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Long-Term Efficacy and Safety of TDM-Assisted Combination of Voriconazole plus Efavirenz in an AIDS Patient with Cryptococcosis and Liver Cirrhosis

Associate Director, Clinic of Infectious Diseases, University of Bari, Bari, Italy

Mario Regazzi, PharmD

Head of Clinical Pharmacokinetics and Therapeutic Drug Monitoring Unit, Clinical Pharmacokinetics Unit, Foundation IRCCS S. Matteo, Pavia, Italy

Emanuela Ciracì, MD

Researcher, Clinic of Infectious Diseases, University of Bari

Paola Villani, BiolD

Researcher, Clinical Pharmacokinetics Unit, Foundation IRCCS S. Matteo

Francesca Stano, MD

Researcher, Clinic of Infectious Diseases, University of Bari

Maria Cusato, PharmD

Researcher, Clinical Pharmacokinetics Unit, Foundation IRCCS S. Matteo

Manuela Heichen, MD

Researcher, Clinic of Infectious Diseases, University of Bari

Laura Monno, MD

Associate Professor, Clinic of Infectious Diseases, University of Bari

Reprints: Dr. Carbonara, Clinica di Malattie Infettive, Università di Bari, Piazza G. Cesare 11, Bari, Italy 70124, fax 390805478333, s_carbonara{at}yahoo.it

OBJECTIVE: To report the efficacy, tolerability, and pharmacokinetic effects of combined voriconazole and efavirenz treatment administered at therapeutic drug monitoring (TDM)-based adjusted doses to a patient with AIDS, cryptococcosis, and mild liver cirrhosis.

CASE SUMMARY: A 40-year-old man with AIDS (hemophiliac, antiretroviral-naïve, plasma HIV-RNA = 290,000 copies/mL, CD4+ lymphocytes = 0), hepatitis C virus-related liver cirrhosis (Child-Pugh class A), and cryptococcal meningitis was failing standard antifungal therapies. He received an antifungal-antiretroviral combination treatment based on the association of voriconazole plus efavirenz. Doses of both drugs were serially adjusted based on their plasma concentrations, which were evaluated at steady-state of each dose combination at least once (week 3.1 or later) as full concentration-time profile (samples collected at 0, 1, 2, 3, 4, 6, 8, 12 h postdose). Adequate concentrations of voriconazole in both plasma and cerebrospinal fluid were obtained and target plasma concentrations of efavirenz were achieved at the final dose adjustment (voriconazole 200 mg twice daily plus efavirenz 300 mg once daily, both administered orally). The patient showed prompt and stable suppression of cryptococcosis and plasma viremia of HIV at long-term follow-up (66 wk), with no significant adverse events.

DISCUSSION: Standard therapies for cryptococcosis in patients with AIDS are often not effective. Voriconazole, despite its promising anticryptococcal efficacy, is currently not approved for cryptococcosis therapy in the US and Europe, nor is it recommended for combination with efavirenz due to the significant pharmacokinetic interactions between the 2 compounds. Thus far, published studies regarding the effects of voriconazole in human cryptococcosis are scarce and none has described the clinical and pharmacokinetic outcomes of a voriconazole/efavirenz combination in patients with AIDS, either with or without liver cirrhosis.

CONLUSIONS: The combination of voriconazole and efavirenz at TDM-assisted doses may represent a valuable therapeutic option in AIDS patients with cryptococcosis and mild liver cirrhosis.

Key Words: AIDS, cryptococcosis, efavirenz, therapeutic drug monitoring, voriconazole

Published Online, April 21, 2009. www.theannals.com, DOI 10.1345/aph.1L607