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

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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

Conditions
-----------------
Hepatitis B, Chronic, Hepatocellular Carcinoma, Compensated Cirrhosis

Intervention / Treatment
-----------------
* Drug: Entecavir
* Drug: Tenofovir Disoproxil


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ETV cohort<br>CHB patients with entecavir naive treatment | Drug: Entecavir<br>* entecavir naive for chronic hepatitis B patients<br>|
| TDF cohort<br>CHB patients with naive tenofovir disopropyl naive treatment | Drug: Tenofovir Disoproxil<br>* tenofovir disopropyl naive for chronic hepatitis B patients<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The 5-year cumulative incidence of hepatocellular carcinoma | 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 | 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 | 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 | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
chronic hepatitis B, hepatocellular carcinoma, compensated cirrhosis, Chinese, entecavir, tenofovir disopropyl, multi-center, real-world, respective