Clinical trial NCT01546116: Adefovir and Lamivudine for Entecavir Resistance (ALTER Study)
Official title: Efficacy of Adefovir and Lamivudine Combination Therapy in Patients With Entecavir Resistance
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Hepatitis B
Keywords: adefovir
lamivudine
entecavir resistance
Lead sponsor: Korea University
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2012-03-07
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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 criteria: 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) -

Primary outcomes:
measure: Degree of HBV DNA reduction from baseline
timeFrame: at week 52
Secondary outcomes:
measure: HBV DNA undetectability by PCR (<60 IU/mL)
timeFrame: at week 52
measure: ALT normalization
timeFrame: at week 52
measure: HBeAg loss
timeFrame: at week 52
measure: HBeAg to anti- HBe seroconversion
timeFrame: at week 52
measure: Development of adefovir resistance
timeFrame: at week 52
measure: Virologic breakthrough
timeFrame: at week 52
Other outcomes:
Locations:
city: Cheongju
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chngcheongbuk-do
city: Wonju
country: Korea, Republic of
facility: Yonsei University Wonju Christian Hospital
state: Gangwon-do
city: Anyang
country: Korea, Republic of
facility: Hallym University, Sacred Heart Hospital
state: Gyeonggi-do
city: Euijeongbu
country: Korea, Republic of
facility: The Catholic University of Korea, Euijeongbu Saint Mary's Hospital
state: Gyeonggi-do
city: Ansan
country: Korea, Republic of
facility: Korea University Ansan Hospital
state: Gyeonggi
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
city: Seoul
country: Korea, Republic of
facility: Hallym University, Gangnam Sacred Heart Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
Study officials:
affiliation: Korea University Ansan Hospital
name: HYUNG JOON YIM, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009 Sep;50(3):661-2. doi: 10.1002/hep.23190. No abstract available.
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-naive patients is rare through 5 years of therapy. Hepatology. 2009 May;49(5):1503-14. doi: 10.1002/hep.22841.
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. doi: 10.1002/hep.21290.
citation: Lampertico P, Vigano 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. doi: 10.1053/j.gastro.2007.08.079. Epub 2007 Sep 2.
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: Villet S, Ollivet A, Pichoud C, Barraud L, Villeneuve JP, Trepo 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. doi: 10.1016/j.jhep.2006.11.016. Epub 2006 Dec 18.
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. doi: 10.1002/jmv.20981.