Multicenter study of trimethoprim/sulfamethoxazole-related hepatotoxicity: Incidence and associated factors among HIV-infected patients treated for Pneumocystis jirovecii pneumonia
Journal
PLoS ONE
Journal Volume
9
Journal Issue
9
Pages
e106141
Date Issued
2014
Author(s)
Yang J.-J.
Huang C.-H.
Liu C.-E.
Tang H.-J.
Yang C.-J.
Lee Y.-C.
Lee K.-Y.
Tsai M.-S.
Chen Y.-H.
Lu P.-L.
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. ? 2014 Yang et al.
SDGs
Other Subjects
aminotransferase; arylamine acetyltransferase; bilirubin; cotrimoxazole; fluconazole; noradrenalin transporter; anti human immunodeficiency virus agent; antiinfective agent; arylamine acetyltransferase; cotrimoxazole; fluconazole; isoenzyme; N-acetyltransferase 1; NAT2 protein, human; acetylator phenotype; acute kidney failure; acute psychosis; adult; adverse outcome; aged; Article; clinical feature; esophagus candidiasis; female; Hepatitis B virus; Hepatitis C virus; human; Human immunodeficiency virus infected patient; Human immunodeficiency virus infection; hyperkalemia; hyponatremia; incidence; leukopenia; liver toxicity; major clinical study; male; medical record review; multicenter study; nausea and vomiting; outcome assessment; Pneumocystis pneumonia; polymerase chain reaction; rash; restriction fragment length polymorphism; retrospective study; risk reduction; Roussel UCLAF Causality Assessment Method score; scoring system; single nucleotide polymorphism; Taiwan; very elderly; young adult; clinical trial; complication; drug effects; drug interaction; Drug-Induced Liver Injury; gene expression; genetics; HIV Infections; Human immunodeficiency virus; liver; metabolism; middle aged; multivariate analysis; pathology; physiology; Pneumocystis jiroveci; Pneumonia, Pneumocystis; virology; Pneumocystis jirovecii; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Anti-Infective Agents; Arylamine N-Acetyltransferase; Drug Interactions; Drug-Induced Liver Injury; Female; Fluconazole; Gene Expression; HIV; HIV Infections; Humans; Isoenzymes; Liver; Male; Middle Aged; Multivariate Analysis; Pneumocystis jirovecii; Pneumonia, Pneumocystis; Polymorphism, Single Nucleotide; Retrospective Studies; Trimethoprim-Sulfamethoxazole Combination
Publisher
Public Library of Science
Type
journal article