Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)

Chronic Hepatitis B Clinical Trial

— ALTER  

Official title:

Efficacy of Adefovir and Lamivudine Combination Therapy in Patients With Entecavir Resistance

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01546116
• Other study ID #: ALTER_114093
• Status: Completed
• Phase: Phase 4
• First received: December 22, 2011
• Last updated: February 14, 2014
• Start date: February 2010
• Est. completion date: February 2014

Study information

• Verified date: February 2014
• Source: Korea University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Korea: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

• 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: February 2014
• Est. primary completion date: February 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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) -

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

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

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Korea University	GlaxoSmithKline

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (8)

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. — View Citation

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

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Degree of HBV DNA reduction from baseline	Degree of HBV DNA reduction from baseline during 52 week-period of adefovir and lamivudine combination therapy will be assessed.	at week 52	No
Secondary	HBV DNA undetectability by PCR (<60 IU/mL)		at week 52	No
Secondary	ALT normalization		at week 52	No
Secondary	HBeAg loss		at week 52	No
Secondary	HBeAg to anti- HBe seroconversion		at week 52	No
Secondary	Development of adefovir resistance		at week 52	Yes
Secondary	Virologic breakthrough	virologic breakthrough is defined by increase of HBV DNA above 10 times the lowest level (na dir).	at week 52	Yes