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  International AIDS Conference
July 13-16, 2003, Paris
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Efavirenz (EFV) Well Tolerated: IAS Report
Reported by Judith Aberg, MD , Washington University, St Louis, Missouri and the ACTG
  The central nervous system (CNS) side effects of EFV such as dizziness, trouble sleeping, drowsiness, trouble concentrating, and unusual dreams, typically resolve after the first 2-4 weeks of therapy. Most patients can remain on EFV with the healthcare provider's support and patient education regarding management of these side effects. However, patients with a history of psychiatric disorders appear to be at greater risk of developing EFV-induced psychiatric side effect consisting of severe depression, suicidal ideation, aggressive behavior, paranoid reactions and / or manic reactions. Swiss investigators also reported intolerance of EFV among IVDUs due to development of CNS side effects [AIDS 2002;16:381-385] (ed note: see Aberg study at end of this report). EFV containing regimen is becoming the most commonly prescribed first regimen given its proven efficacy and durability in suppressing HIV.
There were 2 oral abstracts presented at IAS discussing the tolerability of efavirenz and showed that the CNS side effects were transient and that EFV was well tolerated.
Abstract 53. SHORT-TERM TOLERANCE OF EFAVIRENZ IN HIV-INFECTED AFRICAN ADULTS PARTICIPATING IN THE TRIVACAN ANRS 1269 TRIAL, ABIDJAN, CoTE D'IVOIRE C Danel1, R Moh1, E Messou1, A Minga1, C Seyler1, D Sauvageot1, X Anglaret3, E Bissagnene2 and R Salamon3 for the ANRS 1269 Study Group 1 Programme PAC-CI, Abidjan, Cote d'Ivoire; 2 Service des Maladies Infectieuses et Tropicales, CHU de Treichville, Abidjan, Cote d'Ivoire; and 3 INSERM U 593, Université Bordeaux 2, France
Adverse effects to efavirenz are frequent but mostly transitory. There is little data on the tolerance to efavirenz in sub-Saharan Africa. Tolerance to drugs may vary depending on genetics or environmental exposures. The objective of this study was to describe the short-term tolerance of efavirenz in patients included in a therapeutic trial in Abidjan. The Trivacan Structured Treatment Interruption (STI) trial started on December 26, 2002. 840 antiretroviral naive HIV-infected adults with CD4+T cell count > 150 but <350 cells /mm3 were enrolled in a first phase of continuous treatment.
After 6 months, patients with immuno-virological success were randomized into three arms, including two different STI strategies. They described the data on efavirenz tolerance in 362 patients (71% women, median age 34 years, baseline median CD4 count 249/mm3) participating in the first phase who were on AZT, 3TC and EFV. The median follow-up period was 2.2 months with over 95% subjects having a follow-up visit at one month. On Day 7, 68% of subjects complained of a neurological side effect such as dizziness, nightmares and insomnia. At month 1 visit, this number had decreased to 49% and by months 2 and 3 were 7 and 5% respectively. Approximately 7% reported missing at least one dose of EFV during the first month of therapy and only one subject discontinued therapy secondary to neurological side effects. There were no serious adverse events reported.
54. ACTG 5097s: IMPACT OF EFAVIRENZ (EFV) ON NEUROPSYCHOLOGICAL PERFORMANCE, MOOD, AND SLEEP BEHAVIOUR IN HIV-POSITIVE INDIVIDUALS DB Clifford1, S Evans2, Y Yang2, E Acosta3, K Goodkin4 and RM Gulick5 1 Washington University, St Louis; 2 Harvard University, Boston; 3 University of Alabama, Birmingham; 4 University of Miami, Miami; and 5 Cornell University, New York, USA
A5097 is a substudy of A5095, a phase III, randomized, double-blind, placebo-controlled comparison of 3 antiretroviral regimens: AZT/3TC/ABC vs AZT/3TC/ABC/EFV vs AZT/3TC/EFV. Neuropsychological performance was summarized as Z-scores of Digit Symbol Substitution and Trailmaking A and B, (NPZ-3). Additional measures were Pittsburgh Sleep Quality Index (PSQI), Center for Epidemiologic Studies-Depression (CES-D), Spielberger State-Trait Anxiety Inventory (STAI), EFV serum levels and a symptom list. Measures were made at baseline, week (wk) 1, 4, 12 and 24. Changes in test parameters over time were compared in EFV containing and sparing arms.
The objective of this study was to describe the incidence, duration, and cognitive motor effect of neurologic symptoms and signs associated with initiation of EFV therapy compared to therapy without EFV. They also sought to correlate these findings with EFV serum drug levels over the initial 24 weeks of treatment. 303 subjects were randomized of which 200 to EFV. Randomization balanced baseline characteristics. All subjects had improved neuropsychologic performance on ART. There were no significant differences in changes of NPZ3 scores between the EFV-containing and EFV-sparing arms or of the proportion of subjects with neurological deficits.
The symptom questionnaire detected significant increases in neurologic symptoms at week 1 (P<0.001), but not at wk 4, 12 or 24. Similarly, the PSQI revealed more ‘bad dreams' at wk 1 in EFV-treated subjects (P=0.038). However, better global PSQI scores and ‘sleep quality' were found in the EFV-containing arm at wk 4. No significant differences in changes in total depressed mood (CES-D) or anxiety (STAI) were noted, nor in the proportion of subjects with clinically significant anxiety or high levels of depressive symptoms. Small negative significant correlations between EFV levels and NPZ3 persisted over time [range of r=(-0.15, -0.25)] but there was no correlation of EFV level with mood.
In conclusion, early neuropsychologic symptoms distinct from depression or anxiety were associated with EFV use, and resolved by week 4. Improvement in neuropsychologic performance was comparable in EFV and non-EFV treated subjects. Another interesting finding is that the neurologic symptoms were most consistent to those that could be attributed to vestibular dysfunction such as falling over, room spinning and unsteady gait. This may help investigators localize the etiology (cause) of these side effects.
Both these studies are supportive of the use of EFV. Although multiple studies have shown EFV-containing regimens to be one of the more potent therapies for suppressing HIV, there still are provider biases that EFV may not be the best therapy in patients with histories of substance abuse and psychiatric disorders. There have been reports (approximately 1 or 2 per thousand EFV-treated subjects) of delusions and aberrant behavior, predominantly in subjects with a history of mental illness or substance abuse. Recently, colleagues and I published a study suggesting that there was not an increase of CNS side effects among non-IVDU substance abusers (HIV Clinical Trials 2003;4:145-9). These studies are reassuring to know that the EFV CNS side effects are transient and that EFV containing regimens do improve neuro-psychiatric function over time.