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Stepwise Efavirenz Decreases Neurotoxicity

Neuropsychiatric side effects during the initial weeks of efavirenz therapy can be reduced by building up to the full dose gradually.

Efavirenz is an important component of many antiretroviral therapy (ART) regimens, but patients often experience severe and debilitating neuropsychiatric adverse events (NPAEs) during the first weeks of treatment. Although firm evidence that these NPAEs are dose related is lacking, investigators in Spain (several of whom have received honoraria and grants from the manufacturer of efavirenz) postulated that initiating efavirenz in a stepwise fashion might diminish NPAEs while maintaining the drug's virologic and immunologic effects.

In a multicenter, randomized, double-blind, clinical trial, 114 patients were started on efavirenz, as part of a standard triple-therapy regimen, at either the standard dose (600 mg/day) or a stepped dose (200 mg/day on days 1–6, 400 mg/day on days 7–13, and 600 mg/day thereafter). NPAEs including dizziness, feelings of drunkenness or hangover, sleep disorders, nightmares, impaired concentration, mood changes, and severe psychiatric symptoms such as depression, suicidal ideation, hallucinations, delirium, and paranoia were assessed and graded for severity using standardized questionnaires.

During the first week of therapy, the incidence and severity of NPAEs were significantly lower in the stepwise group than in the standard-dose group. During the second week, the incidence was similar between groups, but the severity remained lower in the stepwise group. Viral loads and CD4-cell counts were similar between groups at baseline and throughout the 24 weeks of follow-up.

Comment: These findings suggest that, when initiating ART regimens containing efavirenz, patients have much to gain and little to lose with the use of stepwise incremental dosing. One can't help but wonder whether patients could get away with lower efavirenz doses throughout therapy.

— Stephen G. Baum, MD

Published in Journal Watch Infectious Diseases July 15, 2009

Citation(s):

Gutiérrez-Valencia A et al. Stepped-dose vs. full-dose efavirenz for HIV infection and neuropsychiatric adverse events: A randomized trial. Ann Intern Med 2009 Jul 7; [e-pub ahead of print].

Reader Remarks:

Review and add to remarks on this article

• efavirenz induces it's own metabolism
  Karen Williams, Pharm D, 30 Jul 2009 4:05 PM EST
  Since efavirenz induces it's own metabolism, it's not too surprising that this worked. It's irresponsible to say that patients might... [more]

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