Prediction of Neuropsychiatric Adverse Events Associated with
Long-term Efavirenz Therapy Using Plasma Drug Level Monitoring
Data on long-term central nervous system
(CNS) toxicity associated with efavirenz
(Sustiva) therapy are scarce, and risk
factors remain largely unknown. The objective of the
current study was to determine whether monitoring the plasma
concentration of efavirenz could predict neuropsychiatric adverse events associated with long-term therapy
with efavirenz.
The researchers performed a longitudinal
study involving 17 consecutive HIV positive subjects
with virological
suppression
after at least 6 months of antiretroviral
therapy with an efavirenz-containing 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.
A
plasma level of 2.74 g/mL had a sensitivity
of 90.9% and specificity of 72% to predict
CNS toxicity.
Patients
having efavirenz plasma concentrations >2.74 microgram/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)
The study authors conclude, “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.”
Discussion
This study includes a patient population that has achieved
long-lasting virological
suppression and which was receiving a typical efavirenz-based
regimen that included 2 NRTIs (usually zidovudine
and lamivudine).
This is a commonly-seen regimen.
Surprisingly, more than one-half of the patients
reported neuropsychiatric symptoms during long-term
efavirenz therapy (mostly mild sleep disturbances
and morning dizziness), according to the study authors.
They note that 25% of these patients experienced “delayed CNS
toxicity that led to discontinuation of efavirenz therapy.
All those who discontinued efavirenz had been on the
drug for greater than 12 months. This fact raises concerns about
the potential long-term neuropsychiatric toxicity of efavirenz.
Patients experiencing neuropsychiatric symptoms
during efavirenz therapy usually had drug plasma
concentrations >2.74 microgram/mL. This cutoff point
was found to have the best discriminatory
power to evaluate the risk of CNS toxicity
in the study, according to the study.
The authors suggest that the association between efavirenz
therapy and CNS-related adverse events opens the possibility to
look at therapeutic
drug monitoring as a means of “optimizing management
of efavirenz-based therapy.”
Dose reduction could improve the symptoms, although there
is no evidence of this as yet.
In
closing the authors write, “Future studies are needed
to assess whether therapeutic drug monitoring
will result in a decrease in the percentage
of patients developing neuropsychiatric abnormalities
while receiving efavirenz-containing regimens with
no loss of efficacy.”
Infectious Diseases Unit, Internal
Medicine Department, and Clinical
Pharmacy Section, Hospital General
Universitario de Elche, Alicante,
Spaim.
10/28/05
Reference
F
Gutierrez and others. Prediction of Neuropsychiatric
Adverse Events Associated with
Long-Term Efavirenz Therapy,
Using Plasma Drug Level
Monitoring. Clinical Infectious Diseases 41(10):
000. December 1, 2005 (Latest Articles, Online edition).
