB - Background & Aims: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous group of patients in North America. Methods: We collected data from the Hepatitis B Research Network—an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). Results: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th–75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P<.0001), at risk alcohol use (OR, 2.27 vs none or moderate; P=.02), and higher FIB-4 values (OR, 1.85 per log2; P<.0001). Older age was associated with lower odds of an ALT flare (OR, 0.63 per 10 years; P=.004). Rate of decrease in level of HBV DNA by 1 log10 or more (59 vs 23 per 100 person-years for HB e antigen (HBeAg)-positive vs HBeAg-negative patients; P=.003) and HBeAg loss (47 vs 15 per 100 person-years; P=.002) were higher in patients with an ALT flare than in patients without, but the rate of HBsAg loss was similar (4 vs 2 per 100 person-years; P=.26). No hepatic decompensation, liver transplants, or deaths were observed in participants with ALT flares. Conclusion: In a large racially heterogeneous cohort of adults with chronic HBV infection, the cumulative incidence of severe ALT flares was low and associated with greater decreases in HBV DNA and loss of HBeAg, but not with loss of HBsAg.

KW - Biomarker

KW - HBRN

KW - Immune Response

KW - Prognosis

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UR - http://www.scopus.com/inward/citedby.url?scp=85073598751&partnerID=8YFLogxK

U2 - 10.1016/j.cgh.2019.02.005

DO - 10.1016/j.cgh.2019.02.005

M3 - Article

C2 - 30743006

AN - SCOPUS:85073598751

VL - 17

SP - 2541-2551.e2

JO - Clinical Gastroenterology and Hepatology

JF - Clinical Gastroenterology and Hepatology

SN - 1542-3565

IS - 12

ER -