TDF VS LAM + ADV in LAM + ADV Treated LAM-resistant CHB Patients With Undetectable Hepatitis B Virus DNA

Study Description

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Brief Summary:

This study will provide a rationale for switch from lamivudine plus adefovir to tenofovir monotherapy in Lamivudine plus Adefovir Treated Lamivudine-resistant chronic hepatitis B patients with Undetectable Hepatitis B Virus DNA

Condition or disease	Intervention/treatment	Phase
Chronic Hepatitis B	Drug: Lamivudine plus adefovir; Drug: Tenofovir	Phase 4

Detailed Description:

Recently, in Korea, long-term medication of antiviral agents and their resulting resistance expression have been the most serious cause of failure to treat chronic hepatitis B. Exp.

In particular, the annual resistance rate to lamivudine currently widely being used in Korea amounts to about 15 to 20 percents and the rate is expected to reach 70 to 80 percent in four to five years.

The guidelines by the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) recommend a combination therapy with adefovir or tenofovir for patients with lamivudine resistant HBV .

In Korea, however, in case of combined prescription of lamivudine and adefovir, only one of them is covered by the health insurance and therefore many patients are difficult to continue treatment due to their economic conditions.

Tenofovir that has been developed most recently and will be placed on sale sooner or later in Korea has strong antiviral effects, causes little or no emergence of resistant viruses, and is known to have lower nephrotoxicity than adefovir.

In particular, several papers reported that tenofovir has effective and sustaining antiviral effects in patients who had other antiviral agents resistant HBV as well as those who received initial treatment. This shows that patients only with lamivudine resistant HBV can be treated only with tenofovir without a combination therapy and when they have low levels of HBV DNA, treatment is relatively effective despite their resistance to adefovir.

Therefore, it is considered that tenofovir switching therapy in patients with undetectable HBV DNA after lamivudine plus adefovir combination therapy to maintain their virus response.

The results of this study will provide a rationale for switch from lamivudine plus adefovir to tenofovir monotherapy in such patients.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	171 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Randomized Trial of Tenofovir Versus Lamivudine Plus Adefovir in Lamivudine Plus Adefovir Treated Lamivudine-resistant Chronic Hepatitis B Patients With Undetectable Hepatitis B Virus DNA.
Study Start Date :	November 2012
Actual Primary Completion Date :	March 2016
Actual Study Completion Date :	April 2016

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Active Comparator: Lamivudine plus adefovir; Continue lamivudine/adefovir add on treatment (standard treatment)	Drug: Lamivudine plus adefovir; Lamivudine 100mg QD for 96 weeks + Adefovir 10mg QD for 96 weeks; Other Names: Zeffix; Hepsera
Experimental: Tenofovir; Switch from lamivudine/adefovir add on treatment to tenofovir monotherapy	Drug: Tenofovir; Tenofovir 300mg QD for 96 weeks; Other Name: Viread

Outcome Measures

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Primary Outcome Measures :

1. Percentage number of patients with virus reactivation [ Time Frame: Week 96 while on treatment ]
   Percentage number of patients with virus reactivation (HBV DNA > 40 IU/mL on two consecutive samples taken 1 month apart, or persistent HBV DNA levels of 20-40 IU/mL on three consecutive 1 month interval) at Week 96 while on treatment.

Secondary Outcome Measures :

1. Virologic response [ Time Frame: Week 96 while on treatment ]
   Virologic response Percentage number of patients with virus reactivation at Week 48
2. Antiviral resistance [ Time Frame: Week 96 while on treatment ]
   Antiviral resistance percentage number of patients who developed drug resistant mutation at Week 48 and 96 while on randomized therapy.
3. Biochemical response [ Time Frame: Week 96 while on treatment ]
   Biochemical response percentage number of patients with biochemical breakthrough at Week 48 and 96
4. Serologic response [ Time Frame: Week 96 while on treatment ]
   Serologic response (1) HBeAg loss/seroconversion in HBeAg-positive CHB Percentage number of patients with HBeAg loss or seroconversion at Week 48 and 96.
5. Safety assessment [ Time Frame: Week 96 while on treatment ]
   Safety assessment

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Male and female patients aged 18 or older
• The CHB patients (both HBeAg-positive and - negative) who have at least 6 months undetectable HBV DNA (serum HBV DNA ≤ 20 IU/mL) after lamivudine plus adefovir combination therapy.

Exclusion Criteria:

• Patients with decompensated liver disease
• Patients with HCV, HDV or HIV
• Patients with HCC
• Serum ALT > 2x ULN level
• Serum creatinine > 2.0mg/dL
• Pregnant or lactating women
• Women who have a plan for pregnancy within the three coming years
• Patients who have uncontrolled severe concomitant diseases— severe cardiovascular diseases and other infection
• Those who have no capabilities to understand and sign an informed consent

Contacts and Locations

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Locations

Korea, Republic of
Department of Internal Medicine, Keimyung University Dongsan Medical Center
Daegu, Korea, Republic of, ASI|KR|KS002|TAEGU

Sponsors and Collaborators

Keimyung University Dongsan Medical Center

Kyungpook National University

Daegu Catholic University Medical Center

DongGuk University

Pusan National University Hospital

Yeungnam University Hospital

Investigators

Principal Investigator:	Byoung Kuk Jang, M.D	Department of Internal Medicine, Keimyung University Dongsan Medical Center

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lee HJ, Kim SJ, Kweon YO, Park SY, Heo J, Woo HY, Hwang JS, Chung WJ, Lee CH, Kim BS, Suh JI, Tak WY, Jang BK. Evaluating the efficacy of switching from lamivudine plus adefovir to tenofovir disoproxil fumarate monotherapy in lamivudine-resistant stable hepatitis B patients. PLoS One. 2018 Jan 12;13(1):e0190581. doi: 10.1371/journal.pone.0190581. eCollection 2018.

Responsible Party:	Jang Byoung Kuk, Keimyung University Dongsan Medical Center
ClinicalTrials.gov Identifier:	NCT01732367 History of Changes
Other Study ID Numbers:	TDF0001
First Posted:	November 22, 2012
Last Update Posted:	October 28, 2016
Last Verified:	October 2016

Keywords provided by Jang Byoung Kuk, Keimyung University Dongsan Medical Center:

Tenofovir; Lamivudine; Adefovir; Chronic Hepatitis B

Additional relevant MeSH terms:

Hepatitis; Hepatitis A; Hepatitis, Chronic; Hepatitis B; Hepatitis B, Chronic; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Hepadnaviridae Infections	DNA Virus Infections; Tenofovir; Lamivudine; Adefovir; Adefovir dipivoxil; Antiviral Agents; Anti-Infective Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Anti-HIV Agents