Clinical trial NCT00531167: Adding Adefovir Dipivoxil Versus Switching to Entecavir in Patients With Lamivudine-resistant Chronic Hepatitis B
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Hepatitis B
Keywords: lamivudine resistant mutations
rescue therapy
Lead sponsor: Korea University
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2007-09-18
Enrollment: 219
Sex: ALL
Minimum age (years): 16
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility 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)

Primary outcomes:
measure: PCR negativity (<60 IU/ml) of HBV DNA
timeFrame: At the end of year 2 (since starting rescue therapy for lamivudine resistance)
Secondary outcomes:
measure: 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
timeFrame: At the end of year 2 except interim analysis
Other outcomes:
Locations:
city: Ansan
country: Korea, Republic of
facility: Korea University Ansan Hospital
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
Study officials:
affiliation: Korea University
name: Hyung Joon Yim, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Korea University
name: Eileen Yoon
role: STUDY_DIRECTOR
affiliation: Korea University
name: Yeon Seok Seo, M.D
role: STUDY_DIRECTOR
affiliation: Korea University
name: Soon Ho Um, M.D
role: STUDY_DIRECTOR
affiliation: The Catholic University of Korea
name: Chang Wook Kim, M.D
role: STUDY_DIRECTOR
affiliation: The Catholic University of Korea
name: Chang Don Lee
role: STUDY_DIRECTOR
affiliation: Hallym University
name: Sang Hoon Park, M.D
role: STUDY_DIRECTOR
affiliation: Hallym University
name: Myung Seok Lee, M.D
role: STUDY_DIRECTOR
affiliation: Hallym University
name: Choong Kee Park, M.D
role: STUDY_DIRECTOR
affiliation: Chungbuk National University
name: Hee Bok Chae, M.D
role: STUDY_DIRECTOR
affiliation: Yonsei University
name: Moon young Kim, M.D
role: STUDY_DIRECTOR
affiliation: Yonsei University
name: Soon Koo Baik, M.D
role: STUDY_DIRECTOR
affiliation: Gachon University Gil Medical Center
name: Ju Hyun Kim, M.D
role: STUDY_DIRECTOR
affiliation: Gachon University Gil Medical Center
name: Yun Soo Kim, M.D
role: STUDY_DIRECTOR
affiliation: Inha University
name: Jung Il Lee, M.D
role: STUDY_DIRECTOR
affiliation: Inha University
name: Jin Woo Lee, M.D
role: STUDY_DIRECTOR
affiliation: Genematrix Inc.
name: Sun Pyo Hong, PhD
role: STUDY_DIRECTOR
References:
citation: Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007 Feb;45(2):507-39. doi: 10.1002/hep.21513. No abstract available.
citation: 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. doi: 10.1002/hep.21534.
citation: 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. doi: 10.1128/AAC.00833-06. Epub 2006 Dec 18.
citation: Peters MG, Hann Hw Hw, Martin P, Heathcote EJ, Buggisch P, Rubin R, Bourliere M, Kowdley K, Trepo C, Gray Df Df, 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. doi: 10.1053/j.gastro.2003.10.051.