Peginterferon Treatment Study for Inactive Chronic Hepatitis B Patients

Study Overview
=================
Brief Summary
-----------------
There are about 400 million chronic hepatitis B virus (HBV) infection patients worldwide, posing a serious threat to global public health security. In China, HBV infection occured mainly in the perinatal period or infants, and about 10% of patients in the immune tolerance stage spontaneously transit to the immune clearance stage every year and become HBeAg-negative chronic HBV infection, resulting in a significant increase in the number of inactive chronic hepatitis B (CHB) patients. In recent years, different guidelines have not reached consensus on the need to initiate antiviral therapy for inactive CHB patients: In the guidelines of Asian Pacific Association for The Study of Liver(APASL)-2015 and American Association for the Study of Liver Diseases(AASLD)-2018, antiviral therapy is generally not recommended for this group of patients, and regular outpatient follow-up is recommended. Guideline of European Association for the Study of the Liver(EASL)-2017 suggests that people with a family history of cirrhosis and liver cancer at this stage could be treated with antiviral therapy even if they did not meet the indications of antiviral therapy. According to Guidelines for the Prevention and Treatment of Chronic Hepatitis B (version 2019) of China, antiviral therapy is still recommended for some patients with inactive HBsAg carrier status who are HBV DNA positive and meet the treatment indications. Studies have shown that some patients in immune tolerance stage may enter the immune clearance stage and have hepatitis flare. Patients of inactive CHB have the potential to develop HBeAg-negative CHB, and studies of long-term follow-up in this population have indicated the risk of hepatocellular carcinoma. With the popularization of the concept of functional cure for chronic hepatitis B, more and more people with inactive CHB have a strong desire for treatment. In recent years, several studies have demonstrated that Pegylated-interferon therapy can achieve high functional cure rate in patients with inactive CHB. The purpose of this study is to establish a national multi-center, prospective real world study to compare the efficacy of different antiviral treatment regimens for patients with inactive CHB and seek for the factors of functional cure.

Official Title
-----------------
Real World Study of Peginterferon Alpha-2b Treatment for Inactive Chronic Hepatitis B Patients: E-Cure Study

Conditions
-----------------
Hepatitis B, Chronic

Intervention / Treatment
-----------------
* Drug: Peginterferon Alfa-2B
* Drug: Nucleoside Analogs


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18-60, no gender limitation HBsAg is positive for more than 6 months Hepatitis B e antigen(HBeAg) is negative and anti-HBe is positive Serum HBV DNA is less than 2000 IU/mL Alanine aminotransferase(ALT) and/or Aspartate aminotransferase(AST) is normal No antiviral durg (including nucleos(t)ide analogue and interferon) was used before enrollment Good compliance and voluntarily signed informed consent Exclusion Criteria: Allergic to pegylated interferon α-2b Any indication of liver cirrhosis Coinfection with hepatitis A virus(HAV), hepatitis C virus(HCV), hepatitis D virus(HDV), hepatitis E virus(HEV) or human immunodeficiency virus(HIV) Combined with other liver diseases (including drug-related, alcoholic, autoimmune, genetic metabolic liver diseases, etc.) There are serious lesions in the important organs, such as heart, lung, kidney, brain and fundus Patients with autoimmune diseases, unstable diabetes or thyroid diseases(hyperthyroidism or hypothyroidism) Confirmed or suspected liver cancer or other malignant tumors Patients after or preparing for organ transplantation Peripheral blood white blood cell count < 3.5×109/L and/or platelet count < 80×109/L Under immunosuppressant treatment Pregnant or planned pregnancy in a short term or lactation patients Alcohol abuse (average alcohol intake is more than 40 g/d in males or 20g/d in women) or drug addicts Present or past history of mental or psychological diseases Other conditions that the investigators deem inappropriate for the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequential Combination Group<br>Oral nucleos(t)ide analogues (NAs) (Entecavir(ETV), Tenofovir disoproxil fumarate tablets(TDF) or Tenofovir Alafenamide Fumarate(TAF)) is used for 12-24 weeks, followed by combination therapy with peginterferon α-2b. The Maximum course is 96 weeks. Follow-up period is 144 weeks. | Drug: Peginterferon Alfa-2B<br>* Different usage of peginterferon Alfa-2B and/or Nucleos(t)ide analogs in arm/group descriptions are depended on the wishes of the patient and the advice of the attending doctor.<br>Drug: Nucleoside Analogs<br>* Nucleos(t)ide analogs refer to one of the first-line drugs, including ETV, TDF and TAF.<br>|
| Experimental: Initial Combination Group<br>NAs combined with peginterferon are used for 12-24 weeks, followed by peginterferon α-2b. The Maximum course is 96 weeks. Follow-up period is 144 weeks. | Drug: Peginterferon Alfa-2B<br>* Different usage of peginterferon Alfa-2B and/or Nucleos(t)ide analogs in arm/group descriptions are depended on the wishes of the patient and the advice of the attending doctor.<br>Drug: Nucleoside Analogs<br>* Nucleos(t)ide analogs refer to one of the first-line drugs, including ETV, TDF and TAF.<br>|
| Experimental: Whole-course Combination Group<br>NAs combined with peginterferon are used for a maximum course of 96 weeks. Follow-up period is 144 weeks. | Drug: Peginterferon Alfa-2B<br>* Different usage of peginterferon Alfa-2B and/or Nucleos(t)ide analogs in arm/group descriptions are depended on the wishes of the patient and the advice of the attending doctor.<br>Drug: Nucleoside Analogs<br>* Nucleos(t)ide analogs refer to one of the first-line drugs, including ETV, TDF and TAF.<br>|
| Experimental: Peginterferon Monotherapy Group<br>Peginterferon is used for a maximum course of 96 weeks. Follow-up period is 144 weeks. | Drug: Peginterferon Alfa-2B<br>* Different usage of peginterferon Alfa-2B and/or Nucleos(t)ide analogs in arm/group descriptions are depended on the wishes of the patient and the advice of the attending doctor.<br>|
| Experimental: NAs Monotherapy Group<br>NAs is used for a maximum course of 96 weeks. Follow-up period is 144 weeks. | Drug: Nucleoside Analogs<br>* Nucleos(t)ide analogs refer to one of the first-line drugs, including ETV, TDF and TAF.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBsAg clearance rate | HBsAg is detected by Roche or Abbott productions, of which the lower limit is 0.05 IU/ml | From date of the beginning of treatment until the date of the end of treatment, assessed up to 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBsAg serological conversion rate | HBsAg is detected by Roche or Abbott productions, of which the lower limit is 0.05 IU/ml | From date of the beginning of treatment until the date of the end of treatment, assessed up to 96 weeks | 
| The magnitude of HBsAg decline from baseline | HBsAg is detected by quantitative assays from Roche or Abbott | through treatment completion, an anticipated period of 96 weeks | 
| The magnitude of HBV-DNA decline from baseline and the undetectable rate | HBV-DNA is detected by assays from Roche or Abbott, of which the lower limit is 15 or 10 IU/ml. | through treatment completion, an anticipated period of 96 weeks | 
| HBsAg clearance rate, HBsAg serological conversion rate and maintenance response rate of HBsAg clearance | HBsAg is detected by Roche or Abbott productions, of which the lower limit is 0.05 IU/ml | through follow-up completion, an anticipated period of 144 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
inactive chronic hepatitis B, functional cure