Therapeutic monitoring is necessary for the association itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis

A 59-year-old woman from French Guiana with disseminated histoplasmosis and a HIV-1 infection. Direct microscopic examination revealed Histoplasmosis capsulatum in bronchial aspirate and bone marrow. After 21 days of amphotericin B, an oral therapy was introduced using itraconazole (ITRA) Sporanox (600 mg once daily). The maximum and minimum concentrations of ITRA and its active metabolite were determined after 3 days of therapy. After 6 days of ITRA, its clinical status was improved and a highly active antiretroviral treatment (HAART) was initiated, consisting of tenofovir (245 mg/day), lamivudine (150 mg/day) and efavirenz (EFV) (400 mg/day). Ten days after initiation of HAART, EFV and ITRA pharmacokinetic profiles were determined. Venous blood samples were collected before dosing and at 1, 2, 4, 5, 6, 8 and 24 h later and at 1, 3, 19, 20, 21, 23 and 24 h later, respectively, for ITRA and EFV. Drugs concentrations in plasma were measured by HPLC [1,2]. The metabolic ratio (AUC0-10 OHITRA/AUC0-10ITRA) was estimated (Table 1). Efavirenz induced a 50% decrease in CminITRA (50%) and AUC0-10 ITRA, and a 250% increase in CminOHITRA (50%) and AUC0-10 OHITRA, compared to healthy volunteers [3]. In order to obtain therapeutic range of ITRA concentrations, our patient received an increased dose of 800 mg/day. In parallel, the metabolic ratio increased from 1.9 to 12.4. The pharmacokinetic examination in our patient also revealed a ITRA metabolic ratio higher than the previously described data and a lower elimination period t1/2β at steady state [4–6]. Monitoring of EFV concentrations showed that Cmax EFV was in the normal range as described by Lopez-Cortes et al.[7] in 15 patients (3850 ± 1660 ng/ml) and Cmin EFV in the optimal range as recommended by Marzolini et al.[8] (1000–4000 ng/ml). Therefore, no modification of EFV dosage was proposed for this patient. Antiretroviral therapy was well tolerated and no neurologic adverse effects have been reported.Table 1: Results of drug monitoring for a patient who received efavirenz and itraconazole.Our patient was doing well after 3 months of HAART and azole antifungal therapy, and a good immunological response was observed with an increase of CD4 cell counts from 4 to 140 cells/μl. There were no signs of reactivation of the infection with H. capsulatum. Histoplasmosis still causes significant morbidity and mortality in patients with HIV and ITRA is an important oral treatment for this opportunistic infection [9]. Koo et al.[10] reported a first case of efavirenz and ITRA association in a patient with AIDS and disseminated histoplasmosis. These authors only monitored ITRA using minimal concentrations. Despite an increasing dose (200 mg twice daily), ITRA minimal concentrations were not detected. These authors proposed a change of the antiretroviral regimen replacing efavirenz with the association atazanavir (300 mg once daily) and ritonavir as booster (100 mg once daily). Using these two antiproteases, which are inhibitors of ITRA metabolism, the patient's plasma ITRA concentration increased to 3 μg/ml and the patient's urine Histoplasma antigen level decreased to 0.6 U. This increase in ITRA concentrations is related to the change from an inductor to an inhibitor of its metabolism. In our opinion, it would be interesting to monitor hydroxyitraconazole, the major metabolite of ITRA. First, this metabolite is as active as ITRA and monitoring would be based on the sum of ITRA and hydroxyitraconazole [3–5]. Second, hydroxyitraconazole is the product of CYP3A4 metabolism and its monitoring could describe the intensity of drugs interaction. Moreover, ITRA monitoring using only minimal concentrations might be less informative since CYP3A4 metabolism is hepatic and intestinal and the drug absorption could be altered or improved according to inhibition or induction effects. Therefore, a kinetic study could be recommended. Finally, ITRA is a weak inhibitor of CYP3A4 metabolism and it also necessary to verify the lack of its action on the associated drug. This observation shows that the therapeutic monitoring of each drug can allow the individual optimization of their dosage and so a change of antiretroviral treatments is not necessary. This monitoring may contribute to the clinician's ability to evaluate both efficacy and safety in patients taking these two drugs that are at risk of toxicity or ineffectiveness from drug interactions. This observation may also be useful for advanced patients with possible resistant viruses having limited antiretroviral options.

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