Central Nervous System Toxicities and Efavirenz

By Ronald Baker, PhD

Efavirenz (Sustiva) is a potent and effective non nucleoside reverse transcriptase inhibitor (NNRTI) that has emerged as a cornerstone of HAART regimens. The side effect profile of the drug is generally regarded as satisfactory. However, there are conflicting study results in the medical literature as well as conflicting reports from patients and physicians regarding the neuropsychiatric problems associated with efavirenz (Sustiva)-based antiretroviral therapy.

The most commonly reported adverse events of efavirenz are central nervous system (CNS) disturbances-- difficulty concentrating, mild depression, anxiety, and sleep disturbances). However, acute neuropsychiatric adverse events such as severe depression and suicidal thoughts can occur in a significant proportion of individuals.

In most patients, these disturbances are generally mild, resolve relatively quickly, and do not reappear. However, for some these CNS disturbances persist, and they may appear only after many weeks or even months of efavirenz treatment.

Three recent studies address the issue of efavirenz-related CNS toxicities, and one of them proposes a potential cause of these sometimes persistent and debilitating adverse events.

Can Drug Level Monitoring Predict Efavirenz-related Neuropsychiatric Adverse Events?

The first study reviewed here for its focus on efavirenz-associated CNS disturbances appears in the November 1, 2005 issue of Clinical Infectious Diseases [1]. Spanish researchers at the Hospital General Universitario de Elche, Alicante, Spain, sought to determine whether monitoring the plasma concentration of efavirenz [therapeutic drug monitoring] could predict neuropsychiatric adverse events associated with long-term therapy with efavirenz.

Over an 18-month period, the investigators studied 17 HIV patients on stable HAART who had been on an efavirenz-based regimen for at least 6 months. They measured the patients’ efavirenz plasma concentrations at study entry and at different time points throughout the study.

Results

Ten (58.8%) of 17 patients had CNS-related adverse events that ranged in severity from insomnia and vivid or abnormal dreaming to severe depression and suicidal ideation In 4 (23.5%) of the cases, CNS toxicity led to efavirenz discontinuation. Mean efavirenz plasma levels were higher for patients experiencing neuropsychiatric symptoms A plasma level of 2.74 microgram/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 experience CNS toxicity than were other patients.

Based on these findings, the 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

Although small, the Spanish study offers indirect evidence for a higher risk of CNS-related toxicity among patients with higher efavirenz plasma concentrations who receive long-term therapy with efavirenz-containing regimens.

Further, the authors write, “Monitoring of plasma levels should allow patients with higher efavirenz plasma levels who are, consequently, at increased risk for neuropsychiatric adverse events to be detected. 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.”

HIV Patients Initiating Efavirenz-based HAART Experienced More Neuropsychological Symptoms at Week 1 But Not Later in a Large ACTG Trial

Published in the Annals of Internal Medicine (November 15, 2005), this second, much larger study (ACTG 5095) reviewed for this article was conducted among 303 HIV patients who were initiating HAART in a randomized, double-blind, controlled trial at multiple academic medical centers [2].

The stated objective of the ACTG trial was “to characterize efavirenz-associated neurologic symptoms in a randomized, controlled study of initial antiretroviral treatment.”

To measure the patients’ neurological performance, the ACTG investigators used the Digit Symbol Substitution Test and the Trail Making Test (Parts A and B); symptom questionnaires;

standardized assessments of sleep quality, anxiety, and depression; and efavirenz plasma concentrations.

Results

20 of 303 (6.6%) enrolled participants prematurely discontinued the study. Neuropsychological performance improved in both groups over time without significant differences between patients who were receiving efavirenz and those who were not. The efavirenz group experienced more neurologic symptoms at week 1 (P < 0.001) but not at weeks 4, 12, or 24 . A sleep index revealed that participants receiving efavirenz had more "bad dreams" during the first week of therapy (P = 0.038) . No significant changes in anxiety or depressed mood were noted. Changes in efavirenz-associated neurologic symptoms were correlated to efavirenz plasma concentrations at week 1 but not at later time points. 12 (6%) patients receiving efavirenz stopped taking the drug before the end of the study because of central nervous system symptoms.

As possible limitations of their trial, the authors noted, “Participant selection may have been biased in favor of patients with fewer psychiatric complications. The study design permitted substitution of a new drug in place of efavirenz in cases of treatment-limiting toxicity.”

In conclusion, the authors write, “In a large controlled trial, efavirenz use was associated with neurologic symptoms distinct from depression and anxiety that began early in therapy but resolved by week 4. Improvement in neuropsychological performance was comparable in patients who were receiving efavirenz and those who were not.”

Patients Using Efavirenz Report Persistence of Dream Recollection but Express Satisfaction with Sleep Quality and Overall Quality of Life

Perhaps the single most frequently reported CNS adverse event reported by patients using an efavirenz-based regimen is sleep disturbances. In the third and most recently published study that addresses efavirenz-related CNS side effects, researchers at Chelsea and Westminster Hospital and Charing Cross Hospital Sleep Laboratory, London, UK, investigated sleep staging and sleep quality by patient self-report in an open-label cohort pilot study [3].

Assessments were performed prior to the initiation of efavirenz, 2 weeks after the initiation of efavirenz and 3 months after the initiation of efavirenz. The study included HIV-positive individuals without central neurological disease who were antiretroviral treatment-naive. All patients initiated treatment with two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with efavirenz.

Results

Ten patients completed all three study visits. Patients reported an increase in recollection of dreams and morning sluggishness after the initiation of efavirenz which persisted for 3 months Sleep-staging data indicated a modest reduction in stage 2 sleep with a corresponding increase in deep sleep stage 4 and a modest increase in rapid eye movement (REM) sleep. Overall sleep maintenance efficiency did not significantly change from baseline. Changes in sleep staging were most marked 2 weeks after the initiation of efavirenz but remained different from baseline patterns at 3 months

The authors conclude, “The data indicate that efavirenz has a modest but persistent impact on the time spent in several key sleep stages. Patients reported persistence of dream recollection but remained satisfied with sleep quality and overall quality of life.”

Summary and Commentary

Based on the results of these three studies, what are we to believe about the relationship between efavirenz and neuropsychological adverse events?

The small, open-label, 72-week Spanish study of 17 patients by F Gutiérrez et al concludes that a significant number of individuals receiving efavirenz-based HAART who experience elevated plasma efavirenz levels (>/= 2.74 microgram/mL) will be susceptible to possibly severe CNS-related adverse events for months or years after initiating treatment with efavirenz.

Do elevated plasma levels of efavirenz cause late-appearing CNS side effects, as the Spanish researchers suggest? Is it possible that the neuropsychological disturbances documented were brought on by other, non efavirenz-associated causes? If caused by elevated plasma levels of efavirenz, can these adverse events be reduced or eliminated by lowering the currently recommended efavirenz dose (600 mg daily)? The reported minimum therapeutic level of efavirenz is 1.0 microgram/mL, which is significantly lower than the 2.74 microgram/mL level at and above which the Spanish team observed heightened susceptibility to CNS adverse events.

In sharp contrast to the Spanish findings, results of a large, double-blinded, randomized ACTG-sponsored 24-week trial by D Clifford at al suggest that after week 1, neuropsychological performance improved over time without significant differences between patients who were receiving efavirenz and those who were not.

Finally, a small pilot study among 10 patients in the UK by G Moyle et al focusing on sleep quality and brain wave patterns concludes that, although study participants reported experiencing intense dreaming and sluggishness for 3 months after initiating efavirenz, they also reported satisfaction with the quality of their sleep and with their quality of life.

Clearly, a larger study using therapeutic drug monitoring that compares the standard vs a lower dose of efavirenz is warranted to explore the effects of reduced plasma efavirenz levels on CNS toxicity.

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05/05/06

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