Using Entecavir to Reduce Hepatitis in Highly Viremic HBV Patients During Anti-tuberculous Treatment

Tuberculosis Clinical Trial

— HBV  

Official title:

Prophylactic Use of Entecavir to Reduce Hepatitis Flare in Highly Viremic HBV Patients With Active Tuberculosis Receiving Anti-tuberculous Treatment

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT01724723
• Other study ID #: NTUH-IRB-201109046MB
• Status: Not yet recruiting
• Phase: Phase 4
• First received: May 2, 2012
• Last updated: November 7, 2012
• Start date: December 2012
• Est. completion date: June 2014

Study information

• Verified date: November 2012
• Source: National Taiwan University Hospital
• Contact: Jann-Yuan Wang, Ph.D
• Phone: 886-2-23123456
• Email: jywang[@]ntu.edu.tw
• Is FDA regulated: No
• Health authority: Taiwan: Department of Health
• Study type: Interventional

Clinical Trial Summary

Hepatitis during anti-tuberculous treatment (HATT) has been an obstacle in managing TB patients, especially in those with viral hepatitis. A previous study revealed the risk of HATT is significantly higher in TB patients with high serum hepatitis B virus (HBV) DNA level than those with low HBV DNA level. Based on these findings, we thus hypothesize that the risk of HATT in TB patients with high baseline serum HBV DNA level can be reduced by concomitant use of anti-HBV agent. In this proposal, we will conduct a prospective randomized clinical study to assess the reduction of HATT risk by using entecavir in TB patients with high baseline serum HBV DNA level, and to evaluate the risk of other treatment-related adverse events in two hospitals.

Description:

Tuberculosis (TB) remains one of the important infectious diseases worldwide. Timely implementation of optimized anti-tuberculous therapy is still the mainstay to prevent further transmission of TB. However, hepatitis during anti-tuberculous treatment (HATT) has been an obstacle in managing TB patients, especially in those with viral hepatitis. A previous study revealed the risk of HATT is significantly higher in TB patients with high serum hepatitis B virus (HBV) DNA level than those with low HBV DNA level (39% vs. 11%), the latter cases have a similar risk of HATT as those without viral hepatitis (14%). Based on these findings, we thus hypothesize that the risk of HATT in TB patients with high baseline serum HBV DNA level can be reduced by concomitant use of anti-HBV agent. In this proposal, we will conduct a prospective randomized clinical study to assess the reduction of HATT risk by using entecavir in TB patients with high baseline serum HBV DNA level, and to evaluate the risk of other treatment-related adverse events in two hospitals. From January 2012 to June 2014, subjects with culture-confirmed TB and aged from 18 to 80 with high serum HBV viral load prior to anti-tuberculous treatment will be enrolled and randomized into either study or control group. High serum HBV viral load is defined as >20,000 and >2,000 IU/mL for HBeAg-positive and HBeAg-negative subjects, respectively. In addition to standard anti-tuberculous treatment, subjects in the study group will receive entecavir (BARACLUDE®) 0.5 mg per day during anti-tuberculous treatment and for 6 months after stopping anti-tuberculous treatment. Hemogram, liver function, renal function, and serum HBV viral load will be regularly monitored to detect the development of HATT and other adverse events. In this study, HATT is defined as fulfilling anyone of the following conditions: (1) increase in serum AST and/or ALT level of >3 times upper limit of normal (ULN) with symptoms if baseline liver function is normal; (2) increase in serum AST and/or ALT level of >5 times ULN without symptoms if baseline liver function is normal; (3) increase in serum AST and/or ALT level of >2 times baseline if baseline liver function is abnormal; and (4) increase in serum total bilirubin level of > 2.5 mg/dL.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: June 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• culture-confirmed tuberculosis

• serology-confirmed chronic HBV infection without flare-up at present (IgM Anti-HBc-negative and either HBsAg-positive or Anti-HBc-positive)

• high serum HBV viral load, defined as >20,000 and >2,000 IU/mL for HBeAg positive and HBeAg negative patients, respectively

• serum AST and/or ALT level <2 times ULN

• serum level of total bilirubin <2.0 mg/dL

• willing to receive directly observed therapy, short course (DOTs)

Exclusion Criteria:

• Target Disease Exceptions: human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis D virus (HDV) co-infection, multidrug-resistant tuberculosis (defined as simultaneous resistant to isoniazid and rifampin)

• Medical History and Concurrent Diseases

1. . ever receiving anti-viral therapy for HBV

2. . alcoholism or presence of hepatic disease other than hepatitis B

3. . life expectancy less than 1 year

• Sex and Reproductive Status

1. . Pregnancy

2. . Breast-feeding

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• hepatitisB
• Tuberculosis

Intervention

Drug:
• entecavir (BARACLUDE®)
entecavir 0.5 mg per day during and within 6 months after anti-tuberculous treatment

Locations

Country	Name	City	State
Taiwan	National Taiwan University Hospital	Taipei

Sponsors (1)

Lead Sponsor	Collaborator
National Taiwan University Hospital

Country where clinical trial is conducted

Taiwan, 

References & Publications (16)

Albert RK, Iseman M, Sbarbaro JA, Stage A, Pierson DJ. Monitoring patients with tuberculosis for failure during and after treatment. Am Rev Respir Dis. 1976 Dec;114(6):1051-60. — View Citation

American Thoracic Society; CDC; Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep. 2003 Jun 20;52(RR-11):1-77. Erratum in: MMWR Recomm Rep. 2005 Jan 7;53(51):1203. Dosage error in article text. — View Citation

American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: controlling tuberculosis in the United States. Am J Respir Crit Care Med. 2005 Nov 1;172(9):1169-227. — View Citation

Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Epler GR. Isoniazid-associated hepatitis in 114 patients. Gastroenterology. 1975 Aug;69(2):289-302. — View Citation

Chen CJ, Yang HI. Natural history of chronic hepatitis B REVEALed. J Gastroenterol Hepatol. 2011 Apr;26(4):628-38. doi: 10.1111/j.1440-1746.2011.06695.x. Review. — View Citation

Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, Chang FY, Lee SD. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology. 2003 Apr;37(4):924-30. — View Citation

Lee BH, Koh WJ, Choi MS, Suh GY, Chung MP, Kim H, Kwon OJ. Inactive hepatitis B surface antigen carrier state and hepatotoxicity during antituberculosis chemotherapy. Chest. 2005 Apr;127(4):1304-11. — View Citation

Lee HC, Suh DJ, Ryu SH, Kim H, Shin JW, Lim YS, Chung YH, Lee YS. Quantitative polymerase chain reaction assay for serum hepatitis B virus DNA as a predictive factor for post-treatment relapse after lamivudine induced hepatitis B e antigen loss or seroconversion. Gut. 2003 Dec;52(12):1779-83. — View Citation

Lee MH, Yang HI, Jen CL, Lu SN, Yeh SH, Liu CJ, You SL, Sun CA, Wang LY, Chen WJ, Chen CJ; R.E.V.E.A.L.-HCV Study Group. Community and personal risk factors for hepatitis C virus infection: a survey of 23,820 residents in Taiwan in 1991-2. Gut. 2011 May;60(5):688-94. doi: 10.1136/gut.2010.220889. Epub 2010 Nov 10. — View Citation

Ozick LA, Jacob L, Comer GM, Lee TP, Ben-Zvi J, Donelson SS, Felton CP. Hepatotoxicity from isoniazid and rifampin in inner-city AIDS patients. Am J Gastroenterol. 1995 Nov;90(11):1978-80. — View Citation

Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR; ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006 Oct 15;174(8):935-52. Review. — View Citation

Shakya R, Rao BS, Shrestha B. Incidence of hepatotoxicity due to antitubercular medicines and assessment of risk factors. Ann Pharmacother. 2004 Jun;38(6):1074-9. Epub 2004 Apr 30. — View Citation

Ungo JR, Jones D, Ashkin D, Hollender ES, Bernstein D, Albanese AP, Pitchenik AE. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus. Am J Respir Crit Care Med. 1998 Jun;157(6 Pt 1):1871-6. — View Citation

Wang JY, Lee LN, Yu CJ, Chien YJ, Yang PC; Tami Group. Factors influencing time to smear conversion in patients with smear-positive pulmonary tuberculosis. Respirology. 2009 Sep;14(7):1012-9. doi: 10.1111/j.1440-1843.2009.01598.x. Epub 2009 Jul 30. — View Citation

Wang JY, Liu CH, Hu FC, Chang HC, Liu JL, Chen JM, Yu CJ, Lee LN, Kao JH, Yang PC. Risk factors of hepatitis during anti-tuberculous treatment and implications of hepatitis virus load. J Infect. 2011 Jun;62(6):448-55. doi: 10.1016/j.jinf.2011.04.005. Epub 2011 Apr 28. — View Citation

Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW, Wong PC, Tam CM, Leung CC, Lai CL. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology. 2000 Jan;31(1):201-6. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	incidence of hepatitis	the reduction in the incidence of hepatitis during anti-tuberculous treatment by using entecavir in patients with high serum HBV viral load.	1 year after randomization	No
Secondary	HBV viral load	the reduction in HBV viral load in treatment group comparing with control group.	1 year after randomization	No