Stepped-dose versus full-dose efavirenz for HIV infection and neuropsychiatric adverse events: a randomized trial.
BACKGROUND
More than 50% of patients who start efavirenz treatment develop limiting neuropsychiatric adverse events (NPAEs).


OBJECTIVE
To assess whether stepwise dosing of efavirenz decreases the incidence and severity of NPAEs while maintaining virologic efficacy.


METHODS
Randomized, double-blind, controlled trial.


METHODS
7 HIV clinics in Spain.


METHODS
114 HIV-infected patients eligible for efavirenz treatment plus 2 nucleoside or nucleotide reverse transcriptase inhibitors.


METHODS
Random assignment (by computer-generated sequence) to receive efavirenz, 200 mg/d on days 1 through 6, 400 mg/d on days 7 through 13, and 600 mg/d on day 14 and after, or efavirenz, 600 mg/d, from day 1. Both groups received 2 nucleoside or nucleotide reverse transcriptase inhibitors chosen by the patient's physician.


METHODS
Neuropsychiatric symptoms and sleep quality were assessed by questionnaires at 0, 7, 14, and 30 days. The primary outcome was efavirenz-related NPAEs during the first 2 weeks, and the secondary outcome was plasma HIV RNA level at 24 weeks.


RESULTS
Compared with the stepped-dose group, the full-dose group had higher incidence and severity of dizziness (66.0% vs. 32.8%; P = 0.001), hangover (45.8% vs. 20.7%; P = 0.008), impaired concentration (22.9% vs. 8.9%; P = 0.038), and hallucinations (6.1% vs. 0%; P = 0.056) during the first week. From week 2, the incidence of efavirenz-related NPAEs was similar in both groups, although the severity was greater in the full-dose group. Virologic and immunologic efficacy seemed similar in both groups.


CONCLUSIONS
The sample size was calculated on the basis of a high absolute difference in rates of efavirenz-related NPAEs between the groups. A lower absolute difference and a larger sample size could have made the differences between groups reach statistical significance beyond the first week. In addition, the sample size does not allow confirmation of similar efficacy between treatment groups.


CONCLUSIONS
Stepwise dose escalation of efavirenz over 2 weeks reduces the incidence and intensity of efavirenz-related NPAEs while maintaining efficacy.


BACKGROUND
Consejería de Salud, Junta de Andalucía, Spain.
Gutiérrez-Valencia
Alicia
A
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, and Hospital Universitario de Valme, Seville, Spain.
Viciana
Pompeyo
P
Palacios
Rosario
R
Ruiz-Valderas
Rosa
R
Lozano
Fernando
F
Terrón
Alberto
A
Rivero
Antonio
A
López-Cortés
Luis F
LF
D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D018791:CD4 Lymphocyte Count; D003521:Cyclopropanes; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced*; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D018401:Sample Size; D012893:Sleep Wake Disorders / Q000139:chemically induced*; D019562:Viral Load
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz