Adding Adefovir Dipivoxil Versus Switching to Entecavir in Patients With Lamivudine-Resistant Chronic Hepatitis B

Condition(s) targeted: Chronic Hepatitis B

Intervention: combination of lamivudine+adefovir vs entecavir (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Korea University

Official(s) and/or principal investigator(s):
Hyung Joon Yim, M.D., Principal Investigator, Affiliation: Korea University

Overall contact:
Hyung Joon Yim, M.D., Phone: 82-31-412-6565, Email: gudwns21@medimail.co.kr

Antiviral resistance mutations limit the efficacy of therapy for chronic hepatitis B. At year 2, resistance to adefovir may occur as high as 25% in patients with history of lamivudine resistance. Resistance to entecavir is reported to be 10% in lamivudine refractory patients during the same period. However, combination of lamivudine and adefovir decreased the adefovir resistance rate as low as 0% in the recent studies. By overcoming the antiviral resistance, the efficacy of therapy will be maximized. This study is intended to compare the efficacy of two strategies, combination of lamivudine and adefovir vs. entecavir monotherapy in patients with lamivudine resistance.

Official title: Prospective Randomized Study for the Comparison of Adding Adefovir Dipivoxil and Switching to Entecavir in Patients With Lamivudine-Resistant Chronic Hepatitis B

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study

Primary outcome: PCR negativity (<60 IU/ml) of HBV DNA

Secondary outcome: 1. PCR negativity (<60 IU/ml) of HBV DNA at year 1 (interim analysis) 2. Degrees of HBV DNA reduction 3. ALT normalization 4. HBeAg seroconversion 5. Development of resistant mutation 6. Virologic breakthrough 7. Biochemical breakthrough

Detailed description: Recently, published data showed combination of lamivudine and adefovir lead to PCR negativity (<1000 copies/mL) up to 80% in the treatment of lamivudine-resistant chronic hepatitis B at year 2 [Rapti et al. Hepatology 2007 Feb;45(2):307-13.]. Other studies also showed 76% and 69% PCR negativity in mostly HBeAg negative subjects [Lampertico et al. Hepatology 2006 Oct;44(4) Suppl 1: 556A-557A, Lampertico et al. Hepatology 2006 Oct;44(4) Suppl 1: 693A-694A].

In the study for the treatment of lamivudine-resistant chronic hepatitis B patients which included HBeAg positive subjects more predominantly, entecavir monotherapy showed 34% of PCR negativity (<300 copies/mL) at year 2 [Tenney DJ, et al. Antimicrob Agents Chemother. 2007 Mar;51(3):902-11].

Although it is assumed that combination of lamivudine and adefovir would be more effective than entecavir monotherapy for lamivudine resistant patients, we cannot verify the assumption, because there is no data directly comparing these two strategies until now.

The aim of this study is to determine the most effective therapy for the patients with lamivudine resistant chronic hepatitis B. We will compare the PCR negativity (<60 IU/ml) of HBV DNA at year 2 in patients receiving 'the combination of lamivudine and adefovir' and 'entecavir monotherapy'.

Since we are planning to include lamivudine-resistant chronic hepatitis B patients regardless of HBeAg status, we assumed the PCR negativity (<300 copies/mL or <60 IU/mL) in adefovir-lamivudine combination and entecavir monotherapy group as 55% and 34%, respectively, considering HBeAg status and lower detection limit of PCR.

The result of this study will be able to clearly demonstrate the superiority of combination therapy with lamivudine and adefovir to entecavir monotherapy, which provide us the guide to rescue therapy for patients with lamivudine resistant HBV.

Minimum age: 16 Years. Maximum age: 75 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Chronic hepatitis B patients (positive HBsAg > 6 months)

2. Age > 16 year old

3. Serum alanine aminotransferase (ALT) >1. 5 x ULN

4. History of treatment with lamivudine more than 6 months

5. Proven lamivudine resistant mutation

6. HBV DNA level> 20000 IU/mL

7. 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)

8. 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-a, thymosin-alfa 1, or nucleos(t)ide analogue other than lamivudine in 6 months of screening

4. Recipient of organ transplantation

5. Positive antibody test to HIV, HCV or HDV

6. Pregnant or breast feeding women

7. Patients with hepatocellular carcinoma or uncontrolled malignant disease

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

Hyung Joon Yim, M.D., Phone: 82-31-412-6565, Email: gudwns21@medimail.co.kr

Korea University Ansan Hospital, Ansan, Gyeonggi-do, Korea, Republic of; Recruiting
Hyung Joon Yim, M.D., Phone: +82-31-412-6565, Email: gudwns21@medimail.co.kr
Hyung Joon Yim, M.D., Principal Investigator

Related publications:

Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007 Feb;45(2):507-39. No abstract available. Erratum in: Hepatology. 2007 Jun;45(6):1347.

Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology. 2007 Feb;45(2):307-13.

Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ. Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob Agents Chemother. 2007 Mar;51(3):902-11. Epub 2006 Dec 18.

Peters MG, Hann Hw H, Martin P, Heathcote EJ, Buggisch P, Rubin R, Bourliere M, Kowdley K, Trepo C, Gray Df D, Sullivan M, Kleber K, Ebrahimi R, Xiong S, Brosgart CL. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004 Jan;126(1):91-101.

Starting date: April 2007
Ending date: December 2010
Last updated: May 19, 2008