Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)

Korea University20 enrolled

Overview

* 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.

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 Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Chronic Hepatitis B

Interventions

ADEFOVIR, LAMIVUDINEDRUG

Adefovir/10mg tablet/once a day/52week Lamivudine/100mg tablet/once a day/52week

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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) -

Locations (9)

Chungbuk National University Hospital

Cheongju-si, Chngcheongbuk-do, South Korea

Yonsei University Wonju Christian Hospital

Wŏnju, Gangwon-do, South Korea

Korea University Ansan Hospital

Ansan, Gyeonggi-do, South Korea

Outcomes

Primary Outcomes

Degree of HBV DNA reduction from baseline

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

Time frame: at week 52

Secondary Outcomes

HBV DNA undetectability by PCR (<60 IU/mL)

Time frame: at week 52

ALT normalization

Time frame: at week 52

HBeAg loss

Time frame: at week 52

HBeAg to anti- HBe seroconversion

Time frame: at week 52

Development of adefovir resistance

Time frame: at week 52

Virologic breakthrough

virologic breakthrough is defined by increase of HBV DNA above 10 times the lowest level (na dir).

Time frame: at week 52

Data from ClinicalTrials.gov

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