By Liz Highleyman

Efavirenz is one of the most widely used antiretroviral drug and is highly effective. However, it causes neuro-psychiatric symptoms -- such as anxiety, insomnia, hallucinations, and unusual dreams -- in about half of patients who use it. While these side effects are usually mild-to-moderate, they lead many people to either avoid the drug or discontinue therapy.

Researchers with the Sociedad Andaluza de Enfermedades Infecciosas in Spain evaluated whether gradual or stepwise dosing of efavirenz would decrease the incidence and severity of neuro-psychiatric adverse events (AEs), while maintaining virological efficacy.

This randomized, double-blind, controlled trial included 114 HIV patients at 7 Spanish HIV clinics. Participants were randomly assigned to receive either the standard full 600 mg/day dose of efavirenz from day 1, or else to start with 200 mg/day efavirenz on days 1-6, increasing to 400 mg/day on days 7-13, and finally to 600 mg/day from day 14 onward. All patients also took 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) chosen by their physicians.

Neuro-psychiatric symptoms and sleep quality were assessed using questionnaires at study entry (before starting efavirenz) and on days 7, 14, and 30. The primary outcome was efavirenz-related neuro-psychiatric AEs during the first 2 weeks. The secondary outcome was plasma HIV RNA level at 24 weeks.

Results

	As expected, efavirenz concentrations were significantly lower in the stepped-dose group compared with the full-dose group during the first 2 weeks, but similar at week 4.
	The number of patients who discontinued efavirenz due to AEs was similar in both groups.
	Overall, 66% of patients in the full-dose efavirenz group and 47% in the stepped-dose group experienced neuro-psychiatric or sleep-related side effects during the first week on efavirenz (P = 0.04).
	During the first week, the full-dose group experienced a significantly higher incidence and severity of the following AEs compared with the stepped-dose group: Dizziness: 66% vs 33%, respectively (P = 0.001); "Hangover": 46% vs 21% (P = 0.008); Impaired concentration: 23% vs 9% (P = 0.038); Hallucinations: 6% vs 0% (P = 0.056).
	From week 2, the incidence of efavirenz-related neuro-psychiatric AEs was similar in both groups, 58% vs 49%, respectively (not a statistically significant difference).
	Side effect severity, however, remained greater in the full-dose group.
	During the first 2 weeks, 10% of patients in the stepped dose group experienced severe efavirenz-related neuro-psychiatric AEs versus 20% in the full-dose group (but again, not reaching statistical significance).
	4 weeks into treatment, when everyone was taking full-dose efavirenz, 52% of patients overall reported some neuro-psychiatric or sleep-related side effects.
	Virological suppression and immunological recovery appeared similar in both groups.
	1 case of virological failure associated with NNRTI-resistance mutations was observed in each group.

As a limitation of the study, they noted that the sample size was calculated on the basis of a high absolute difference in rates of efavirenz-related AEs between the groups. A lower absolute difference and a larger sample size could have made the differences between the groups reach statistical significance beyond the first week. The sample size did not allow confirmation of equivalent efficacy between treatment groups.

Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, and Hospital Universitario de Valme, Seville, Spain; Hospital Universitario Virgen de la Victoria, Málaga, Spain; Hospital de Jerez, Cádiz; and Hospital Universitario Reina Sofía, Córdoba, Spain.

8/18/09

Reference
A Gutierrez-Valencia, LF Lopez-Cortes, P Viciana, and others (for the Sociedad Andaluza de Enfermedades Infecciosas). Stepped-Dose vs. Full-Dose Efavirenz for HIV Infection and neuropsychiatric Adverse Events: A Randomized Trial. Annals of Internal Medicine 151(3): 149-156. August 4, 2009. (Free full text).