The Efficacy and Safety of Nucleos(t)Ide Analogues in the Treatment of HBV-related Acute-on-chronic Liver Failure

A Multicenter Controlled Open-label Trial of Evaluating Tenofovir Alafenamide, Tenofovir Disoproxil Fumarate and Entecavir in Acute-on-chronic Liver Failure of Chronic Hepatitis B Patients

HBV-related acute-on-chronic liver failure (ACLF) is a clinical syndrome defined as acute hepatic insult with diagnosed or undiagnosed chronic liver disease. Current clinical guidelines advocate oral antiviral treatment in HBV-related ACLF. However, no conclusion on which nucleoside analogue is the most satisfactory drug for the treatment of HBV-related liver failure has not been reached yet. In this cohort study, the investigators will compare the efficacy, safety, and tolerability of tenofovir alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and entecavir (ETV) in HBV-related ACLF in China. In addition, the drug metabolism characteristics of TAF will be explored in such severe liver injury population of HBV-ACLF.

Study Overview

• Status: Recruiting
• Conditions: Liver Failure; Virus Diseases; Hepatitis B
• Intervention / Treatment: Drug: Entecavir; Drug: Tenofovir disoproxil fumarate; Drug: Tenofovir Alafenamide

Detailed Description

Potent antivirals like entecavir (ETV), Tenofovir Disoproxil Fumarate (TDF) and Tenofovir alafenamide (TAF) now are recommended as first-line therapy for patients with chronic HBV infection because of their significant suppression of viral replication and a high barrier to resistance. HBV-related acute-on-chronic liver failure (ACLF) is a clinical syndrome defined as acute hepatic insult with diagnosed or undiagnosed chronic liver disease. Only a limited number of medical treatments are available for ACLF. Although liver transplantation is a life-saving treatment for ACLF, the difficulty in finding a suitable donor and the high cost hinder its extensive clinical use.

The precise mechanism underlying the liver injury caused by HBV-related ACLF and the factors contributing to the progression of liver failure remain unknown. HBV DNA replication is one of the key factors causing the progression from liver damage to liver failure. Current clinical guidelines advocate oral antiviral treatment in HBV-related ACLF. However, the specific antiviral treatment for patients with liver failure remains unclear. In the past years, efficacy of nucleoside analogues, such as lamivudine, entecavir, telbivudine and tenofovir, for HBV-related liver failure has been reported. However, no conclusion on which nucleoside analogue is the most satisfactory drug for the treatment of HBV-related liver failure has not been reached yet.

In this cohort study, the investigators will compare the efficacy, safety, and tolerability of tenofovir alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and entecavir (ETV) in HBV-related ACLF in China. In addition, pharmacokinetic properties of TAF tablets will be explored in the study subjects.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

Study Locations

• China
  • Ankang, China
    • Recruiting
    • Ankang Central Hospital
  • Hanzhong, China
    • Not yet recruiting
    • Hanzhong 3201 Hospital
  • Hanzhong, China
    • Not yet recruiting
    • Hanzhong Infectious Hospital
  • Weinan, China
    • Not yet recruiting
    • weinan Central Hospital
  • Xi'an, China
    • Recruiting
    • The Second Affiliated Hospital of Xi'an Jiaotong University
  • Xi'an, China
    • Recruiting
    • First Affiliated Hospital Xi'an Jiaotong University
  • Xi'an, China
    • Not yet recruiting
    • Shaanxi Provincial People's Hospital
  • Xi'an, China
    • Not yet recruiting
    • Tangdu Hospital, The Fourth Military Medical University,
  • Xi'an, China
    • Active, not recruiting
    • Xi'an Central Hospital
  • Xi'an, China
    • Not yet recruiting
    • Xijing Hospital, the Fourth Military Medical University
  • Yan'an, China
    • Not yet recruiting
    • The Affiliated Hospital of Yan'an University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

All the patients received antivirals will be followed for at least 48 weeks and follow-up assessments were performed at week 1, 2, 3, 4, 12, 24 and 48.All the patients were detected Serum HBV DNA,HBV markers, including HBsAg, HBsAb, HBeAg, HBeAb and HBcAb, routine biochemical tests mainly including ALT,AST,TB and ALB.

Description

Inclusion Criteria:All of below

1. age 18-70 years, male or female.
2. HBsAg positive at least 6 months or more, HBeAg positive or negative.
3. Serum HBV DNA positive (Serum HBV DNA should be determined by the PCR assay at the local laboratory at screening for this study)
4. Recent development of increasing jaundice (a total serum bilirubin concentration of above 85μmol/L) and coagulopathy (INR ≥1.5 or prothrombin activity<40%)
5. Recent development of complications such as hepatic encephalopathy, or abrupt and obvious increase in ascites, or spontaneous bacterial peritonitis, or hepatorenal syndrome.
6. Patient is willing and able to comply with the study drug regimen and all other study requirements.
7. The patient is willing and able to provide written informed consent to participate in the study.

Exclusion Criteria: Any of below

1. Patient has concomitant other chronic viral infection (HCV or HIV)
2. Patient has evidence of renal insufficiency defined as serum creatinine > 1.5 mg/dL
3. Patient has medical condition that requires concurrent use of systemic prednisolone or other immunosuppressive agent (including chemotherapeutic agent)
4. Patient is pregnant or breastfeeding or willing to be pregnant
5. Patient has one or more additional known primary or secondary causes of liver disease, other than hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's Disease, other congenital or metabolic conditions affecting the liver, congestive heart failure or other severe cardiopulmonary disease, etc.).
6. A history of treated malignancy (other than hepatocellular carcinoma) is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding three years.
7. Active ethanol/drug abuse/psychiatric problems such as major depression, schizophrenia, bipolar illness, obsessive-compulsive disorder, severe anxiety, personality disorder that might interfere with participation in the study.
8. Current alcohol or substance abuse judged by the investigator to potentially interfere with participant compliance.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
ETV; patients receive entecavir 0.5 mg/day orally.	Drug: Entecavir; Entecavir 0.5 mg/day orally
TDF; patients receive Tenofovir Disoproxil Fumarate 300 mg/day orally.	Drug: Tenofovir disoproxil fumarate; Tenofovir Disoproxil Fumarate 300 mg/day orally
TAF; patients receive Tenofovir alafenamide 25 mg/day orally.	Drug: Tenofovir Alafenamide; Tenofovir alafenamide 25 mg/day orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival of ACLF subjects	Overall survival in subjects with acute-on-chronic liver failure will be summarized and compared with control subjects through study day 28 and week 48.	study day 1 through week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in serum HBV DNA levels		at week 4 and 48 of treatment
Proportion of patients with hepatitis B e-Ag(HBe-Ag) loss or seroconversion		at week 4 and 48 of treatment
Proportion of patients with HBs-Ag loss or seroconversion		at week 4 and 48 of treatment
Proportion of patients with normal alanine aminotransferase(ALT)		at week 4 and 48 of treatment
Liver function evaluation through Model for End-Stage Liver Disease (MELD) scores	Model for End-Stage Liver Disease(MELD) Score is calculated according to the equation:3.78×ln[serum bilirubin (mg/dl)] + 11.2×ln(INR) + 9.57×ln[serum creatinine (mg/dL)] + 6.43. Liver function improvement defined as the decline of total MELD score, whereas liver function deterioration defined as the rise of total MELD score. The risk of death increased when total MELD score above 25.	at week 4 and 48 of treatment
Proportion of patients with virologic breakthrough	Virologic breakthrough is defined as the increase in serum HBV DNA by >1 log10 (10-fold) above nadir after achieving virologic response as determined by at least 2 consecutive measurements of at least 2 weeks apart, during continued treatment	at week 4 and 48 of treatment
Proportion of patients with complete virologic response	Virologic response is defined as the serum HBV DNA concentrations below 20 IU/mL	at week 4 and 48 of treatment

Collaborators and Investigators

• Sponsor: First Affiliated Hospital Xi'an Jiaotong University

Publications and helpful links

General Publications

• Li J, Hu C, Chen Y, Zhang R, Fu S, Zhou M, Gao Z, Fu M, Yan T, Yang Y, Li J, Liu J, Chen T, Zhao Y, He Y. Short-term and long-term safety and efficacy of tenofovir alafenamide, tenofovir disoproxil fumarate and entecavir treatment of acute-on-chronic liver failure associated with hepatitis B. BMC Infect Dis. 2021 Jun 14;21(1):567. doi: 10.1186/s12879-021-06237-x.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 25, 2019
• Primary Completion (ACTUAL): April 30, 2021
• Study Completion (ANTICIPATED): July 1, 2023

Study Registration Dates

• First Submitted: August 19, 2018
• First Submitted That Met QC Criteria: August 19, 2018
• First Posted (ACTUAL): August 21, 2018

Study Record Updates

• Last Update Posted (ESTIMATE): February 9, 2023
• Last Update Submitted That Met QC Criteria: February 7, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Hepatitis B, Acute-on-Chronic liver failure
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Liver Failure, Acute; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; End Stage Liver Disease; Liver Failure; Hepatic Insufficiency; Acute-On-Chronic Liver Failure; Hepatitis B; Hepatitis; Hepatitis A; Virus Diseases; 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; Entecavir
• Other Study ID Numbers: XJTU1AF2018LSL-002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No