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

Gregory M Lucas, Alicia Young, Deborah Donnell, Paul Richardson, Apinun Aramrattana, Yiming Shao, Yuhua Ruan, Wei Liu, Liping Fu, Jun Ma, David D Celentano, David Metzger, J. Brooks Jackson, David Burns

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)139-145
Number of pages7
JournalDrug and Alcohol Dependence
Volume142
DOIs
StatePublished - Sep 1 2014

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Thailand
Opioid Analgesics
China
Alanine Transaminase
HIV
Injections
Bilirubin
Therapeutics
Naloxone Drug Combination Buprenorphine
Liver
Hepatitis C
Toxicity
Hazards
Confidence Intervals

Keywords

  • Alanine aminotransferase
  • Buprenorphine/naloxone
  • Hepatitis C virus
  • Hepatotoxicity
  • HIV prevention
  • Injection drug use
  • Opioid dependence
  • Safety

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Toxicology
  • Pharmacology
  • Pharmacology (medical)

Cite this

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. / Lucas, Gregory M; Young, Alicia; Donnell, Deborah; Richardson, Paul; Aramrattana, Apinun; Shao, Yiming; Ruan, Yuhua; Liu, Wei; Fu, Liping; Ma, Jun; Celentano, David D; Metzger, David; Jackson, J. Brooks; Burns, David.

In: Drug and Alcohol Dependence, Vol. 142, 01.09.2014, p. 139-145.

Research output: Contribution to journalArticle

Lucas, Gregory M ; Young, Alicia ; Donnell, Deborah ; Richardson, Paul ; Aramrattana, Apinun ; Shao, Yiming ; Ruan, Yuhua ; Liu, Wei ; Fu, Liping ; Ma, Jun ; Celentano, David D ; Metzger, David ; Jackson, J. Brooks ; Burns, David. / 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. In: Drug and Alcohol Dependence. 2014 ; Vol. 142. pp. 139-145.
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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.",
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T1 - 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

AU - Lucas, Gregory M

AU - Young, Alicia

AU - Donnell, Deborah

AU - Richardson, Paul

AU - Aramrattana, Apinun

AU - Shao, Yiming

AU - Ruan, Yuhua

AU - Liu, Wei

AU - Fu, Liping

AU - Ma, Jun

AU - Celentano, David D

AU - Metzger, David

AU - Jackson, J. Brooks

AU - Burns, David

PY - 2014/9/1

Y1 - 2014/9/1

N2 - 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.

AB - 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.

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