Study on Effect of Intestinal Microbiota Transplantation in Chronic Hepatitis B

Study Overview
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Brief Summary
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Chronic hepatitis B(CHB) is a common infectious disease affecting up to 2 billion people worldwide. Around 650 thousand people died of liver failure, cirrhosis and primary liver cancer caused by chronic hepatitis B every year. Age is the main factor affecting the chronicity of hepatitis B, while 90% and 25% to 30% of hepatitis b virus(HBV) infection in perinatal and infant period will develop into chronic infection respectively. Whereas the proportion in patients above 5 years old is only 5% to 10%. Intestinal microbiota plays an important role in maintaining normal physiological function of the intestine and the immune function of the body. It has been found that the disorder of intestinal microbiota is associated with numerous intestinal and parenteral diseases. Intestinal microbiota transplantation(IMT) is a significant method to reconstruct intestinal flora. Recently, the relationship between immune response and intestinal microbiota has been claimed. In a previous study using IMT to treat HBeAg positive chronic hepatitis B patients combined with antiviral therapy, 80% of them has reached HBeAg clearance. The investigators propose a randomised trial of IMT in patients with chronic hepatitis B combined with antiviral therapy. The investigators will assess the serum HBsAg, anti-HBs, HBeAg, anti-HBe, anti-hepatitis B core antigen, the relief of gastrointestinal symptoms, and the fecal microbiota before and after IMT. Patients will be randomized to either antiviral therapy or IMT combined antiviral therapy over a 26 weeks period.

Detailed Description
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A group of 60 chronic hepatitis B patients combined with antiviral therapy will be recruited for study, which involved a 6 times IMT with gastroduodenoscopy and the time interval is generally 2 weeks. All participants will keep their present antiviral therapy. All participants will be assessed at baseline, after 1 months, 3 months, 6 months from baseline in order to evaluate the possible changes in:(1)Decrease of serum hepatitis B virus surface antigen(HBsAg) levels(as measured in IU/mL) and hepatitis B virus e antigen(HBeAg) levels(as measured in S/CO); (2)Appearance of serum anti-hepatitis B virus surface antigen(anti-HBs) and anti-hepatitis B virus e antigen(anti-HBe); (3)Relief of gastrointestinal symptoms:The onset and duration of gastrointestinal symptoms will be assessed by Evaluation Score Table of Gastrointestinal Symptoms; (4)Changes of gut microbiota: The changes of gut microbiota will be assessed by High-throughput sequencing (16S rRNA) in fecal samples from recruited patients before and after IMT.

Official Title
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A Randomised Study on Intestinal Microbiota Transplantation for Chronic Hepatitis B Combined With Antiviral Therapy

Conditions
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Chronic Hepatitis b

Intervention / Treatment
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* Other: intestinal microbiota transplant
* Drug: Antiviral Agents


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent/assent as appropriate 18 to 65 years of age No alcohol consumption or alcohol consumption <140g per week in men, and <70g per ween in women Been diagnosed with chronic hepatitis B Exclusion Criteria: Alcoholic liver disease (ALD), chronic hepatitis C, autoimmune liver disease, Wilson's disease Drug treatment (tamoxifen, amiodarone, sodium valproate, methotrexate, glucocorticoids, etc.), total parenteral nutrition, inflammatory bowel disease, hypothyroidism, Cushing's syndrome, beta lipoprotein deficiency, insulin resistance related syndromes (lipid wasting diabetes mellitus, Mauriac syndrome), gastrointestinal surgery Hepatocellular carcinoma (HCC), biliary tract diseases and taking or taking chinese and western medicines that can lead liver enzymes elevation in the near future. Moderate and severe renal injury(serum creatinine>2mg/dL or 177mmol/L), moderate and severe chronic obstructive pulmonary disease, severe hypertension, cerebrovascular accident, congestive heart failure, unstable angina pectoris. Antibiotics treatment in 7 days before recruited and unwilling to stop it, long-term lipid-lowering drugs, antidiabetic drugs and other liver protecting drugs treatment Antibiotics, other probiotics, gastrointestinal motility drugs and other preparation that may influence intestinal microbiota treatment Other serious diseases that may interfere the recruitment or affect the survival, such as cancer or acquired immune deficiency syndrome Mentally or legally disabled person Preparing for pregnancy Medical or social condition which in the opinion of the principal investigator would interfere with or prevent regular follow up Participating in other clinical trials.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: an open label, parallel study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMT Combined with Antiviral Therapy<br>60 chronic hepatitis B patients ongoing antiviral therapy will be recruited for the study, which involved a 6 times intestinal microbiota transplant and the time interval is generally 2 weeks. Interventions: Procedure: Intestinal Microbiota Transplantation Procedure: antiviral therapy | Other: intestinal microbiota transplant<br>* Participants in experimental group take 6 times IMT with 2-week intervals.<br>Drug: Antiviral Agents<br>* All participants continue present antiviral therapy over 12 months.<br>|
| Other: Antiviral Agents<br>60 chronic hepatitis B patients ongoing antiviral therapy will be recruited for the study, which involved 12 months antiviral therapy. Interventions: Procedure: antiviral therapy | Drug: Antiviral Agents<br>* All participants continue present antiviral therapy over 12 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of serum hepatitis B virus e antigen(HBeAg) level | Serum hepatitis B virus e antigen(HBeAg) levels is measured in S/CO | 1 month, 3 months, 6months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of serum hepatitis B virus surface antigen(HBsAg) level | Serum hepatitis B virus surface antigen(HBsAg) levels is measured in IU/mL . | 1 month, 3 months, 6months | 
| Change of serum anti-hepatitis B virus e antigen(anti-HBe) | Appearance of serum anti-hepatitis B virus e antigen(anti-HBe) suggest the ability of body to resistant HBV. | 1 month, 3 months, 6months | 
| Change of serum anti-hepatitis B virus surface antigen(anti-HBs) | Appearance of serum anti-hepatitis B virus surface antigen(anti-HBs) suggest the ability of body to resistant HBV. | 1 month, 3 months, 6months | 
| Changes of gut microbiota | Alpha and Beta diversity of GI microbiota by High-throughput sequencing (16S rRNA) on baseline line and1 month, 3 months, 6months after treatment | 1 month, 3 months, 6months | 
| relief of constipation | The onset and duration of constipation will be assessed by Evaluation Score Table of Gastrointestinal Symptoms. | 1 month, 3 months, 6months | 
| relief of diarrhea | The onset and duration of diarrhea will be assessed by Evaluation Score Table of Gastrointestinal Symptoms. | 1 month, 3 months, 6months | 
| relief of abdominal pain | The onset and duration of abdominal pain will be assessed by Evaluation Score Table of Gastrointestinal Symptoms. | 1 month, 3 months, 6months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic hepatitis B, intestinal microbiota transplantation, microbiota, antiviral therapy