Blood levels of efavirenz are not associated with discontinuation of treatment with the drug as a result of neuropsychiatric problems, investigators report in the October edition of AIDS.
A retrospective analysis of a randomised trial showed no significant differences in blood levels of the drug between patients who ceased therapy with the drug because of these side-effects and those who continued to take efavirenz in the longer term. The results contrast with a recent Dutch study which found that efavirenz dose-reduction in people with high blood concentrations resulted in fewer toxicity-related discontinuations of efavirenz treatment.
An intriguing finding of the study was the smokers were more likely to stop therapy with efavirenz because of neuropsychological problems than were non-smokers.
The investigators note that “epidemiological and clinical studies have demonstrated elevated rates of tobacco use in adults with mental disorders.” (Paradoxically, a recently reported study showed that in people who have a genetic predisposition to metabolise efavirenz more quickly, smokers had lower efavirenz blood levels than non-smokers.)
Efavirenz (Sustiva, also in the combination pill Atripla) is a powerful, easy-to-take, and generally well-tolerated antiretroviral drug that is recommended for first-line HIV treatment.
However, approximately 50% of patients report side-effects such as dizziness, depression and sleep problems soon after commencing therapy in the drug. These disappear in the majority of patients within a month or so, but in a small number of individuals they persist and are so problematic that treatment with efavirenz is stopped.
Some (but not all) studies have shown that patients who stop treatment with efavirenz due to neuropsychiatric side-effects have high blood concentrations of the drug.
Investigators from the randomised-controlled INITIO study therefore retrospectively compared blood levels of efavirenz in patients who stopped therapy with efavirenz after at least four weeks of treatment with the drug because of neuropsychiatric side-effects to those of patients who continued therapy with the drug for at least six months.
All the patients took efavirenz in combination with d4T (stavudine, Zerit) and ddI (didadosine, Videx), and some individuals were also randomised to take the protease inhibitor nelfinavir (Viracept). None of these drugs are now recommended for routine use in resource-rich settings.
The investigators’ analysis included 35 patients who stopped treatment with efavirenz and 75 individuals who took the drug in the longer term.
The only significant difference between these two groups of patients was that those stopping therapy were significantly more likely to be smokers (62 vs 27%, p = 0.0011).
Median blood concentrations of efavirenz were comparable between the two groups of patients (2259 vs 2085 mg/l), and individuals stopping therapy with the drug were no more likely to have concentrations of the drug above 3000 mg/l (17% vs 27%), or 4000 mg/l (7% vs 16%).
Despite the finding that smokers were more likely to stop efavirenz treatment because of neuropsychiatric side-effects, blood levels of the drug were comparable between those who smoked and those who did not (2254 vs 2048 mg/l).
“In a large randomized trial, efavirenz plasma concentrations did not predict drug cessation due to neuropsychiatric symptoms after at least one month of therapy,” write the investigators.
They therefore conclude, “from these results we cannot recommend randomly-timed measurements of efavirenz plasma concentrations to predict central nervous system toxicities.”
Other recent research has shown that gradual increases in the efavirenz dose over several weeks reduce the incidence of central nervous system side-effects, and that reducing the dose of efavirenz is safe in people with a genetic predisposition to metabolise efavirenz slowly.
Reid TRH et al. Efavirenz plasma concentrations did not predict cessation of therapy due to neuropsychitatic symptoms in a large randomized trial. AIDS 23: 2222-23, 2009.