Spanish researchers have found that patients who have been taking long-term antiretroviral therapy including the non-nucleoside transcriptase inhibitor (NNRTI) efavirenz (Sustiva) are much more likely to develop neuropsychological side-effects if they have high blood concentrations of efavirenz.
In a study, to be published in the December 1st edition of Clinical Infectious Diseases, the researchers from Alicante found that over 50% of individuals still had neuropsychiatric side-effects attributable to efavirenz a year after starting treatment with the drug. They also found that individuals with a plasma concentration of efavirenz above 2.74μg/ml were almost six times more likely to develop a neuropsychological side-effect such as depression or sleeping problems. They suggest that therapeutic drug monitoring might allow doses of efavirenz to be adjusted and side-effects to be avoided.
Efavirenz is an extremely popular antiretroviral drug, often providing the basis for an anti-HIV treatment regimen. However, it is well known that many people taking efavirenz develop central nervous system side-effects when they start taking the drug. These side-effects can include sleep disturbances such as insomnia and vivid dreams or nightmares, depression, poor concentration, dizziness or even suicidal thoughts. Generally, central nervous system side-effects caused by efavirenz tend to become mild and disappear or become less intense after the first few weeks and months of treatment with the drug.
It is not known, however, what proportion of people taking efavirenz have long-term neuropsychological side-effects caused by the drug and how such side-effects can be avoided. Therefore, investigators from the Hospital General Universitario de Elche in Alicante designed a longitudinal study involving 17 patients who had been taking an efavirenz-containing antiretroviral regimen for at least six months. They particularly wished to see if monitoring plasma concentrations of efavirenz could predict which individuals would develop central nervous system side-effects.
Blood concentrations of efavirenz were monitored on entry to the study and then at three-monthly intervals for 18 months.
Of the 17 patients recruited to the study, 14 were men, 16 were white, eight had been infected with HIV by injecting drug use and eight were coinfected with hepatitis C virus. The median duration of efavirenz therapy before entry to the study was 18 months. Median CD4 cell count was 417 cells/mm3 and all 17 patients had an undetectable viral load.
At the end of the 18 month study period, 13 patients (77%) were still taking an efavirenz-containing HIV treatment regimen. However, four patients (23%) stopped taking efavirenz because of side-effects.
Overall, ten individuals (59%) reported central nervous system side-effects. In six people these were classified as mild, but in the remaining four they were moderate-to-severe and lead to efavirenz therapy being discontinued.
No patient characteristic, such as sex, race, HIV transmission group, hepatitis C coinfection status or body weight was found to be significantly associated with the occurrence of central nervous system side-effects and treatment discontinuation.
The investigators then looked at plasma concentrations of efavirenz to see if these were associated with neuropsychiatric side-effects or treatment cessation. Mean plasma concentrations were significantly higher in patients experiencing central nervous system side-effects than those who did not (5.1 μg/ml versus 2.2 μg/ml, p = 0.024). What’s more, the investigators found that patients who had a plasma concentration of efavirenz above 2.74 μg/ml at any point during the study were almost six times more likely than other patients to experience central nervous system side-effects (p = 0.0001). In multivariate analysis only a concentration of efavirenz above 2.74 μg/ml was significantly associated with the development of central nervous system side-effects.
“Unexpectedly, more than one-half of the patients reported neuropsychiatric symptoms during long-term efavirenz therapy”, write the investigators. As all four patients who stopped efavirenz treatment during the study had been taking the drug for over a year, the investigators also express concerns “about the delayed neuropsychiatric toxicity of efavirenz”. They also speculate “the prevalence of persistent neuropsychiatric symptoms in patients receiving long-term therapy with efavirenz may be high.”
Therapeutic drug monitoring might, the investigators suggest, help identify individuals with blood concentrations of efavirenz. Earlier studies have suggested that 1 g/ml may be the target plasma concentration of efavirenz in NNRTI-naive patients and the investigators write that therapeutic drug monitoring might identify patients with “room" for dose reduction to avoid toxicity.
Several limitations with the study are noted by the investigators, not least the small number of patients involved. Nevertheless they conclude, “monitoring of plasma levels should allow patients with higher efavirenz plasma levels who are, consequently, at increased risk of neruopsychiatric adverse events to be detected.”
Gutierrez F et al. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis 41 (online edition), 2005.