Tenofovir Plus Entecavir vs. Tenofovir in Adefovir-Resistant Chronic Hepatitis B

NCT ID: NCT01639066

Last Updated: 2018-02-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 102 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-09-25
• Study Completion Date: 2017-09-22

Brief Summary

With the availability of potent nucloes(t)ide analogues (NA), such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV), suppression of serum HBV DNA to undetectable levels by polymerase chain reaction (PCR) assays became achievable in most NA treatment-naïve patients. Until recently, however, many patients commenced antiviral treatment with inferior NAs prior to the availability of TDF or ETV, such as lamivudine (LAM) or adefovir (ADV) which has a low genetic barrier to resistance.

For patients who developed genotypic resistance against ADV, the efficacy of TDF monotherapy is controversial. In recent studies, TDF monotherapy produced significant suppression of HBV replication. However, only half of patients with initial ADV resistance achieved an undetectable viral load (<15 IU/ml) with 48 weeks of therapy.

On the other hand, there was a retrospective cohort study reporting that, with the combination of TDF and ETV, most of patients became HBV DNA undetectable after median 6 months of treatment. Probability of reaching complete HBV DNA suppression was not decreased in patients with ADV or ETV resistance.

Together, these observations indicate that there is a controversy about the efficacy of TDF monotherapy in patients with genotypic resistance to ADV.

Thus, in this clinical trial, the investigators will clarify whether tenofovir monotherapy is effective in inducing complete virologic response compared with tenofovir plus entecavir in CHB patients with genotypic resistance to ADV and partial virologic response to ongoing treatment.

Detailed Description

A multi-center randomized active-controlled open-label trial

• Patients will be randomly assigned 1:1 to receive tenofovir (300 mg/day) or tenofovir (300 mg/day) plus entecavir (1 mg/day) for 48 weeks.
• Because over 98% of Korean patients with CHB have HBV genotype C, HBV genotype will not be determined or be regarded as a stratification factor.
• Patients' treatment information before randomization will be retrospectively collected.(DNA change, HBeAg status, HBsAg titre, ALT, and treatment duration. etc)
• Patients will be screened within 4 weeks before randomization to determine study eligibility.

Conditions

Chronic Viral Hepatitis B Without Delta-agent

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Tenofovir plus Entecavir combination

Tenofovir 300 mg/day orally and Entecavir 1 mg/day orally

Group Type: EXPERIMENTAL

Tenofovir

Intervention Type: DRUG

Tenofovir 300mg daily Oral

Entecavir

Intervention Type: DRUG

Entecavir 1 mg daily Oral

Tenofovir monotherapy

Tenofovir 300 mg/day orally

Group Type: ACTIVE_COMPARATOR

Tenofovir

Intervention Type: DRUG

Tenofovir 300mg daily Oral

Interventions

Tenofovir

Tenofovir 300mg daily Oral

Intervention Type: DRUG

Entecavir

Entecavir 1 mg daily Oral

Intervention Type: DRUG

Tenofovir

Tenofovir 300mg daily Oral

Intervention Type: DRUG

Other Intervention Names

Viread; Baraclude; Viread

Eligibility Criteria

Inclusion Criteria

• Compensated liver disease (Child-Pugh class A)
• HBsAg positive at least 6 months or more
• HBeAg positive or negative
• Confirmation of ADV resistance mutation at any time before screening (rtA181V or rtA181T or rtN236T)
• Serum HBV DNA ≥ 60 IU/mL despite continued preceding oral antiviral treatment (Serum HBV DNA should be determined by the PCR assay at the local laboratory at screening for this study)
• Patient is ambulatory.
• Patient is willing and able to comply with the study drug regimen and all other study requirements.
• The patient is willing and able to provide written informed consent to participate in the study.

Exclusion Criteria

• Patient previously received TDF for more than 1 week
• Patient has a history of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC, such as suspicious foci on imaging studies. In patients with such findings, HCC should be ruled-out prior to randomizing the patient for the present study.
• Patient has received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study.
• Patient has concomitant other chronic viral infection (HCV or HIV)
• Patient has evidence of renal insufficiency defined as serum creatinine > 1.5 mg/dL
• Patient has medical condition that requires concurrent use of systemic prednisolone or other immunosuppressive agent (including chemotherapeutic agent)
• Patient is currently abusing alcohol (more than 40 g/day) or illicit drugs, or has a history of alcohol abuse or illicit substance abuse within the preceding two years.
• Patient is pregnant or breastfeeding or willing to be pregnant
• Patient has one or more additional known primary or secondary causes of liver disease, other than hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's Disease, other congenital or metabolic conditions affecting the liver, congestive heart failure or other severe cardiopulmonary disease, etc.).
• A history of treated malignancy (other than hepatocellular carcinoma) is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding three years.
• Clinical signs of decompensated liver disease as indicated by any one of the following:

1. serum bilirubin > 3 mg/dL

2. prothrombin time > 6 seconds prolonged or INR >1.5

3. serum albumin < 2.8 g/dL

4. History of ascites, variceal hemorrhage, or hepatic encephalopathy

5. Child-Pugh score ≥7

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Samsung Medical Center

OTHER

Sponsor Role: collaborator

Konkuk University Medical Center

OTHER

Sponsor Role: collaborator

Korea University Guro Hospital

OTHER

Sponsor Role: collaborator

Seoul National University Hospital

OTHER

Sponsor Role: collaborator

Asan Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Young-Suk Lim

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Young-Suk Lim, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Asan Medical Center

Locations

Asan Medical Center

Seoul, , South Korea

Countries

South Korea

References

Lim YS, Yoo BC, Byun KS, Kwon SY, Kim YJ, An J, Lee HC, Lee YS. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial. Gut. 2016 Jun;65(6):1042-51. doi: 10.1136/gutjnl-2014-308435. Epub 2015 Mar 23.

Reference Type: RESULT

PMID: 25800784 (View on PubMed)

Lim YS, Gwak GY, Choi J, Lee YS, Byun KS, Kim YJ, Yoo BC, Kwon SY, Lee HC. Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B: A 5-year clinical trial. J Hepatol. 2019 Jul;71(1):35-44. doi: 10.1016/j.jhep.2019.02.021. Epub 2019 Mar 13.

Reference Type: DERIVED

PMID: 30876946 (View on PubMed)

Study Documents

Document Type: pubmed

Publication for the primary study results

View Document

Other Identifiers

AMC2012-1208

Identifier Type: -

Identifier Source: org_study_id