Tenofovir in Chronic Hepatitis B With Mild ALT Elevation

Efficacy of Tenofovir Disoproxil Fumarate in Chronic Hepatitis B Patients With High Viral Load But Slight Aminotransferase Elevation

This study aims to clarify whether patients with chronic hepatitis B with high viral load will benefit from oral antiviral therapy despite only mildly elevated serum liver enzyme.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: tenofovir disoproxil fumarate 300mg per day; Drug: Placebo

Detailed Description

Chronic hepatitis B (CHB) is a serious disease in Taiwan, leading to substantial morbidity and mortality including hepatic failure, liver cirrhosis, and hepatocellular carcinoma (HCC). Recently a large body of evidence supports that high level of serum HBV DNA is an independent risk factor for late complications in CHB patients. Nucleos(t)ide analogues (NUC) are effective antiviral therapy that can potently inhibit replication of hepatitis B virus (HBV), and has been widely used in management of patients with CHB. Current practice guidelines recommend using serum alanine aminotransferase (ALT) > 2 times of the upper limit of normal (ULN) as the prerequisite to initiate antiviral therapy in compensated CHB patients without liver cirrhosis. However, serum ALT level does not exactly correlate with serum HBV DNA or liver tissue injury. Whether antiviral therapy improves outcomes of patients with slightly elevated ALT (i.e. 1-2 folds of ULN) remains unknown.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 4

Contacts and Locations

Study Locations

• Taiwan
  • Chiayi City, Taiwan, 539
    • Chia-Yi Christine Hospital
  • Kaohsiung, Taiwan, 824
    • E-Da Hospital
  • Taichung, Taiwan, 407
    • Taichung Veterans General Hospital
  • Tainan, Taiwan
    • Chi Mei Medical Center, Liouying
  • Taipei, Taiwan, 104
    • Mackay Memorial Hosp
  • Yunlin, Taiwan, 640
    • National Taiwan University Hospital Yun-Lin Branch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age between 25 to 70 years,
• serum HBsAg positivity for more than 6 months,
• positive or negative serum HBeAg,
• serum HBV DNA more than 2,000 IU/mL,
• highest serum ALT > 1 fold of ULN, but < 2 X ULN on at least two occasions (≧ 3 months apart) in the preceding one year,

Exclusion Criteria:

• co-infection with HIV, HCV, or HDV,
• previous exposure to HBV antiviral therapy for more than 12 weeks,
• presence of cirrhosis on histopathology,
• hepatic decompensation defined as serum bilirubin > 2mg/dl and prolonged prothrombin time > 3 seconds,
• concurrent malignant diseases including hepatocellular carcinoma,
• severe co-morbidity with life expectancy < 1year,
• pregnant or lactating women,
• organ transplantation except cornea or hair transplant,
• suspected or confirmed chronic liver diseases from etiologies other than HBV (e.g. alcoholic hepatitis, Wilson disease, Hemochromatosis…etc),
• serum creatinine >1.5mg/dL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo, identical to TDF in appearance, once daily for 3years
Experimental: TDF; tenofovir disoproxil fumarate (TDF) 300mg	Drug: tenofovir disoproxil fumarate 300mg per day; tenofovir disoproxil fumarate 300mg per day for 3 years; Other Names: Viread® (Gilead Sciences Inc)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of hepatic necroinflammation and fibrosis	Primary outcome is the severity of necroinflammation and fibrosis in liver tissue as evaluated by Knodell and Ishak scoring system	Within one month after completion of antiviral therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Undetectable hepatitis B viral DNA	HBV DNA viral DNA not detected in serum	Within one month after completion of antiviral therapy
Normalization of serum alanine aminotransferase	serum ALT <40 IU/mL	Within one month after completion of antiviral therapy
Serum level of HBsAg	quantification of serum HBV serface antigen	Within one month after completion of antiviral therapy
Serious adverse reaction	Defined as death, life threatening event, permanent or temporary disability, and hospitalization	Within one month after completion of antiviral therapy

Collaborators and Investigators

• Sponsor: E-DA Hospital
• Collaborators: Gilead Sciences; Taipei Institute of Pathology
• Investigators: Principal Investigator: Yao-Chun Hsu, MD, MSc, E-Da Hospital, Kaohsiung, Taiwan; Study Chair: Jaw-Town Lin, MD, PhD, National Taiwan University

Publications and helpful links

General Publications

• Hsu YC, Chen CY, Chang IW, Chang CY, Wu CY, Lee TY, Wu MS, Bair MJ, Chen JJ, Chen CC, Tseng CH, Tai CM, Huang YT, Ku WH, Mo LR, Lin JT. Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial. Lancet Infect Dis. 2021 Jun;21(6):823-833. doi: 10.1016/S1473-3099(20)30692-7. Epub 2021 Jan 29. Erratum In: Lancet Infect Dis. 2021 May;21(5):e122.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): November 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: January 27, 2012
• First Submitted That Met QC Criteria: January 30, 2012
• First Posted (Estimate): January 31, 2012

Study Record Updates

• Last Update Posted (Actual): February 12, 2019
• Last Update Submitted That Met QC Criteria: February 10, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: antiviral therapy; Tenofovir; chronic hepatitis B; hepatitis B viral DNA
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir
• Other Study ID Numbers: EMRP36100N