Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)

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.

Full Title of Study: “Efficacy of Adefovir and Lamivudine Combination Therapy in Patients With Entecavir Resistance”

Study Type

  • Study Type: Interventional
  • Study Design
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: February 2012

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.

Interventions

  • Drug: ADEFOVIR, LAMIVUDINE
    • Adefovir/10mg tablet/once a day/52week Lamivudine/100mg tablet/once a day/52week

Arms, Groups and Cohorts

  • Experimental: Adefovir and lamivudine combination

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

  • 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
    • Time Frame: at week 52
    • virologic breakthrough is defined by increase of HBV DNA above 10 times the lowest level (na dir).

Participating in This Clinical Trial

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)

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Korea University
  • Collaborator
    • GlaxoSmithKline
  • Provider of Information About this Clinical Study
    • Principal Investigator: Hyung Joon Yim, Associate Professor – Korea University
  • Overall Official(s)
    • HYUNG JOON YIM, M.D., Ph.D., Principal Investigator, Korea University

References

Lee WM. Hepatitis B virus infection. N Engl J Med. 1997 Dec 11;337(24):1733-45. Review.

Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009 Sep;50(3):661-2. doi: 10.1002/hep.23190.

Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, Wichroski MJ, Xu D, Yang J, Wilber RB, Colonno RJ. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology. 2009 May;49(5):1503-14. doi: 10.1002/hep.22841.

Yim HJ, Hussain M, Liu Y, Wong SN, Fung SK, Lok AS. Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology. 2006 Sep;44(3):703-12.

Lampertico P, Viganò M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology. 2007 Nov;133(5):1445-51. Epub 2007 Sep 2.

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.

Citations Reporting on Results

Villet S, Ollivet A, Pichoud C, Barraud L, Villeneuve JP, Trépo C, Zoulim F. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient. J Hepatol. 2007 Mar;46(3):531-8. Epub 2006 Dec 18.

Yatsuji H, Hiraga N, Mori N, Hatakeyama T, Tsuge M, Imamura M, Takahashi S, Fujimoto Y, Ochi H, Abe H, Maekawa T, Suzuki F, Kumada H, Chayama K. Successful treatment of an entecavir-resistant hepatitis B virus variant. J Med Virol. 2007 Dec;79(12):1811-7.

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