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.

Liver injury correlates with biomarkers of autoimmunity and disease activity and represents an organ system involvement in patients with systemic lupus erythematosus

“…Anti-DNA has been previously associated with chronic liver diseases [26]. Elevated AST relative to ALT has been associated with alcoholic hepatitis as well as progression of chronic viral hepatitis to cirrhosis [8,27]. Recently, we noted an elevation of AST but not ALT in liver disease caused by predisposition to oxidative stress-induced necrotic cell death in transaldolase deficiency [28].…”

“…This initiative was prompted by the common dilemma that the clinician face in daily practice with respect to handling of liver enzyme elevations. Recent studies set the threshold for drug-induced liver injury at a 2-fold elevation of ALT or AST, depending on the patient population involved [8,9]. In immunocompromised patients, such as those infected by human immunodeficiency virus (HIV) or hepatitis C virus (HCV), the threshold of liver injury was set at a 2-fold elevation of ALT or AST [8,9].…”

“…Recent studies set the threshold for drug-induced liver injury at a 2-fold elevation of ALT or AST, depending on the patient population involved [8,9]. In immunocompromised patients, such as those infected by human immunodeficiency virus (HIV) or hepatitis C virus (HCV), the threshold of liver injury was set at a 2-fold elevation of ALT or AST [8,9]. Therefore, we have undertaken a longitudinal study of ALT and AST elevations in SLE patients by excluding subjects with alcohol abuse, hepatitis and human immunodeficiency virus infection, or thyroid disease, all of which can cause liver disease independent of SLE [10–12].…”

The outcome predictors and therapeutic strategy of pneumocystis pneumonia in North China: a double-center retrospective study

“…Globally, TMP/SMX has been used as the first-line agent for anti-PCP given its cost and effectiveness in both treatment and prophylaxis [18]. Over half of patients those admitted TMP/SMX anti-PCP treatment experienced adverse drug reactions (ADRs) of sulfamide, which could lead to discontinuous treatment [19][20][21]. ADRs of sulfamide included gastrointestinal symptoms, fever, rash, thrombocytopenia, neutropenia, and transaminase elevation [19], rarely severe ADRs including Stevens-Johnson syndrome or toxic epidermal necrolysis [2].…”

Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk

“…(Gordin et al 1984;Kovacs et al 1984;Medina et al 1990;Hennessy et al 1995;Walmsley et al 1998;Hughes et al 2005;Chantachaeng et al 2011) The typical manifestation of sulfonamide HS is maculopapular rash with or without fever, (Alfirevic et al 2003;Yunihastuti et al 2014) but can also include hepatotoxicity or other organ involvement. (Yang et al 2014;Chang et al 2016;Hernandez et al 2016) The risk of sulfonamide HS increases with HIV disease progression, with higher risk seen at lower CD4 + counts. (Carr et al 1993;Kennedy et al 1993;Hennessy et al 1995;Ryan et al 1998;Rabaud et al 2001;Eliaszewicz et al 2002) This risk has been attributed, at least in part, to acquired alterations in SMX biotransformation in HIV infection.…”