title: Multicenter study of trimethoprim/sulfamethoxazole-related hepatotoxicity: incidence and associated factors among HIV-infected patients treated for Pneumocystis jirovecii pneumonia.
abstract: The incidence of hepatotoxicity related to trimethoprim/sulfamethoxazole (TMP/SMX) administered at a therapeutic dose may vary among study populations of different ethnicities and hepatotoxic metabolites of TMP/SMX may be decreased by drug-drug interaction with fluconazole. We aimed to investigate the incidence of hepatotoxicity and the role of concomitant use of fluconazole in HIV-infected patients receiving TMP/SMX for Pneumocystis jirovecii pneumonia. We reviewed medical records to collect clinical characteristics and laboratory data of HIV-infected patients who received TMP/SMX for treatment of P. jirovecii pneumonia at 6 hospitals around Taiwan between September 2009 and February 2013. Hepatotoxicity was defined as 2-fold or greater increase of aminotransferase or total bilirubin level from baselines. Roussel UCLAF Causality Assessment Method (RUCAM) was used to analyze the causality of drug-induced liver injuries. NAT1 and NAT2 acetylator types were determined with the use of polymerase-chain-reaction (PCR) restriction fragment length polymorphism to differentiate common single-nucleotide polymorphisms (SNPs) predictive of the acetylator phenotypes in a subgroup of patients. During the study period, 286 courses of TMP/SMX treatment administered to 284 patients were analyzed. One hundred and fifty-two patients (53.1%) developed hepatotoxicity, and TMP/SMX was considered causative in 47 (16.4%) who had a RUCAM score of 6 or greater. In multivariate analysis, concomitant use of fluconazole for candidiasis was the only factor associated with reduced risk for hepatotoxicity (adjusted odds ratio, 0.372; 95% confidence interval, 0.145-0.957), while serostatus of hepatitis B or C virus, NAT1 and NAT2 acetylator types, or receipt of combination antiretroviral therapy was not. The incidence of hepatotoxicity decreased with an increasing daily dose of fluconazole up to 4.0 mg/kg. We conclude that the incidence of TMP/SMX-related hepatotoxicity was 16.4% in HIV-infected Taiwanese patients who received TMP/SMX for pneumocystosis. Concomitant use of fluconazole was associated with decreased risk for TMP/SMX-related hepatotoxicity.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, Po Jen General Hospital, Taipei, Taiwan.
authors.forename: Jen-Jia
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chung-Hao
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Chun-Eng
authors.initials: CE
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan.
authors.forename: Hung-Jen
authors.initials: HJ
authors.lastname: Tang
authors.affiliation: Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Yi-Chien
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan.
authors.forename: Kuan-Yeh
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Mao-Song
authors.initials: MS
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Clinical Pharmacy, National Taiwan University, Taipei, Taiwan; Department of Pharmacy, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yen-Hsu
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Po-Liang
authors.initials: PL
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; China Medical University, Taichung, Taiwan.
authors.forename: Chien-Ching
authors.initials: CC
authors.lastname: Hung
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000473:pathology; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use*; D015870:Gene Expression; D006678:HIV / Q000187:drug effects / Q000502:physiology; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D045363:Pneumocystis carinii / Q000187:drug effects / Q000502:physiology; D011020:Pneumonia, Pneumocystis / Q000150:complications* / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D007527:Isoenzymes; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D015725:Fluconazole; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human