A Randomized Controlled Trial on the Efficacy of Tenofovir Disoproxil Fumarate (TDF)-Switch Therapy in Chronic Hepatitis B Patients With Incomplete Response to Entecavir

Study Overview
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Brief Summary
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Currently, five nucleos(t)ide analogs are approved for the treatment of chronic hepatitis B, namely lamivudine, adefovir dipivoxil, telbivudine, entecavir (ETV) and tenofovir disoproxil fumarate (TDF). ETV and TDF are recommended as first-line therapy by all regional guidelines due to their high anti-viral potency and low risk of inducing resistance. ETV monotherapy for chronic HBV infection is highly effective in both HBeAg-positive and negative treatment-naïve patients. The cumulative probability of maintained virologic suppression with undetectable HBV DNA at year 1, 2 and 3 were 76.5%, 83.0% and 88.3% respectively. TDF is another potent anti-viral treatment for chronic hepatitis B. Up to 72% and 87% of HBeAg-positive and -negative patients achieved undetectable HBV DNA by week 144 of TDF monotherapy. It is also effective in patients with prior exposure to other nucleo(s)tide analogs. Previous studies demonstrated that TDF can be used as an effective rescue therapy in lamivudine or adefovir-treated patients with incomplete virologic response. However, the optimal treatment for patients with suboptimal response to ETV is uncertain. With this background, we will conduct a randomized controlled trial to evaluate the efficacy of TDF switch therapy in patients with incomplete virologic response to ETV treatment.

Detailed Description
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Chronic hepatitis B virus (HBV) infection affects approximately 400 million people worldwide, and three-quarter of them are from Asia-Pacific region [1-3]. Nucleos(t)ide analogs treatment can suppress viral replication, delay cirrhotic complications and reduce the risk of hepatocellular carcinoma (HCC) [4-5]. Currently, five nucleos(t)ide analogs are approved for the treatment of chronic hepatitis B, namely lamivudine, adefovir dipivoxil, telbivudine, entecavir (ETV) and tenofovir disoproxil fumarate (TDF). ETV and TDF are recommended as first-line therapy by all regional guidelines due to their high anti-viral potency and low risk of inducing resistance [6-8]. ETV monotherapy for chronic HBV infection is highly effective in both HBeAg-positive and negative treatment-naïve patients [9-10]. The cumulative probability of maintained virologic suppression with undetectable HBV DNA at year 1, 2 and 3 were 76.5%, 83.0% and 88.3% respectively [11]. TDF is another potent anti-viral treatment for chronic hepatitis B. Up to 72% and 87% of HBeAg-positive and -negative patients achieved undetectable HBV DNA by week 144 of TDF monotherapy [12]. It is also effective in patients with prior exposure to other nucleo(s)tide analogs. Previous studies demonstrated that TDF can be used as an effective rescue therapy in lamivudine or adefovir-treated patients with incomplete virologic response [13-14]. The importance of complete viral suppression should be emphasized. In treatment-naïve patients, there is a positive correlation between HBV DNA level with risk of developing cirrhosis and HCC [15-17]. In a recent report on 372 ETV-treated patients, suppression of HBV DNA to less than 2000 IU/ml was associated with lower risk of disease progression among those with cirrhosis at baseline [18]. Therefore, suppressing HBV DNA to undetectable level should be the treatment target, especially in patients with established cirrhosis who are at the greatest risk of HCC.

Conditions
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Chronic Heptitis B

Intervention / Treatment
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* Drug: tenofovir disoproxil fumarate
* Drug: Entecavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 or above Positive hepatitis B surface antigen for at least 6 months On ETV monotherapy as anti-viral treatment for at least 52 weeks HBV DNA (>20 IU/ml) at week 52 or more of ETV treatment Written informed consent obtained Exclusion Criteria: Concurrent use of other antiviral treatment (including oral nucleos(t)ide analogs, interferon or pegylated interferon) for chronic hepatitis B. Concurrent use of steroids or immunosuppressive agents more than two week consecutively Co-infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV). Features suggestive of concomitant chronic liver diseases: positive anti-nuclear antibody (ANA) titer above 1/160, positive anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (SMA), abnormal serum ceruloplasmin or iron profile, or histological features of alternative chronic liver disease Pregnancy or breast feeding. Inability or unwillingness to give informed consent or abide by the requirements of the study. History of other evidence of severe illness or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study. Patients with baseline significant impaired renal function with creatinine clearance <30 ml/min or receiving dialysis for end stage renal disease.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Entecavir<br>Entecavir 0.5mg QD for 48 weeks | Drug: Entecavir<br> <br> |
| Active Comparator: tenofovir disoproxil fumarate<br>tenofovir disoproxil fumarate 300mg QD for 48 weeks | Drug: tenofovir disoproxil fumarate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maintained virologic response | Undetectable HBV DNA by PCR assay | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Undetectable HBV DNA at week 24 and 48 |  | At week 24 and 48 | 
| Amino acid substitutions or drug resistance |  | At week 48 | 
| Normal ALT, RFT and bone profile |  | At week 24 and 48 | 
| Numbers of adverse events or serious adverse events | An adverse event is any undesirable medical event occurring in the subject within the trial period, whether or not it is related to the study drug. A serious adverse event is an adverse event that results in one of the following outcomes: Death Life-threatening In-patient hospitalization or prolongation of existing hospitalization A persistent or significant disability/incapacity | At week 48 |