Combination or Sequential Therapy of Peginterferon Alfa-2a and Entecavir for Patients With Chronic Hepatitis B

Study Overview
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Brief Summary
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Currently, seven medications are approved for the treatment of hepatitis B: two formulations of interferon and five nucleons(t)ide analogues. The current treatment strategy of chronic hepatitis B is now standard: initial selection of entecavir, tenofovir, or peginterferon alfa-2a (peg-IFNα-2a). Interferon is administered for a finite duration while nucleotide analogues are usually administered for many years. But among hepatitis B e antigen （HBeAg） positive patients with high serum hepatitis B virus DNA levels, the rates of virological response are poor. And antiviral drug resistance is a major limiting factor to the success of nucleotide analogue treatment. Therefore, combination therapy using peginterferon with an oral agent with a high genetic barrier to resistance might be superior to standard current monotherapy. However, the addition of lamivudine to peg-IFNα-2a therapy led to a greater decrease in serum HBV DNA levels during treatment but did not increase the rate of HBeAg sero¬conversion. Entecavir is a nucleoside analogue superior to lamivudine and adefovir in achieving higher virological response, histological improvement and normalisation of ALT. Moreover, Entecavir has a high genetic barrier with a very low incidence of drug resistance. This study is aimed to investigate the efficacy of combination or sequential therapy using peg-IFNα-2a and entecavir in HBeAg-positive chronic hepatitis B(CHB) patients.

Official Title
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Combination or Sequential Therapy of Peginterferon Alfa-2a and Entecavir for Hepatitis B e Antigen-positive Patients With Chronic Hepatitis B

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Peg-IFNα-2a
* Drug: Entecavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age≥16 years HBsAg positive for more than 6 months, and HBeAg detection is positive for two times in 6 months before enrollment Serum HBVDNA >2×10^4IU/ml 80U/L < serum ALT < 400U/L, and TBIL < 34 umol/L Serum ALT < 80U/L, but hepatic inflammation scores ≥ G2 or hepatic fibrosis stage ≥ S3 Exclusion Criteria: Co-infected with HCV, HDV or HIV, or autoimmune liver diseases combined Hepatic decompensation received antiviral therapy or immunosuppressant drugs before 6 months prior to enrollment Blood routine examination: WBC <3×10^9/L，neutrophile granulocyte < 1.5×10^9/L，PLT <80×10^9/L Renal function: creatinine >1.5 times of upper normal limit Alcoholism or a history of addiction and abuse Combined with hepatocarcinoma

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 60 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Peg-IFNα-2a monotherapy<br>Participants will receive 180ug peg-IFNα-2a therapy for 72 weeks, and then followed to 96 weeks. | Drug: Peg-IFNα-2a<br>* 180ug peg-IFNα-2a, subcutaneous injection per week<br>* Other names: peginterferon alfa-2a;|
| Experimental: Sequential therapy<br>Participants will receive entecavir monotherapy for 12 weeks, and 180ug peg-IFNα-2a therapy is added for the following 12 weeks. After that, entecavir will be stopped and 180ug peg-IFNα-2a monotherapy for the following 48 weeks. All participants will followed to 96 weeks. | Drug: Peg-IFNα-2a<br>* 180ug peg-IFNα-2a, subcutaneous injection per week<br>* Other names: peginterferon alfa-2a;Drug: Entecavir<br>* 0.5mg,oral administration every day<br>* Other names: Baraclude;|
| Experimental: Combination therapy<br>Participants will receive 180ug peg-IFNα-2a combined with entecavir therapy for 72 weeks, and then followed to 96 weeks. | Drug: Peg-IFNα-2a<br>* 180ug peg-IFNα-2a, subcutaneous injection per week<br>* Other names: peginterferon alfa-2a;Drug: Entecavir<br>* 0.5mg,oral administration every day<br>* Other names: Baraclude;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the rates of HBeAg seroconversion |  | at week 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| normalisation of ALT |  | at week 2、4、12、24、36、48、60、72、84、96 | 
| liver histological improvement |  | at baseline and at week 72 | 
| The rates of HBsAg negative |  | at week12、24、36、48、60、72、84、96 | 
| the rate of virological response |  | at week 4、12、24、36、48、60、72、84、96 | 
| the rate of HBeAg negative |  | at week 12、24、36、48、60、72、84、96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HBV, entecavir, peginterferon