Switch to Tenofovir Versus Continue Lamivudine/Adefovir Treatment in Lamivudine-resistance Chronic Hepatitis B Patients

Chronic Hepatitis B Clinical Trial

Official title:

Randomized Trial of Switch to Tenofovir Versus Continue Lamivudine/Adefovir Treatment in Lamivudine-resistance Chronic Hepatitis B Patients Who Have Undergone Lamivudine/Adefovir Add-on Treatment

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01491295
• Other study ID #: IN-US-174-0194
• Status: Recruiting
• Phase: Phase 4
• First received: October 27, 2011
• Last updated: March 31, 2016
• Start date: September 2012
• Est. completion date: December 2019

Study information

• Verified date: March 2016
• Source: Taipei Veterans General Hospital, Taiwan
• Contact: Yi-Hsiang Huang, MD, PhD
• Phone: 886-2-28712121
• Email: yhhuang[@]vghtpe.gov.tw
• Is FDA regulated: No
• Health authority: Taiwan : Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

1. Adefovir add-on therapy is superior to switching to adefovir monotherapy or entecavir 1mg monotherapy for chronic hepatitis B (CHB) patients with lamivudine resistance (LAM-R)

2. Long-term adefovir add-on therapy was effective for viral suppression. However, the economic burden for such dual antiviral therapy is heavy because of infinite treatment.

3. Tenofovir disoproxil fumarate (TDF) is a potent antiviral agent. TDF demonstrated potent antiviral efficacy in a subset of lamivudine experienced HBeAg-positive patients. TDF is also superior to ADV in HBeAg-negative and HBeAg-positive treatment-naive patients.

4. Theoretically, TDF can replace LAM/ADV when viral suppression has been achieved by LAM/ADV combination treatment in LAM-R CHB patients.

Description:

Hepatitis B virus (HBV) is a partially double-stranded DNA virus. HBV infection can induce a spectrum of disease ranging from asymptomatic infection to severe chronic liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). Chronic HBV infection is also a major cause of HCC in Taiwan. Over 350 millions people worldwide are chronically infected with HBV. Lamivudine was the first marketing and is the first-line oral anti-viral agent for the therapy of chronic hepatitis B. Infinite nucleoside analogue therapy may be needed for long-term viral suppression especially in patients with HBeAg-negative chronic hepatitis B. The initial randomized studies demonstrated the clinical benefit and safety of lamivudine in both hepatitis B e antigen (HBeAg)-positive and -negative chronic hepatitis B patients. But as high as 20% of the cases under 1-year lamivudine treatment developed genotypic resistance, which defined as the presence of YMDD mutation on the HBV polymerase region. Genotypic resistance is almost always associated with virological breakthrough and exacerbation of liver function. Long-term lamivudine therapy was reported increase HBeAg seroconversion and provided clinical improvement in ALT levels. However, in a four-year follow-up study, YMDD-variant HBV was detected in as high as 67% of patients under lamivudine treatment. Several clinical studies have proven that adefovir add-on therapy is superior to switching to adefovir monotherapy or entecavir 1mg monotherapy for chronic hepatitis B (CHB) patients with lamivudine resistance (LAM-R). Currently, AASLD and EASL guidelines recommend adefovir add-on therapy as a standard treatment for LAM-R CHB patients. Long-term adefovir add-on therapy was effective for viral suppression (8). However, the economic burden for such dual antiviral therapy is heavy because of infinite treatment.

Tenofovir disoproxil fumarate (TDF) is a potent antiviral agent. TDF and ETV are recommended oral first-line therapies for CHB. TDF demonstrated potent antiviral efficacy in a subset of lamivudine experienced HBeAg-positive patients. TDF is also superior to ADV in HBeAg-negative and HBeAg-positive treatment-naive patients. Theoretically, TDF can replace LAM/ADV when viral suppression has been achieved by LAM/ADV combination treatment in LAM-R CHB patients. This clinical trial is a proof of concept study to evaluate the efficacy of switching to TDF monotherapy in such patients.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: December 2019
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

• HBsAg-positive for more than 6 months (HBeAg-positive or HBeAg-negative).

• Age > 20 y/o.

• Under lamivudine/adefovir treatment for more than 1 year due to previous lamivudine resistance (LAM-R), current HBV DNA is undetectable (< 20 IU/ml) during enrollment.

Exclusion Criteria:

• HCV, HIV, HDV coinfection.

• Uncontrolled HCC, malignancy or decompensated liver cirrhosis (CTP score = 7).

• Uremia patients or Creatinine = 2 mg/dl.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate 300mg QD for 36 months (adjust dosage according to renal function)
• Lamivudine plus adefovir
Lamivudine 100mg QD for 36 months (adjust dosage according to renal function) Adefovir 10mg QD for 36 months (adjust dosage according to renal function)

Locations

Country	Name	City	State
Taiwan	Taipei Veterans General Hospital-Division of Gastroenterology	Taipei

Sponsors (5)

Lead Sponsor	Collaborator
Taipei Veterans General Hospital, Taiwan	Chi Mei Medical Hospital, Chia-Yi Christian Hospital, China Medical University Hospital, Kaohsiung Medical University Chung-Ho Memorial Hospital

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of virological breakthrough (defined as HBV DNA > 100 IU/ml)		Sustained viral suppression after switching to TDF for 36 months	No
Secondary	HBeAg seroconversion (for HBeAg-positive patients)		HBeAg seroconversion rate at 1, 2 and 3 years	No
Secondary	Incidence of HBsAg loss		Incidence of HBsAg loss at 1-, 2-, and 3 -years	No