Effectiveness of Antiviral Treatment in Cirrhotic Patients With Low-level Hepatitis B Virus DNA Levels

Overview

Multicenter, Open-label, Single arm Trial with Matched Historical controls. Male and female adults with compensated liver cirrhosis due to chronic hepatitis B virus infection who have low-level viremia.

To assess the efficacy of Tenofovir Alafenamide (TAF) in reducing liver-related events (hepatocellular carcinoma, liver-related events and death, decompensated liver cirrhosis) in cirrhotic chronic hepatitis B patients with low-level viremia compared with matched historical controls.

Description

This clinical trial is a multicenter, open label, single arm trial in cirrhotic chronic hepatitis B patients with low-level viremia beyond treatment indications by current guidelines.

A total of 200 subjects meeting eligibility criteria will be enrolled and assigned to Treatment Arm (A) and 200 subjects from matched historical cohort will be compared to Treatment Arm.

• Treatment Arm (A): 200 subjects, TAF 25mg once daily with food for 3 years
• Matched Historical Controls Arm (B): 200 subjects, patients who did not receive antiviral treatment during their follow-up period, and were matched with the treatment group in a 1:1 ratio according to their baseline characteristics by propensity-score matching method Treatment Arm is scheduled to be followed up to 3 years. The primary analysis set for efficacy analyses will be defined as all enrolled patients who received at least 1 dose of study medication (modified intention-to-treat analysis). Patients who discontinue the study drug prior to year 3 will be considered failures for all endpoints after the time of discontinuation.

Propensity scores will be computed using the following variables; age; sex; HBeAg positivity, HBV DNA level, ALT, platelet, albumin, total bilirubin, creatinine, prothrombin time, diabetes, hypertension, family history of HCC. Treatment arm will be matched to historical matched cohort by propensity score matching.

The primary endpoint will be analyzed with Kaplan-Meier methods and compared by the log-rank test between the two groups. Between-group comparisons of continuous or categorical baseline characteristics will be conducted using absolute standardized difference. Baseline factors predictive of virologic response will be also evaluated by univariate and multivariable analyses using logistic regression. All statistical analyses will be performed using and R (http://cran.r-project.org/). A P-value less than 0.05 will be considered statistically significant.

Eligibility

Inclusion Criteria:

1. Willing and able to provide written informed consent prior to study entry
2. Age ≥30 years and ≤80 years at the time of screening
3. Chronic hepatitis B infection defined as HBsAg (+) or HBV DNA (+) for at least 6 months prior to the Screening visit, or medical records indication a chronic hepatitis B virus infection by meeting all of the following criteria at the time of screening. (1) HBsAg (+), (2) HBV DNA (+), and (3) HBcAb IgM (-)
4. Either HBeAg (+) or HBeAg (-)
5. Serum HBV DNA levels ≥20 IU/mL and <2,000 IU/mL at the time of screening
6. Evidence of liver cirrhosis defined as meeting any of the following criteria:
   • Radiological evidence of liver cirrhosis by ultrasound, CT, or MRI
   • Platelet count <150,000 /mm3
   • Presence of esophageal or gastric varices by endoscopy in 2 years before the timing of screening
   • Clinically significant portal hypertension
   • Fibroscan ≥12.0 kPa (if the test was done in 6 months before the time of screening)
7. Estimated creatinine clearance ≥30 ml/min (by calculation of creatinine clearance or

   using the CKD-EPI equation)

8. Ability to comply with all study requirements

Exclusion Criteria:

1. Confirmed known co-infection with HCV, HIV, or HDV
2. Current alcohol (60g/day) or substance abuse judged by the investigator that will potentially interfere with subject compliance
3. Any history of, or current evidence of, clinical hepatic decompensation (e.g., ascites, encephalopathy, variceal hemorrhage, or Child-Pugh score of ≥8, with the exception of Gilbert syndrome) in 1 year before the time of screening
4. Currently on or have received therapy with Interferon or immunosuppressant (including systemic chemotherapy) within 12 months prior to the screening
5. Requirement for chronic use of systemic immunosuppressant including, but not limited to, corticosteroid (prednisone equivalent of >40 mg/day for >2 weeks), azathioprine, or monoclonal antibodies
6. Received solid organ or bone marrow transplant
7. History of severe, life-threatening or other significant sensitivity to any excipients of the study drugs
8. Any other clinical conditions (cardiovascular, respiratory, neurologic, or renal conditions) or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with dosing requirements.
9. Currently on or have received antiviral treatment for ≥ 2 weeks within 6 months prior to the screening
10. History or current evidence of hepatocellular carcinoma (HCC), or high α-fetoprotein (AFP) > 20 ng/mL. But, the patients with AFP > 20 ng/mL can be enrolled if AFP shows decreasing trend and there is no evidence of HCC by dynamic CT or MRI)
11. Malignancy other than hepatocellular carcinoma within the 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (within 2 years prior to screening with confirmation of no evidence of disease). Subjects under evaluation for possible malignancy are not eligible.
12. Concurrent enrollment in another clinical study for other type of antiviral treatment for CHB or immune modulatory drug within 3 months prior to randomization, participation to an observational (non-interventional) clinical studies or interventional studies not using anti-HBV or immune modulatory drugs, or during the follow-up period of an interventional study are not exclusion criteria.
13. Pregnant women, women who are breastfeeding or who believe they may wish to become pregnant during the course of the study