title: Factors Associated With Persistent Increase in Level of Alanine Aminotransferase in Patients With Chronic Hepatitis B Receiving Oral Antiviral Therapy.
abstract: OBJECTIVE
  Despite complete suppression of viral DNA with antiviral agents, in some patients with chronic hepatitis B (CHB), serum levels of alanine aminotransferase (ALT) do not normalize. We investigated factors associated with persistent increases in ALT level in patients with CHB given long-term tenofovir disoproxil fumarate.
  
  
  METHODS
  We analyzed data from 471 hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with CHB participating in 2 phase 3 trials. We identified patients with an increased level of ALT (above the upper limit of normal range) after 5 years (240 weeks) of tenofovir disoproxil fumarate therapy. We analyzed findings from liver biopsy specimens collected from 467 patients (99%) at baseline and 339 patients (72%) at year 5 of treatment; biopsy specimens were evaluated by an independent pathologist. We performed stepwise, forward, multivariate regression analyses of specified baseline characteristics and on-treatment response parameters to identify factors associated with persistent increases in ALT level.
  
  
  RESULTS
  Of the 471 patients, 87 (18%) still had an increased ALT level at year 5 of treatment. Factors associated significantly with a persistent increase in ALT level were a steatosis score of 5% or greater (grade 1 or more) at baseline (odds ratio [OR], 2.236; 95% confidence interval [CI], 1.031-4.852; P = .042) and at year 5 (OR, 3.392; 95% CI, 1.560 ≥ 7.375; P = .002), HBeAg seropositivity at baseline (OR, 3.297; 95% CI, 1.653-6.576; P < .001), and age 40 years or older (OR, 2.099; 95% CI, 1.014-4.342; P = .046). Of the 42 HBeAg-positive patients with steatosis at baseline, 21 (50%) had an increased ALT level at year 5 of treatment. Patients with persistent increases in ALT level were more likely to have an increase in steatosis at year 5 than those with a normal ALT level.
  
  
  CONCLUSIONS
  HBeAg seropositivity and hepatic steatosis contribute to persistent increases in ALT level in patients with CHB receiving suppressive antiviral treatment. ClinicalTrials.gov registration numbers: NCT00117676 and NCT00116805.
authors.affiliation: Department of Medicine, Mount Sinai Beth Israel Medical Center, New York, New York. Electronic address: ira.jacobson@nyumc.org.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Servei de Medicina Interna-Hepatologia, Hospital General Universitari Vall d'Hebron, and Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERHED) del Instituto Carlos III, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Buti
authors.affiliation: Hepatology Research, St Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Nezam
authors.initials: N
authors.lastname: Afdhal
authors.affiliation: Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Flisiak
authors.affiliation: Department of Gastroenterology, Ege Universitesi Tip Fakultesi, Izmir, Turkey.
authors.forename: Ulus Salih
authors.initials: US
authors.lastname: Akarca
authors.affiliation: Department of Internal Diseases, Medical University, Sofia, Bulgaria.
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Tchernev
authors.affiliation: Departments of Clinical Research and Clinical Biometrics, Gilead Sciences, Inc, Foster City, California.
authors.forename: John F
authors.initials: JF
authors.lastname: Flaherty
authors.affiliation: Departments of Clinical Research and Clinical Biometrics, Gilead Sciences, Inc, Foster City, California.
authors.forename: Raul
authors.initials: R
authors.lastname: Aguilar Schall
authors.affiliation: Departments of Clinical Research and Clinical Biometrics, Gilead Sciences, Inc, Foster City, California.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Myers
authors.affiliation: Departments of Clinical Research and Clinical Biometrics, Gilead Sciences, Inc, Foster City, California.
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
authors.affiliation: Departments of Clinical Research and Clinical Biometrics, Gilead Sciences, Inc, Foster City, California.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, Virginia.
authors.forename: Zobair
authors.initials: Z
authors.lastname: Younossi
authors.affiliation: Service d'Hépatologie, Viral Hepatitis Research Centre, Hôpital Beaujon, Clichy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.affiliation: Division of Gastroenterology, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Keyur
authors.initials: K
authors.lastname: Patel
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood*; D000998:Antiviral Agents / Q000008:administration & dosage*; D001706:Biopsy; D017326:Clinical Trials, Phase III as Topic; D005234:Fatty Liver / Q000473:pathology; D005260:Female; D006513:Hepatitis B e Antigens / Q000097:blood; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000473:pathology*; D006651:Histocytochemistry; D006801:Humans; D008099:Liver / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000068698:Tenofovir / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D006513:Hepatitis B e Antigens; D000068698:Tenofovir; D000410:Alanine Transaminase
keywords: Adiponutrin/Patatin-Like Phospholipase-3; HBV; Hepatitis B Virus Infection; Serum Transaminase