Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)

Korea University

Status and phase: Completed; Phase 4

Conditions: Chronic Hepatitis B

Treatments: Drug: ADEFOVIR, LAMIVUDINE

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT01546116

ALTER_114093

Details and patient eligibility

About

• 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.

Full 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.

Enrollment: 20 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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) -

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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20 participants in 1 patient group

Adefovir and lamivudine combination

Experimental group

Treatment:

Drug: ADEFOVIR, LAMIVUDINE