Risk of Hepatocellular Carcinoma in Patients Treated With ETV vs TDF for Chronic Hepatitis B With Compensated Cirrhosis

November 10, 2019 updated by: Qing XIe

Risk of Hepatocellular Carcinoma in Patients Treated With ETV vs TDF for Chronic Hepatitis B With Compensated Cirrhosis: A Multicenter, Real-world and Respective Study

The current first-line treatment for HBV is long-term oral antiviral drugs to inhibit HBV DNA replication. First-line antiviral drugs recommended by the Chinese 2015 Hepatitis B Guidelines include ETV and TDF. This study is based on a real-world clinical cohort to retrospectively analyze the effects of ETV and TDF on the long-term (5-year) incidence of HCC in Chinese patients with chronic hepatitis B with compensated cirrhosis. The results will guide the revision of the Chinese HBV guidelines.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

HBV infection is a global problem, and China has a heavy disease burden with approximately 86 million people infected with HBV. According to the epidemiological survey of nearly 230,000 people in Northeast China in 2010-2013, the positive rate of HBsAg reached 6.1%, of which 10.7% had cirrhosis.

According to the latest authoritative guidelines, including the guidelines published in 2018 by American Association for the Study of Liver Diseases (AASLD) and in 2017 by European Association for the Study of Liver Diseases (EASL), entecavir (ETV) and tenofovir diisopropyl (TDF) are recommended as first-line antiviral drugs. ETV is a guanosine nucleoside analog that inhibits HBV polymerase and inhibits the synthesis of HBV DNA. TDF is a cyclic nucleoside phosphorylated diester structural analog of adenosine monophosphate, and its hydrolysis and phosphorylation products can inhibit the activity of HBV reverse transcriptase and also inhibit the synthesis of HBV DNA. In 2005, ETV was listed in China Mainland and TDF was listed in 2014. Over the years, clinical studies have shown that both have good antiviral effects and low drug resistance rates, so they are chosen as first-line antiviral drugs.

HBV infection is one of the risk factors for hepatocellular carcinoma (HCC). Previous studies based on the Chinese patients have shown that antiviral therapy (such as ETV) can significantly reduce the incidence of HCC in patients with cirrhosis (the 4-year cumulative incidence of HCC decreased from 17.5% to 9.4%). However, a study from South Korea published online in September 2018 in JAMA Oncology showed that TDF significantly reduced the incidence of HCC compared to ETV (HR 0.68, 95% CI 0.46-0.99) . In contrast, another multicenter study in Korea, published in March 2019 in The JOURNAL OF HEPATOLOGY showed no significant difference between ETV and TDF (HR 0.975, p=0.852) [4]. In the latter study, there was a problem with the small sample size, and the sample size was not sufficient to test the difference between the two antiviral drugs, and the sample size needed to be expanded to verify the result.

Compared with Koreans, the incidence of HCC in Chinese is significantly lower (in patients with cirrhosis, the 5-year cumulative incidence of HCC is about: China vs Korea: 12% vs 20%), showing the differences between countries. There is at present no similar study based on Chinese patients, especially in patients with cirrhosis to compare the effects of ETV and TDF on the incidence of HCC.

China has a huge disease burden and a high incidence of HCC. The ETV and TDF both have generic drugs marketing in China Mainland which through quality consistency evaluation and entering the 4+7 drug procurement (the centralized drug procurement in "4+7 Cities": Beijing, Tianjin, Shanghai, Chongqing, Shenyang, Dalian, Xiamen, Guangzhou, Shenzhen, Chengdu and Xian), bringing good antiviral effect to patients at preferential prices. If we can detect the difference in the occurrence of HCC between ETV and TDF, rational selection of drugs will reduce the incidence of HCC in Chinese patients with chronic hepatitis B (Korean studies showed that cumulative HCC patients can reduce 32% in 5 years), greatly reducing the burden on Chinese patients and health care.

This research is a real-world, multi-center, retrospective, and observational study.

Patient data are collected from 5-10 research centers in mainland China, including basic demographic information, antiviral regimen, time of stating antivirus, endpoint event, time of endpoint event, last follow-up time, important testing data, etc.

Patients with the time of last follow-up (or the time of the endpoint event) between 2013-1-1 and 2019-12-31 are included in this study.

Based on the data we collect, the Propensity Score Matching and Inverse Probability Multiple Weighted methods and the Competing Risk Model are utilized to correct the confounding factors to calculate the impact of TDF and ETV on HCC events.

Study Type

Observational

Enrollment (Anticipated)

4000

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Shanghai
      • Shanghai, Shanghai, China, 200025
        • Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

This study was conducted in high-risk populations of HCC (patients with cirrhosis). According to the studies from Taiwan and Hongkong, the cumulative incidence of HCC in Chinese patients with cirrhosis in the ETV group was about 11.8-13.8% over 5 years, and we estimate it to be 12.8%; the 5-year incidence of HCC in the TDF group is estimated to be 8.0% according to the studies from Korea with the HR=0.55-0.75. Actual patients' use of ETV and TDF in China is about 3:1. We calculated that for this study to have 80% power to detect a 5% relative difference between the TDF and ETV groups, there would have to be 202 events and enroll 539 and 1616 patients at least in TDF and ETV treatment group based on log-rank (Lakatos) test.

On the basis of these calculations, we planned to enroll 4,000 patients (1,000 patients in the TDF group, 3,000 patients in the ETV group).

Description

Inclusion Criteria:

  • HBsAg+ > 6 months
  • age 18-80
  • TDF or ETV Treatment Naive
  • cirrhosis

Exclusion Criteria:

  • TDF/ETV treatment duration<12 m
  • decompensated cirrhosis
  • previous H/O organ or stem cell transplant
  • IFN exposure or combination of IFN>4 w
  • HCC, death or OLT within 12 m after TDF or ETV treatment;
  • previous HCC history;
  • key data (such as key medical history, hematological and biochemical tests, HBV DNA and HBV antibody/antigen before treatment, et al) missing or error.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Retrospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
ETV cohort
CHB patients with entecavir naive treatment
Drug: Entecavir
entecavir naive for chronic hepatitis B patients
TDF cohort
CHB patients with naive tenofovir disopropyl naive treatment
Drug: Tenofovir Disoproxil
tenofovir disopropyl naive for chronic hepatitis B patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The 5-year cumulative incidence of hepatocellular carcinoma
Time Frame: 5 years
Compare the difference in the 5-year cumulative incidence of HCC in Chinese patients with chronic hepatitis B with cirrhosis in real world between ETV and TDF.
5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The 5-year cumulative all-cause mortality rate
Time Frame: 5 years
Compare the difference in the 5-year cumulative all-cause mortality rate in Chinese patients with chronic hepatitis B with cirrhosis in real world between ETV and TDF.
5 years
The 5-year cumulative liver transplantation rate
Time Frame: 5 years
Compare the difference in the 5-year cumulative liver transplantation rate in Chinese patients with chronic hepatitis B with cirrhosis in real world between ETV and TDF.
5 years
The 5-year cumulative liver disease-related mortality
Time Frame: 5 years
Compare the difference in the 5-year cumulative liver disease-related mortality in Chinese patients with chronic hepatitis B with cirrhosis in real world between ETV and TDF.
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Qing XIe

Collaborators

Shanghai MedSci Healthcare Co. Ltd

Investigators

  • Study Chair: Qing Xie, MD, Director of Department of Infectious Disease, Rui Jin Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 22, 2019

Primary Completion (Anticipated)

October 31, 2020

Study Completion (Anticipated)

October 31, 2020

Study Registration Dates

First Submitted

November 10, 2019

First Submitted That Met QC Criteria

November 10, 2019

First Posted (Actual)

November 13, 2019

Study Record Updates

Last Update Posted (Actual)

November 13, 2019

Last Update Submitted That Met QC Criteria

November 10, 2019

Last Verified

November 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ISR-CN-9-10708

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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