Ira M Jacobson1, Mary K Washington2, Maria Buti3, Alexander Thompson4, Nezam Afdhal5, Robert Flisiak6, Ulus Salih Akarca7, Konstantin G Tchernev8, John F Flaherty9, Raul Aguilar Schall9, Robert P Myers9, G Mani Subramanian9, John G McHutchison9, Zobair Younossi10, Patrick Marcellin11, Keyur Patel12. 1. Department of Medicine, Mount Sinai Beth Israel Medical Center, New York, New York. Electronic address: ira.jacobson@nyumc.org. 2. Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee. 3. 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. 4. Hepatology Research, St Vincent's Hospital, Fitzroy, Victoria, Australia. 5. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 6. Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland. 7. Department of Gastroenterology, Ege Universitesi Tip Fakultesi, Izmir, Turkey. 8. Department of Internal Diseases, Medical University, Sofia, Bulgaria. 9. Departments of Clinical Research and Clinical Biometrics, Gilead Sciences, Inc, Foster City, California. 10. Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, Virginia. 11. Service d'Hépatologie, Viral Hepatitis Research Centre, Hôpital Beaujon, Clichy, France. 12. Division of Gastroenterology, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
Abstract
BACKGROUND & AIMS: 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-termtenofovir 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) oftenofovir 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.
RCT Entities:
BACKGROUND & AIMS: 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.
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