Tenofovir in Chronic Hepatitis B With Mild ALT Elevation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: tenofovir disoproxil fumarate 300mg per day
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic hepatitis B, hepatitis B viral DNA, antiviral therapy, Tenofovir