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Prediction of Neuropsychiatric Adverse Events Associated with Long-Term Efavirenz Therapy, Using Plasma Drug Level Monitoring
F elix Gutie rrez
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Andre s Navarro
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Sergio Padilla
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Rosa Anto n
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Mar Masia
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Joaqun Borra s
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Alberto Martn-Hidalgo
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mains unknown
,
but plasma and intracellular drug con-
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sponsible for CNS toxicity associated with efavirenz re-
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Clinical Pharmacy Section, Hospital General Universitario de Elche
,
Alicante
,
Spain
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mild and transient, and they generally resolve after a few
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Infectious Diseases Unit, Internal Medicine Department
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Received 6 June 2005; accepted 25 July 2005; electronically published 19 October 2005. Infecciosas, Hospital General Universitario de Elche
,
Cam de la Almazara S/N; 03203 Elche, Alicante
,
Spain
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CNS toxicity in patients receiving chronic therapy with
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Limited information exists on persistent
,
long-term
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disturbances in patients starting therapy with efavirenz-
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been found to be predictors of early neuropsychological
Background. Data on long-term central nervous system (CNS) toxicity associated with efavirenz therapy are scarce, and risk factors remain largely unknown. We aimed to determine whether monitoring the plasma concentration of efavirenz could predict neuropsychiatric adverse events associated with long-term therapy with efavirenz. Methods. We performed a longitudinal study involving 17 consecutive human immunodeficiency virus (HIV)infected subjects with virological suppression after at least 6 months of antiretroviral therapy with an efavirenzcontaining regimen. Efavirenz plasma concentrations were measured at study entry and at different time points through an 18-month study period. Results. Median duration of efavirenz therapy before study entry was 18 months (range, 6-27 months). Ten (58.8%) of the patients experienced CNS-related adverse effects, ranging from insomnia and abnormal dreams to depression with suicidal ideation. In 4 (23.5%) of the cases, CNS toxicity led to efavirenz discontinuation. Mean ( standard deviation) plasma levels were higher for patients experiencing neuropsychiatric symptoms (5.10 2.15 mg/mL vs. 2.79 1.31 mg/mL; P p .024). A plasma level of 2.74 mg/mL had a sensitivity of 90.9% and specificity of 72% to predict CNS toxicity (area under the curve, 0.839; 95% confidence interval, 0.73-0.95; P ! .0001). Patients having efavirenz plasma concentrations 12.74 mg/mL at any time point of the study were 5.68 times more likely to experiencing CNS toxicity than were other patients (95% confidence interval, 1.97-16.37). Conclusions. In patients with HIV infection receiving long-term therapy with efavirenz-containing antiretroviral regimens, CNS toxicity is related to efavirenz plasma levels. Patients achieving higher plasma levels are at increased risk of experiencing neuropsychiatric adverse events. Efavirenz is a potent and effective nonnucleoside reversetranscriptase inhibitor (NNRTI) that has become a cornerstone of antiretroviral combination regimens [1]. Although its safety profile is considered to be satisfactory, available information has mainly been based on shortterm follow-up studies [2-6]. CNS disturbances are the most frequently reported adverse events [3-6]. Acute neuropsychiatric adverse reactions can occur in a significant proportion of subjects soon after initiation of therapy [4, 5]. These disorders are thought to be usually
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tients receiving long-term therapy with efavirenz are largely
unknown.
The increasing recognition of antiretroviral drug toxicities
and the potential for later morbidity associated with
drugrelated adverse effects is of great concern. Therefore, avoidance
of drug toxicity should be a factor in future strategic approaches
to the management of HIV infection. The aim of this study
was to explore whether monitoring the plasma concentration
of efavirenz could predict chronic CNS toxicity in patients
receiving long-term antiretroviral therapy with
efavirenz-containing regimens.
Study population. Patients were recruited into the study at
the outpatient HIV clinic of a university hospital (Hospital
General Universitario de Elche, Alicante, Spain). Eligible
patients were all HIV-infected adults (age, 18 years) treated in
the clinic during a 3-month period who were clinically stable
and had virological suppression (HIV RNA level, !50 copies/
mL) while receiving combination antiretroviral therapy with
efavirenz at the standard dose (600 mg once per day at bedtime)
and 2 nucleoside reverse-transcriptase inhibitors (NRTIs) for
at least 6 months. Other inclusion criteria were a good
adherence to antiretroviral drugs ( 95%) and the absence of active
opportunistic infection or acute illnesses. Patients were not to
have had a previous history of depression or other mental
disorders and were not to be receiving psychiatric medication
or methadone at the time of recruitment. The local ethics
committee approved the study. All patients meeting the inclusion
criteria were asked to participate in the (...truncated)