title: Hepatotoxicity in a 52-week randomized trial of short-term versus long-term treatment with buprenorphine/naloxone in HIV-negative injection opioid users in China and Thailand.
abstract: BACKGROUND
  Buprenorphine/naloxone (BUP/NX), an effective treatment for opioid dependence, has been implicated in hepatic toxicity. However, as persons taking BUP/NX have multiple hepatic risk factors, comparative data are needed to quantify the risk of hepatoxicity with BUP/NX.
  
  
  METHODS
  We compared rates of alanine aminotransferase (ALT) elevation≥grade 3 (ALT≥5.1 times the upper limit of normal) and graded bilirubin elevations in HIV-negative opioid injectors randomized to long-term (52 weeks) or short-term (18 days) medication assisted treatment (LT-MAT and ST-MAT, respectively) with BUP/NX in a multisite trial conducted in China and Thailand. ALT and bilirubin were measured at baseline, 12, 26, 40 and 52 weeks, times temporally remote from BUP/NX exposure in the ST-MAT participants.
  
  
  RESULTS
  Among1036 subjects with at least one laboratory follow-up measurement, 76 (7%) participants experienced ALT elevation≥grade 3. In an intent-to-treat analysis, the risk of ALT events was similar in participants randomized to LT-MAT compared with ST-MAT (adjusted hazard ratio 1.25, 95% confidence interval 0.79 to 1.98). This finding was supported by an as-treated analysis, in which actual exposure to BUP/NX was considered. Hepatitis C seroconversion during follow-up was strongly associated with ALT events. Bilirubin elevations≥grade 2 occurred in 2% of subjects, with no significant difference between arms.
  
  
  CONCLUSIONS
  Over 52-week follow-up, the risk of hepatotoxicity was similar in opioid injectors receiving brief and prolonged treatment with BUP/NX. These data suggest that most hepatotoxic events observed during treatment with BUP/NX are due to other factors.
authors.affiliation: Johns Hopkins University School of Medicine, Department of Medicine, 1830 E. Monument St., Room 435A, Baltimore, MD 21287, United States. Electronic address: glucas@jhmi.edu.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Lucas
authors.affiliation: Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, 1100 Fairview Ave N, Seattle, WA 98109, United States.
authors.forename: Alicia
authors.initials: A
authors.lastname: Young
authors.affiliation: Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, 1100 Fairview Ave N, Seattle, WA 98109, United States.
authors.forename: Deborah
authors.initials: D
authors.lastname: Donnell
authors.affiliation: Johns Hopkins School of Medicine, Department of Pathology, 600North Wolfe St., Baltimore, MD 21287, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.affiliation: Chiang Mai University, Faculty of Medicine, Department of Family Medicine, 110 Intavaroros Road, Chiang Mai, Thailand.
authors.forename: Apinun
authors.initials: A
authors.lastname: Aramrattana
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Shao
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Guangxi Centers for Disease Control and Prevention, Guangxi Center for HIV/AIDS Prevention and Control, No. 18 Jinzhou Road, Nanning 530028, Guangxi, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Xinjiang Autonomous Region Center for Disease Control and Prevention, Jianquanyi Street no. 380, Urumqi 830002, Xinjiang, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Fu
authors.affiliation: Xinjiang Autonomous Region Center for Disease Control and Prevention, Jianquanyi Street no. 380, Urumqi 830002, Xinjiang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, 615 North Wolfe Street, Suite W6041, Baltimore, MD 21205, United States.
authors.forename: David D
authors.initials: DD
authors.lastname: Celentano
authors.affiliation: Department of Psychiatry, University of Pennsylvania, 3535 Market Street, Suite 4000, Philadelphia, PA, 19104, United States.
authors.forename: David
authors.initials: D
authors.lastname: Metzger
authors.affiliation: Johns Hopkins School of Medicine, Department of Pathology, 600North Wolfe St., Baltimore, MD 21287, United States.
authors.forename: J Brooks
authors.initials: JB
authors.lastname: Jackson
authors.affiliation: National Institute of Allergy and Infectious Diseases, Division of AIDS, Prevention Sciences Branch, 6700 B Rockledge Drive, Room 5121, Bethesda, MD 20892, United States.
authors.forename: David
authors.initials: D
authors.lastname: Burns
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000627:therapeutic use; D001663:Bilirubin / Q000097:blood; D002047:Buprenorphine / Q000009:adverse effects* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000175:diagnosis*; D002681:China; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009270:Naloxone / Q000009:adverse effects* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D058850:Opiate Substitution Treatment / Q000009:adverse effects*; D009293:Opioid-Related Disorders / Q000097:blood / Q000188:drug therapy*; D013785:Thailand; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone; D002047:Buprenorphine; D000410:Alanine Transaminase; D001663:Bilirubin
keywords: Alanine aminotransferase; Buprenorphine/naloxone; HIV prevention; Hepatitis C virus; Hepatotoxicity; Injection drug use; Opioid dependence; Safety