Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)

Phase 4

Completed

• Conditions: Chronic Hepatitis B
• Interventions: Drug: ADEFOVIR, LAMIVUDINE

• Registration Number: NCT01546116
• Lead Sponsor: Korea University

Brief Summary

* Entecavir has been one of the option for treatment of lamivudine resistant chronic hepatitis B (CHB).

* In case of entecavir resistance, adefovir could be used. However, sequential monotherapy may result in multidrug resistance.

* It is thought that adefovir and lamivudine combination therapy reduce the risk of adefovir resistance, thereby continued therapy will lead to suppression of hepatitis B virus (HBV) DNA to be undetectable in patients with entecavir resistance.

* This study aim to evaluate the efficacy of adefovir and lamivudine combination therapy in CHB patients with entecavir resistance.

Detailed Description

Entecavir is a potent antiviral agent for the treatment of chronic hepatitis B (CHB). However, the incidence of entecavir resistance increases over 50% at 5th year in lamivudine-refractory CHB patients. Considering cross resistance profile, adefovir is a good option for managing entecavir resistance. However adefovir monotherapy may lead to adefovir resistance, because entecavir resistant hepatitis B virus (HBV) retain lamivudine resistance. Previously, combination of adefovir and lamivudine was reported to be effective in a patient with entecavir resistance, but only as a case report form. No further data are available on this combination therapy in a sufficient number of patients. It is thought that adefovir and lamivudine combination therapy reduce the risk of adefovir resistance, thereby continued combination treatment will result in suppression of HBV DNA to be undetectable in patients with entecavir resistance.

The aim of this study is to evaluate the efficacy of adefovir and lamivudine combination therapy in CHB patients with entecavir resistance.

Study Timeline

• Study Start: 2010-02
• Study First Submitted: 2011-12-22
• Primary Completion: 2012-02
• Study First Submitted QC: 2012-03-01
• Study First Posted: 2012-03-07
• Status Verified: 2014-02
• Study Completion: 2014-02
• Last Update Submitted: 2014-02-14
• Last Update Posted: 2014-02-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

1. Chronic hepatitis B patients (positive HBsAg > 6 months)
2. Age > 18 year old
3. History of treatment with entecavir more than 6 months
4. Proven entecavir resistant mutation (rtT184S/A/I/L/G/C/M, rtS202G/C/I, or rtM250I/V)
5. HBV DNA level> 2000 IU/mL
6. Compensated liver disease (Child-Pugh-Turcotte score over 7; prothrombin time prolonged more than 3 sec above ULN or INR over 1.5; serum albumin >3 g/dL; total bilirubin <2.5 mg/dL; No history of variceal bleeding, ascites, or hepatic encephalopathy)
7. Patients willing to give informed consent

Exclusion Criteria

1. Out of inclusion criteria

2. Any one of following

   • Serum phosphorus level under 2.4 mg/dL
   • Serum creatinine level over 1.5 mg/dL or creatinine clearance <50 mL/min
   • Absolute neutrophil count lower than 1000 cell/mL
   • Hb level under 10 g/dL (male), under 9 g/dL (female)
   • Serum AFP >100 ng/mL

3. History of treatment with interferon-alfa, thymosin-alfa 1, or nucleos(t)ide analogue other than entecavir in 6 months of screening

4. History of adefovir resistance (detection of rtA181T/Vor rtN236T at screening or in the past)

5. Recipient of organ transplantation

6. Positive antibody test to HIV, HCV or HDV

7. Pregnant or breast feeding women

8. Patients with hepatocellular carcinoma or uncontrolled malignant disease

9. Habitual alcohol drinker (>140 g/week for men, >70 g/week for women) -

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Adefovir and lamivudine combination	ADEFOVIR, LAMIVUDINE	-

Primary Outcome Measures

Name	Time	Method
Degree of HBV DNA reduction from baseline	at week 52	Degree of HBV DNA reduction from baseline during 52 week-period of adefovir and lamivudine combination therapy will be assessed.

Secondary Outcome Measures

Name	Time	Method
HBV DNA undetectability by PCR (<60 IU/mL)	at week 52
ALT normalization	at week 52
HBeAg loss	at week 52
HBeAg to anti- HBe seroconversion	at week 52
Development of adefovir resistance	at week 52
Virologic breakthrough	at week 52	virologic breakthrough is defined by increase of HBV DNA above 10 times the lowest level (na dir).

Trial Locations

Locations (9)

Hallym University, Gangnam Sacred Heart Hospital; 🇰🇷 Seoul, Korea, Republic of

Gachon University Gil Medical Center; 🇰🇷 Incheon, Korea, Republic of

Korea University Anam Hospital; 🇰🇷 Seoul, Korea, Republic of

Chungbuk National University Hospital; 🇰🇷 Cheongju, Chngcheongbuk-do, Korea, Republic of

Yonsei University Wonju Christian Hospital; 🇰🇷 Wonju, Gangwon-do, Korea, Republic of

Hallym University, Sacred Heart Hospital; 🇰🇷 Anyang, Gyeonggi-do, Korea, Republic of

The Catholic University of Korea, Euijeongbu Saint Mary's Hospital; 🇰🇷 Euijeongbu, Gyeonggi-do, Korea, Republic of

Inha University Hospital; 🇰🇷 Incheon, Korea, Republic of

Korea University Ansan Hospital; 🇰🇷 Ansan, Gyeonggi, Korea, Republic of