Long-Term Impact of Efavirenz on Neuropsychological Performance and Symptoms in HIV-Infected Individuals (ACTG 5097s)

Washington University School of Medicine, St. Louis, MO 63110, USA.
HIV Clinical Trials (Impact Factor: 2.63). 11/2009; 10(6):343-55. DOI: 10.1310/hct1006-343
Source: PubMed


Efavirenz (EFV) is an antiretroviral (ARV) drug associated with neuropsychological effects. Limited data describing the long-term impact of EFV-based regimens on neuropsychological performance over more than 3 years are available.
We enrolled a subset of participants from a large initially EFV placebo-controlled trial of therapies for HIV subjects naïve to ARV treatment (A5095). Clinical follow-up continued for 184 weeks of study. Subjects were assessed with brief neuropsychological testing, a symptom questionnaire of EFV-associated symptoms, the Pittsburgh Sleep Index, Center for Epidemiologic Studies-Depression Scale, and an anxiety rating interview.
Over 184 weeks on EFV, the median NPZ3 score in 86 evaluable patients improved from baseline by +0.5 (p < .01); all components improved, although higher EFV levels were associated with slightly lower responses. Overall symptom scores did not change, while EFV-associated CNS symptoms increased (p = .01). Median change of bad dream sleep scores and anxiety increased from the baseline while global depression score decreased.
In participants who continued EFV-based regimens, neuropsychological performance improvement from baseline was maintained over 3 years. EFV-based treatment was generally well tolerated, but small increases from baseline in EFV-associated symptoms, bad dreams, and anxiety were detected.

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Available from: David B Clifford, Feb 03, 2014
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    • "EFV is primarily metabolised by the CYP2B6 enzyme and to a lesser extent by CYP3A5, CYP3A4, CYP2A6 and CYP1A2 isoforms of the cytochrome P450 system in the liver [20, 21] . The gene coding for CYP2B6 is highly polymorphic and the CYP2B6 c.516G > T SNPs [11,212223242526272829303132 and CYP2B6 c.983 T > C SNPs [23, 25,3334353637 have been reportedly associated with reduced EFV oral clearance resulting in increased plasma EFV concentrations. The single nucleotide variant CYP2B6 c.516 T is linked to a CYP2B6 mRNA splice variant that lacks exons four to six and consequently lower levels of functional CYP2B6 enzyme [24], while the CYP2B6 c.983C variant causes a non-synonymous amino acid change from isoleucine to threonine at position 328 in exon 7 and, thus, reduced CYP2B6 activity [37] . "
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    ABSTRACT: Background Efavirenz, widely used as part of antiretroviral drug regimens in the treatment of paediatric human immunodeficiency virus infection, has central nervous system side effects. We describe four children presenting with serious, persistent central nervous system adverse events who were found to have elevated plasma efavirenz concentrations as a result of carrying CYP2B6 single nucleotide polymorphisms, known to play a role in the metabolism of EFV. None of the children had a CYP2B6 wildtype haplotype. We believe this is the first case of cerebellar dysfunction associated with efavirenz use to be described in children. Case presentation Four black African children, between the ages of 4 and 8 years presenting between 1 and 20 months post-efavirenz initiation, are described. Cerebellar dysfunction, generalised seizures and absence seizures were the range of presenting abnormalities. Plasma efavirenz levels ranged from 20-60 mg/L, 5–15 times the upper limit of the suggested reference range. All abnormal central nervous system manifestations abated after efavirenz discontinuation. Conclusion Efavirenz toxicity should always be considered in human immunodeficiency virus-infected children with unexplained central nervous system abnormalities. Our findings further our understanding of the impact of genetic variants on antiretroviral pharmacokinetics in children across various ethnic groups. Screening for potential EFV-toxicity based on the CYP2B6 c.516 SNP alone, may not be adequate.
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    • "Recently, investigators more specifically identified damage to neuronal dendrites by metabolites of efavirenz at concentrations readily detected in CSF of patients receiving efavirenz containing regimens [92]. However, a long-term study of subjects followed for 3 years on efavirenz containing regimens showed stability of neuropsychological testing performance in subjects with normal testing at baseline, suggesting if tolerated, efavirenz does not appear to lead to accumulated neurotoxicity which is clinically detectable [94]. Importantly, the ease of consistently adhering to efavirenz-containing regimens in terms of convenience of dosing must be weighed against potential neurotoxicity in terms of cost-benefit to the CNS. "
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