Roll-over After 3-year Trial for Tenofovir in Mild Chronic Hepatitis B

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.