A Real-World Study of Pegylated Interferon In Nucleoside-treated Patients With Chronic Hepatitis B

Study Overview
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Brief Summary
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The aim of the prospective real-world study is to evaluate whether sequential combination therapy with pegylated interferon plus entecavir/tenofovir could induce higher rates of HBsAg loss in nucleoside-treated patients with chronic hepatitis B compared to continuous nucleoside treatment.

Detailed Description
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Patents who were treated with NA at least one year and achieved hepatitis B virus (HBV) DNA suppression and HBsAg level<3000 international unit (IU) /mL are enrolled in this study, they are assigned into two groups, in group I, patients will receive pegylated interferon plus entecavir/tenofovir for 48/72/96 weeks, in group II, patients will receive entecavir/tenofovir for 96 weeks. HBsAg loss rates at the end of treatment and sustained response at the end of follow up will be evaluated.

Official Title
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A Real-World Study of Sequential Combination Therapy With Pegylated Interferon In Nucleoside-treated Patients With Chronic Hepatitis B

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Pegylated interferon
* Drug: Entecavir
* Drug: Tenofovir disoproxil fumarate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients from 18 to 65 years of age; HBsAg positive, entecavir and or adefovir dipivoxil are used at least 1 year including patients with nucleotides or nucleoside resistance history; Before nucleotides or nucleosides treatment, ALT > 2 upper limit of normal value (ULN), HBV DNA >10000 copies/ml, HBsAg positive; Serum HBV DNA ≤ 500 copies/ml; HBsAg<3000 IU/ml; HBsAg positive; Negative urine or serum pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of test drug; Absence of cirrhosis confirmed by ultrasonic test; Agree to participate in the study and sign the patient informed consent. Exclusion Criteria: HBV DNA > 500 copies/ml; Other antiviral, anti-neoplastic or immunomodulatory treatment (including supra physiologic doses of steroids and radiation) 6 months prior to the first dose of randomized treatment (except for 7 days of acyclovir for herpetic lesions more than 1 month prior to first administration of randomized treatment). Patients who are expected to need systemic antiviral therapy other than that provided by the study at any time during their participation are also excluded; Women with ongoing pregnancy or breast-feeding; Co-infection with active hepatitis A, hepatitis C, hepatitis D(Those hospitals which have the ability to do the test will do) and/or human immunodeficiency virus (HIV); ALT >10 ULN; Evidence of decompensated liver disease (Child-Pugh score > 5). Child-Pugh > 5 means, if one of the following 5 conditions are met, the patient has to be excluded: one of the following 5 conditions are met, the patient has to be excluded: Serum albumin < 3.5 g/L; Prothrombin time > 3 seconds prolonged; Serum bilirubin > 34 µ mol/L; History of encephalopathy; History of variceal bleeding; Ascites; History or other evidence of a medical condition associated with chronic liver disease other than viral hepatitis (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposures, thalassemia); Signs or symptoms of hepatocellular carcinoma, patients with a value of alpha-fetoprotein > 100 ng/mL are excluded, unless stability (less than 10% increase) has been documented over at least the previous 3 months. Patients with values < 20 ng/mL but > 100 ng/mL may be enrolled, if hepatic neoplasia has been excluded by liver imaging; Neutrophil count < 1500 cells/mm3 or platelet count <90,000 cells/mm3 at screening; Hemoglobin < 11.5 g/dL for females and <12.5 g/dL for men; Serum creatinine level > 1.5 ULN in screening period. Phosphorus < 0.65 mmol/L; antinuclear antibody (ANA) > 1:100; History of severe psychiatric disease, especially depression. Severe psychiatric disease is defined as treatment with an antidepressant medication or a major tranquilizer at therapeutic doses for major depression or psychosis, respectively, for at least 3 months at any previous time or any history of the following: a suicidal attempt hospitalization for psychiatric disease, or a period of disability due to a psychiatric disease; History of a severe seizure disorder or current anticonvulsant use; History of immunologically mediated disease, (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, rheumatoid arthritis etc.); History of chronic pulmonary disease associated with functional limitation; Diseases that interferon and nucleotides or nucleosides are not suitable.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequential combination therapy group<br>Patients are treated with pegylated Interferon (180ug, subcutaneously, once a week) plus entecavir (0.5mg, orally, every day) or tenofovir disoproxil fumarate (300mg, orally, every day) for 48/72/96 weeks | Drug: Pegylated interferon<br>* 180ug Pegylated interferon is injected subcutaneously once a week<br>* Other names: Pegylated interferon (PegIFN);Drug: Entecavir<br>* 0.5mg entecavir is orally taken every day<br>* Other names: Entecavir (ETV);Drug: Tenofovir disoproxil fumarate<br>* 300mg tenofovir is orally taken every day<br>* Other names: Tenofovir disoproxil fumarate (TDF);|
| Active Comparator: Nucleoside therapy group<br>Patients are treated with entecavir (0.5mg, orally, every day) or tenofovir disoproxil fumarate (300mg, orally, every day) for 96 weeks | Drug: Entecavir<br>* 0.5mg entecavir is orally taken every day<br>* Other names: Entecavir (ETV);Drug: Tenofovir disoproxil fumarate<br>* 300mg tenofovir is orally taken every day<br>* Other names: Tenofovir disoproxil fumarate (TDF);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBsAg loss rate | Percentages of patients who achieve HBsAg loss at week 48 | at week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBsAg loss rate | Percentages of patients who achieve HBsAg loss at week 72 | at week 72 | 
| HBsAg loss rate | Percentages of patients who achieve HBsAg loss at week 96 | at week 96 | 
| HBsAg level | Dynamic change in HBsAg level from baseline to week 48 | at week 48 | 
| HBsAg level | Dynamic change in HBsAg level from baseline to week 72 | at week 72 | 
| HBsAg level | Dynamic change in HBsAg level from baseline to week 96 | at week 96 | 
| sustained HBsAg loss rate | Percentages of patients who achieve HBsAg loss at week 120 | at week 120 | 
| decline in HBsAg level | Decline in HBsAg level from baseline to week 48 | at week 48 | 
| decline in HBsAg level | Decline in HBsAg level from baseline to week 72 | at week 72 | 
| decline in HBsAg level | Decline in HBsAg level from baseline to week 96 | at week 96 | 
| HBsAb appearance rate | Percentages of HBsAb appearance at week 48 | at week 48 | 
| HBsAb appearance rate | Percentages of HBsAb appearance at week 72 | at week 72 | 
| HBsAb appearance rate | Percentages of HBsAb appearance at week 96 | at week 96 | 
| HBsAb seroconversion rate | Percentages of HBsAb seroconversion at week 48 | at week 48 | 
| HBsAb seroconversion rate | Percentages of HBsAb seroconversion at week 72 | at week 72 | 
| HBsAb seroconversion rate | Percentages of HBsAb seroconversion at week 96 | at week 96 | 
| HBeAg loss rate | Percentages of HBeAg loss in the HBeAg-positive patients at week 48 | at week 48 | 
| HBeAg loss rate | Percentages of HBeAg loss in the HBeAg-positive patients at week 72 | at week 72 | 
| HBeAg loss rate | Percentages of HBeAg loss in the HBeAg-positive patients at week 96 | at week 96 | 
| HBeAg seroconversion rate | Percentages of HBeAg seroconversion in the HBeAb-negative patients at week 48 | at week 48 | 
| HBeAg seroconversion rate | Percentages of HBeAg seroconversion in the HBeAb-negative patients at week 72 | at week 72 | 
| HBeAg seroconversion rate | Percentages of HBeAg seroconversion in the HBeAb-negative patients at week 96 | at week 96 | 
| Rate of HBV DNA level <1000 copies/mL | Percentages of HBV DNA level <1000 copies/mL at week 96 | at week 96 | 
| Rate of alanine aminotransferase (ALT) normalization | Percentages of ALT normalization at week 96 | at week 96 | 
| The rate of progression to cirrhosis | The rate of progression to cirrhosis at week 120 | at week 120 | 
| The incidence rate of hepatocarcinoma | The incidence rate of hepatocarcinoma at week 120 | at week 120 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic hepatitis B, Nucleoside analog, Pegylated Interferon, Sequential combination therapy, HBsAg loss