Adefovir and Lamivudine for Entecavir Resistance (ALTER Study) - Full Text View

Purpose

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.

Condition	Intervention	Phase
Chronic Hepatitis B	Drug: ADEFOVIR, LAMIVUDINE	Phase 4

Study Type:	Interventional
Study Design:	Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Efficacy of Adefovir and Lamivudine Combination Therapy in Patients With Entecavir Resistance

Resource links provided by NLM:

MedlinePlus related topics: Hepatitis Hepatitis A Hepatitis B

Drug Information available for: Lamivudine Entecavir Adefovir dipivoxil

U.S. FDA Resources

Further study details as provided by Korea University:

Primary Outcome Measures:

Degree of HBV DNA reduction from baseline [ Time Frame: at week 52 ] [ Designated as safety issue: No ]
Degree of HBV DNA reduction from baseline during 52 week-period of adefovir and lamivudine combination therapy will be assessed.

Secondary Outcome Measures:

HBV DNA undetectability by PCR (<60 IU/mL) [ Time Frame: at week 52 ] [ Designated as safety issue: No ]
ALT normalization [ Time Frame: at week 52 ] [ Designated as safety issue: No ]
HBeAg loss [ Time Frame: at week 52 ] [ Designated as safety issue: No ]
HBeAg to anti- HBe seroconversion [ Time Frame: at week 52 ] [ Designated as safety issue: No ]
Development of adefovir resistance [ Time Frame: at week 52 ] [ Designated as safety issue: Yes ]
Virologic breakthrough [ Time Frame: at week 52 ] [ Designated as safety issue: Yes ]
virologic breakthrough is defined by increase of HBV DNA above 10 times the lowest level (na dir).

Enrollment:	20
Study Start Date:	February 2010
Estimated Study Completion Date:	June 2013
Primary Completion Date:	February 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Adefovir and lamivudine combination	Drug: ADEFOVIR, LAMIVUDINE Adefovir/10mg tablet/once a day/52week Lamivudine/100mg tablet/once a day/52week Other Names: Adefovir (Hepasera) Lamivudine (Zeffix)

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Chronic hepatitis B patients (positive HBsAg > 6 months)
Age > 18 year old
History of treatment with entecavir more than 6 months
Proven entecavir resistant mutation (rtT184S/A/I/L/G/C/M, rtS202G/C/I, or rtM250I/V)
HBV DNA level> 2000 IU/mL
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)
Patients willing to give informed consent

Exclusion Criteria:

Out of inclusion criteria
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
History of treatment with interferon-alfa, thymosin-alfa 1, or nucleos(t)ide analogue other than entecavir in 6 months of screening
History of adefovir resistance (detection of rtA181T/Vor rtN236T at screening or in the past)
Recipient of organ transplantation
Positive antibody test to HIV, HCV or HDV
Pregnant or breast feeding women
Patients with hepatocellular carcinoma or uncontrolled malignant disease
Habitual alcohol drinker (>140 g/week for men, >70 g/week for women) -

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01546116

Locations

Korea, Republic of
Chungbuk National University Hospital
Cheongju, Chngcheongbuk-do, Korea, Republic of
Yonsei University Wonju Christian Hospital
Wonju, Gangwon-do, Korea, Republic of
Hallym University, Sacred Heart Hospital
Anyang, Gyeonggi-do, Korea, Republic of
The Catholic University of Korea, Euijeongbu Saint Mary's Hospital
Euijeongbu, Gyeonggi-do, Korea, Republic of
Korea University Ansan Hospital
Ansan, Gyeonggi, Korea, Republic of
Gachon University Gil Medical Center
Incheon, Korea, Republic of
Inha University Hospital
Incheon, Korea, Republic of
Korea University Anam Hospital
Seoul, Korea, Republic of
Hallym University, Gangnam Sacred Heart Hospital
Seoul, Korea, Republic of

Sponsors and Collaborators

Korea University

GlaxoSmithKline

Investigators

Principal Investigator:

HYUNG JOON YIM, M.D., Ph.D.

Korea University

More Information

Publications:

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.

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. No abstract available.

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.

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.

Responsible Party:	Hyung Joon Yim, Associate Professor, Korea University
ClinicalTrials.gov Identifier:	NCT01546116 History of Changes
Other Study ID Numbers:	ALTER_114093
Study First Received:	December 22, 2011
Last Updated:	March 3, 2013
Health Authority:	Korea: Food and Drug Administration

Keywords provided by Korea University:

adefovir
lamivudine
entecavir resistance

Additional relevant MeSH terms:

Hepatitis
Hepatitis A
Hepatitis B
Hepatitis, Chronic
Hepatitis B, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections

Adefovir
Adefovir dipivoxil
Lamivudine
Entecavir
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents

ClinicalTrials.gov processed this record on May 23, 2013