BRIEF REPORT
and multiple fungal organisms consistent with Histoplasma cap-
Drug-Drug Interaction between
Itraconazole and Efavirenz in
a Patient with AIDS and Disseminated
Histoplasmosis
Hoonmo L. Koo, Richard J. Hamill, and Roberto A. Andrade
Section of Infectious Diseases, Baylor College of Medicine, Houston, Texas
Although there is a presumed drug-drug interaction between
itraconazole and nonnucleoside reverse-transcriptase inhib-
itors, the medical literature lacks such documentation. We
describe a drug-drug interaction between itraconazole and
efavirenz in a patient with disseminated histoplasmosis and
acquired immunodeficiency syndrome (AIDS). The drug
combination resulted in persistently elevated urinary His-
toplasma antigen levels and subtherapeutic plasma itracon-
azole concentrations. Changing treatment from efavirenz to
a protease inhibitor was accompanied by improvements in
the desired urinary Histoplasma antigen level and plasma
itraconazole concentration.
Case report. A 42-year-old man with a history of AIDS pre-
sented to our hospital with respiratory distress and hypoten-
sion. The patient had been receiving antiretroviral therapy con-
sisting of efavirenz, lamivudine, and stavudine. Examination of
the patient revealed tachycardia, hypotension, 100% oxygen
saturation, and absence of fever. Maculopapular lesions were
noted on the patient’s forehead. Laboratory investigations re-
vealed pancytopenia (WBC count, 1200 cells/mL; hemoglobin
level, 5.6 g/dL; platelet count, 87,000 platelets/mL) and an el-
evated alkaline phosphatase level and lactate dehydrogenase
level (363 U/L). The patient’s HIV RNA load was !400 copies/
mL, and his CD4 cell count was 13 cells/mL. A chest radiograph
revealed bilateral interstitial infiltrates. The patient’s urine His-
toplasma polysaccharide antigen level was elevated (15 U;
MiraVista Diagnostics). Examination of a skin biopsy specimen
of a forehead lesion revealed a nodular collection of histiocytes
Received 21 March 2007; accepted 18 May 2007; electronically published 6 August 2007.
Reprints or correspondence: Dr. Roberto A. Andrade, Thomas Street Health Center, 2015
Thomas St., Houston, TX 77030 (randrade@bcm.tmc.edu).
Clinical Infectious Diseases 2007; 45:e77–9
 2007 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2007/4506-00E1$15.00
DOI: 10.1086/520978
sulatum. Treatment with amphotericin B deoxycholate was ini-
tiated, with good clinical response. After 14 days of ampho-
tericin B treatment, the patient was discharged from the
hospital, receiving itraconazole capsules (200 mg once daily).
Over the following several months, there was continued im-
provement in the patient’s clinical symptoms, pancytopenia,
and CD4 cell count (up to 140 cells/mL). The patient’s urine
Histoplasma antigen level correspondingly decreased initially to
4.28 U but did not decrease further. After 11 year of itracon-
azole treatment, a 12-h plasma itraconazole concentration was
measured, but itraconazole was not detected (!0.05 mg/mL).
The patient’s itraconazole capsule dosage was increased to 200
mg twice daily. However, the patient’s urine Histoplasma an-
tigen level was unchanged, and his plasma itraconazole con-
centration remained undetectable. In addition, no effect was
seen when the itraconazole formulation was changed to solu-
tion. It was suspected that a drug-drug interaction between
itraconazole and the nonnucleoside reverse-transcriptase in-
hibitor efavirenz was contributing to the low plasma itracon-
azole concentration. As a result, the patient’s antiretroviral reg-
imen was changed to atazanavir (300 mg once daily), ritonavir
(100 mg once daily), and emtricitabine-tenofovir (200 mg/300
mg once daily).
Two months later, the patient’s plasma itraconazole concen-
tration increased to 3 mg/mL. Three months after the change
in antiretroviral treatment, the patient’s urine Histoplasma an-
tigen level decreased to 0.6 U. Table 1 summarizes the response
in the urine Histoplasma antigen level and plasma itraconazole
concentration after the change in treatment.
Discussion. Although the incidence of histoplasmosis has
decreased in patients with AIDS since the advent of HAART,
histoplasmosis still causes significant morbidity and mortality
in this patient population. More than 95% of HIV-infected
patients who have histoplasmosis will develop the disseminated
form of the disease [1].
Itraconazole is an important component of treatment for
this opportunistic infection—after induction therapy with am-
photericin B and as long-term maintenance therapy for HIV-
infected individuals [2]. Although one study demonstrated the
safety of discontinuation of maintenance therapy for HIV-
infected patients [3], lifelong secondary prophylaxis is still rec-
ommended for HIV-infected patients with a history of Histo-
plasma infection [4]. As a result, it is quite likely that many
HIV-infected patients with histoplasmosis will eventually re-
ceive both itraconazole and antiretroviral therapy concurrently
BRIEF REPORT • CID 2007:45 (15 September) • e77
Table 1. Response of the urinary Histoplasma antigen level and plasma itraconazole concentration to changes in treatment in a
patient with AIDS and disseminated histoplasmosis.

Urinary
CD4 Histoplasma Plasma itra
cell count, Viral load, antigen level, concentration,
a
Year, month cells/mL copies/mL units mg/mL Treatment
2003
January 50 !400 15 … EFV, 3TC, d4t; itra capsule (200 mg QD)
April 60 !400 9.8 … EFV, 3TC, d4t; itra capsule (200 mg QD)
2004
January 130 !400 4.28 … EFV, 3TC, d4t; itra capsule (200 mg QD)
September 140 !400 EFV, 3TC, d4t; itra capsule (200 mg QD)
October 113 !400 4.28 !0.05 EFV, 3TC, d4t; itra capsule (200 mg BID)
2005
January 106 !400 !0.05 EFV, 3TC, d4t; change to itra solution (200 mg BID)
April 130 !400 4.28 !0.05 ATZ, rit, emtricitabin, tenofovir; itra solution (200 mg BID)
June 176 !400 3 ATZ, rit, emtricitabin, tenofovir; itra solution (200 mg BID)
July 196 !400 0.6 … ATZ, rit, emtricitabin, tenofovir; itra solution (200 mg BID)

NOTE. ATZ, atazanavir; BID, twice daily; d4T, stavudine; EFV, efavirenz; itra, itraconazole; QD, once daily; rit, ritonavir; 3TC, lamivudine.
a
Changes in treatment were made after the laboratory results were obtained for the corresponding date.

at some point. However, there are very few studies in the lit-
erature regarding drug-drug interactions between itraconazole
and antiretroviral medications.
This article describes the first known reported case involving
a drug-drug interaction between itraconazole and a nonnu-
cleoside reverse-transcriptase inhibitor. Despite clinical im-
provement in this patient, there was concern about the per-
sistent elevation of his urine Histoplasma antigen level (4.28
U), even after a year of antifungal therapy with itraconazole.
The patient was fortunate, however, that no clinical manifes-
tations of treatment failure or relapse of histoplasmosis were
associated with this elevated Histoplasma antigen level. Some
experts recommend observing the antigen level until it becomes
negative or at least ⭐4 U. Close follow-up to monitor for
relapse is advised for patients who have not had a known re-
version to a negative antigen test result [2]. Increases of the
Histoplasma antigen level of ⭓2 U have been shown to be a
strong predictor of relapse [5].
In this case, we considered that the lower dose of itraconazole
(200 mg once daily) and use of the capsule formulation may
have resulted in the mildly increased urine Histoplasma antigen
level. Consequently, the patient’s itraconazole dosage was first
increased, with no change in the antigen level, and then changed
to the solution formulation, which also had no effect.
Itraconazole is predominantly metabolized by the cyto-
chrome P450 3A4 (CYP3A4) enzyme to hydroxyitraconazole
and other metabolites [6]. This enzyme pathway also mediates
the metabolism of the nonnucleoside reverse-transcriptase in-
hibitors, including efavirenz and nevirapine [7]. Studies have
shown that, when coadministered, nevirapine induces the me-
tabolism of ketoconazole, leading to reduced ketoconazole bi-
oavailability [8]. We speculated that efavirenz was causing a
reduced concentration of itraconazole through CYP3A4 en-
zyme induction in a similar fashion. As a result, we changed
the patient’s nonnucleoside reverse-transcriptase inhibitor–
based antiretroviral regimen to a protease inhibitor–based
regimen.
There are a few reports describing the interaction between
protease inhibitors and itraconazole. Crommentuyn et al. [9]
described how lopinavir-ritonavir increased the concentration
of itraconazole by inhibiting CYP3A4, although no changes in
lopinavir-ritonavir concentrations were seen. We surmised that
the combination of atazanavir and ritonavir would also produce
a similar increase in the itraconazole concentration through
inhibition of this hepatic enzyme pathway. The patient’s lab-
oratory findings were consistent with this drug-drug interac-
tion, with an increase in his plasma itraconazole concentration
from undetectable (!0.05 mg/mL) to 3 mg/mL and a decrease
in his Histoplasma antigen level from 4.28 U to 0.6 U. We
considered this itraconazole concentration to be sufficient, be-
cause Wheat et al. [1] proposed that a therapeutic plasma con-
centration of itraconazole should be at least 2 mg/mL.
As demonstrated by this case report, caution should be taken
when prescribing the combination of efavirenz and itracona-
zole. Careful monitoring of the patient’s clinical status for any
signs of relapse should be performed, because lower bioavail-
ability of itraconazole may be experienced by the patient. Close
follow-up of plasma itraconazole concentrations and Histo-
plasma antigen levels should be considered. If concern about
the efficacy of itraconazole treatment in combination with efa-
virenz arises, a change in antiretroviral therapy to a protease
inhibitor–based regimen is a reasonable option.

e78 • CID 2007:45 (15 September) • BRIEF REPORT

Acknowledgments
Potential conflicts of interest. All authors: no conflicts.
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