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      Multicenter Study of Trimethoprim/Sulfamethoxazole-Related Hepatotoxicity: Incidence and Associated Factors among HIV-Infected Patients Treated for Pneumocystis jirovecii Pneumonia

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          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.

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          Most cited references 43

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          Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries.

          Despite the great number of methods proposed, assessing the causal role of a drug in the occurrence of an adverse medical event remains one of the most controversial issues. Qualifying terms for criteria, such as "compatible", "suggestive" of "inconclusive", have never been strictly defined, leading to low reproducibility. Weights of the criteria are usually not adapted to the injured organ, decreasing the specificity of the method. In this paper, a new method for drug causality assessment is described. Contents and limits of the criteria have been defined by experts convened to organ-oriented international consensus meetings. Additional criteria have been introduced and weights attributed. The method was applied to reports of acute liver injuries. The reproducibility was tested by an independent team. The validity of this novel method is studied in the following paper, based on an original approach using reports with positive rechallenge as external standard.
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            Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.

            Progress in the understanding of susceptibility factors to drug-induced liver injury (DILI) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases. A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form. The liver damage was characterized according to hepatocellular, cholestatic, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed. Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DILI. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (P < .0001), and had the worst outcome (Cox regression, P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had jaundice at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (P < .04). Factors associated with the development of fulminant hepatic failure were female sex (OR = 25; 95% CI: 4.1-151; P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6-37; P < .009), and higher baseline plasma bilirubin value (OR = 1.15; 95% CI: 1.09-1.22; P < .0001). Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI.
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              Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.

              Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled. Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months. Patients with acetaminophen liver injury were excluded. DILI was caused by a single prescription medication in 73% of the cases, by dietary supplements in 9%, and by multiple agents in 18%. More than 100 different agents were associated with DILI; antimicrobials (45.5%) and central nervous system agents (15%) were the most common. Causality was considered to be definite in 32%, highly likely in 41%, probable in 14%, possible in 10%, and unlikely in 3%. Acute hepatitis C virus (HCV) infection was the final diagnosis in 4 of 9 unlikely cases. Six months after enrollment, 14% of patients had persistent laboratory abnormalities and 8% had died; the cause of death was liver related in 44%. DILI is caused by a wide array of medications, herbal supplements, and dietary supplements. Antibiotics are the single largest class of agents that cause DILI. Acute HCV infection should be excluded in patients with suspected DILI by HCV RNA testing. The overall 6-month mortality was 8%, but the majority of deaths were not liver related.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                3 September 2014
                : 9
                : 9
                Affiliations
                [1 ]Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
                [2 ]Department of Internal Medicine, Po Jen General Hospital, Taipei, Taiwan
                [3 ]Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan
                [4 ]Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
                [5 ]Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
                [6 ]Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
                [7 ]Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
                [8 ]Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan
                [9 ]Graduate Institute of Clinical Pharmacy, National Taiwan University, Taipei, Taiwan
                [10 ]Department of Pharmacy, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
                [11 ]Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
                [12 ]China Medical University, Taichung, Taiwan
                University of British Columbia, Canada
                Author notes

                Competing Interests: The authors declare that no competing interests exist.

                Conceived and designed the experiments: J-JY C-EL H-JT Y-HC P-LL C-CH. Performed the experiments: J-JY C-HH C-EL H-JT C-JY Y-CL K-YL M-ST. Analyzed the data: J-JY M-ST S-WL. Contributed reagents/materials/analysis tools: S-WL Y-HC P-LL C-CH. Contributed to the writing of the manuscript: J-JY C-HH P-LL C-CH.

                Article
                PONE-D-14-21168
                10.1371/journal.pone.0106141
                4153565
                25184238

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Pages: 9
                Funding
                This study was supported by grants from the Centers for Disease Control, Taiwan (grant number DOH102-DC-1401 to C.-C. H.). The funding source played no role in study design and conduct, data collection, analysis or interpretation, writing of the manuscript, or the decision to submit it for publication.
                Categories
                Research Article
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobials
                Antibiotics
                Medicine and health sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Infectious diseases
                Fungal Diseases
                Pneumocystis
                Viral diseases
                HIV infections
                Opportunistic Infections
                Pharmacology
                Adverse Reactions
                Clinical Pharmacology
                Drug Interactions
                Drug Research and Development
                Drugs
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

                Uncategorized

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