Hepatic safety of voriconazole after allogeneic hematopoietic stem cell transplantation

Abstract

Voriconazole is increasingly used in allogeneic hematopoietic stem cell transplantation (HSCT) for prophylaxis and treatment of fungal infections. Hepatic dysfunction is common in patients undergoing HSCT and may have an impact on the clinical decision to institute voriconazole. We conducted a retrospective review of all adult and pediatric HSCT recipients who received >2 consecutive doses of voriconazole between January 2005 and February 2008. Clinical hepatotoxicity was defined as the subjective attribution of liver enzyme elevation (even a mild one) to hepatotoxicity because of voriconazole by the treating physician and leading to discontinuation of voriconazole. Biochemical hepatotoxicity was defined as an elevation in one or more liver enzymes to >3 times the upper limit of normal or >3 times the baseline value if abnormal at baseline. Liver enzymes assessed included aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin. Simple and multiple logistic regressions were used to define the risks for hepatic dysfunction. The Wilcoxon signed-rank test was used to assess the differences in liver function test values before, during, and after the use of voriconazole. Sixty-eight of 200 patients (34%) developed hepatotoxicity while on voriconazole. The median duration of voriconazole therapy was 72 days (range, 1-804 days). Biochemical hepatotoxicity occurred in 51 patients (75%); clinical hepatotoxicity, in 17 patients (25%). Thirty-five (51%) of the patients with hepatotoxicity required discontinuation of therapy. In simple logistic regression, acute graft-versus-host disease (GVHD) was a risk factor for hepatotoxicity, and receipt of a T-cell depleted allograft was protective. In multiple logistic regression, acute GVHD (P = .002) remained significant. There were no cases of liver failure or death attributed to voriconazole. In this cohort of patients undergoing allogeneic HSCT, the rate of hepatotoxicity while on voriconazole was 34%. In general, the hepatic dysfunction was mild and reversible. Voriconazole therapy with monitoring appears to be reasonably safe for use in HSCT recipients at high risk for invasive fungal infections.