Roll-over After 3-year Trial for Tenofovir in Mild Chronic Hepatitis B
Roll-over After 3-year Trial for Tenofovir in Mild Chronic Hepatitis B
This open-label study is an roll-over extension of a randomized trial "Efficacy of Tenofovir
 Disoproxil Fumarate in Chronic Hepatitis B Patients with High Viral Load but Slight
 Aminotransferase Elevation" (NCT01522625).

 After finishing the 3-year therapeutic trial, all patients receive open-label TDF for another
 3 years. All patients undergo liver biopsy to evaluate the stage of fibrosis after the 3-year
 open-label therapy. During the 3-year period, patients were followed up every 12 weeks for
 the biochemical, serological, virological parameters, and adverse reactions.

 The primary outcome is the progression of liver fibrosis. Safety issues such as change of
 renal function and bone mineral density are 2nd outcomes.
Background The indication to start NUCs remains controversial in non-cirrhotic compensated
 patients with chronic hepatitis B (CHB). Specifically, it has not been clarified whether high
 serum concentration of HBV DNA warrants treatment despite only mild elevation of serum
 alanine aminotransferase (ALT). In order to elucidate this unresolved issue, we've conducted
 a double blind placebo controlled randomized trial to investigate the efficacy of Tenofovir
 Disoproxil Fumarate (TDF) in CHB patients with high viral load but only mildly elevated serum
 ALT.

 This open-label rollover study is an extension of the aforementioned randomized trial. For
 those who are initially randomized to placebo and later receive open-label TDF, there is a
 rare opportunity to study the efficacy of TDF by using the same patient as his/her own
 control. For those already randomized to TDF in the trial, the investigators will be able to
 closely monitor all aspects of therapeutic responses (i.e., biochemical, virological,
 serological, and histological) during a 6-year treatment course in an Asian cohort.

 Regardless of their initial treatment assignment, these enrolled patients offer a unique
 opportunity to further explore the effectiveness of TDF in CHB in that they have paired
 biopsied liver tissue and comprehensive information.

 Objectives:

 The primary endpoint of this study is the evolution of liver fibrosis during the therapeutic
 course. The secondary endpoints are virological response including not only serum viral load
 but also intracellular HBV markers such as viral covalently closed circular (ccc) DNA,
 serological response including HBsAg seroconversion, HBeAg seroconversion, and quantification
 of HBsAg, biochemical response such as AST, ALT, and adverse reactions with particular
 attention to clinical events regarding bone and renal safety.

 Occurrence of drug resistance is also an important end point.

 Methods:

 After enrollment, all patients are interviewed with a structured questionnaire to obtain
 information regarding demographic data, social-economic status, life style, and medical
 history. Physical checkup, hemogram, blood biochemistry, serology of HBV, serum viral load,
 HBV genotype, and abdominal sonography are performed at baseline.

 Enrolled patients are followed up by telephone or interview every 4 weeks and physically
 examined every 12 weeks. At each follow-up visit, patients are instructed to return the
 untaken drugs. A patient is defined as compliant if she or he completes at least 80% of the
 drugs. AST, ALT, HBV DNA, and quantitative HBsAg will be measured every 12 weeks. Serum
 biochemistry (bilirubin, PT, P, K, Cre), urinalysis, alpha-fetoprotein, HBeAg, and anti-HBe
 and abdominal sonography are measured every 24 weeks. Hemogram and anti-HBs will be checked
 annually.

 Percutaneous liver biopsy will be performed at the beginning of this project and after
 completing the 3-year (156 weeks) trial period. Serology of HBV (HBsAg, anti-HBs, HBeAg, and
 anti-HBe) is determined by commercially available immunoassays (ABBOTT GmbH& Co., Wiesbaden,
 Germany). Serum HBV DNA is measured quantitatively by quantitative polymerase chain reaction
 method (Roche COBAS TaqMan Assay). Histopathological specimens obtained by liver biopsy will
 be evaluated independently by two central histopathologists who are unaware of patients'
 clinical information. The final report of liver histology is based on the agreement of these
 two pathologists and if necessary a third pathologist may be invited to settle disagreement.

 Analysis Both Intent-to-treat (ITT) and per-protocol (PP) analyses will be performed to
 assess therapeutic efficacy. All randomized patients are included in the ITT analysis and all
 protocol violators (compliance less than 80%, loss to follow-up, withdrawal from study) will
 be excluded from PP analysis. Quantitative data are summarized as mean ± standard deviation
 (SD) and categorical variables as percentages. Fisher's exact test is used to compare
 proportions of categorical variables. Unpaired and paired student's t-tests are used to
 compare means of continuous variables between groups and within groups respectively.

 The investigators will apply a multiple logistic regression analysis to investigate factors
 associated with therapeutic efficacy. All tests are two-tailed and a p value less than 0.05
 is considered as statistically significant.
Inclusion Criteria:

 -  all participants should have finished the clinical trial <Efficacy of Tenofovir
 Disoproxil Fumarate in Chronic Hepatitis B Patients with High Viral Load but Slight
 Aminotransferase Elevation> without drop-out.

 -  willingness to adhere to treatment and follow-up plans

 Exclusion Criteria:

 -  co-infection with HIV, HCV, or HDV

 -  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

 -  refusal to undergo liver biopsy

 -  lack of informed consent