Efavirenz Has Minimal Long-term Neuropsychological Effects

By Brian Boyle, MD

The primary adverse events associated with efavirenz (Sustiva®, EFV) are neuropsychological (NP) in nature, for example, vivid dreams, dizziness/imbalance, and sleep disturbances. While earlier data have demonstrated that in most patients these adverse events are relatively short-term in duration, lasting days to weeks, there are limited data on the long-term impact of EFV-based regimens on NP performance. 

A5097s enrolled a representative subset of patients entered into A5095, a placebo controlled trial that initially had 3 arms: Trizivir® (co-formulated abacavir [ABC]/zidovudine [ZDV]/lamivudine [3TC] vs. EFV + Combivir® (co-formulated zidovudine [ZDV]/lamivudine [3TC]) vs. EFV + Trizivir®. The Trizivir arm was stopped due to underperformance and the 3 year comparison of EFV + Combivir® vs. EFV + Trizivir®, which were presented at the 45^th ICAAC in December, 2005, showed the 2 regimens to be equivalent in efficacy, with no benefit derived from the addition of ABC.

The initial results of A5097s, which evaluated NP adverse events for the initial 6 months of A5095, demonstrated that by 1 month into therapy the NP adverse events associated with EFV had remitted in most patients and that there was no difference in any NP evaluation between the patients on and not on EFV at that time point.

Data presented at the 13^th CROI involve follow-up of 184 weeks which was available on 117/200 subjects enrolled in EFV-based arms initially, and on an additional 46 subjects rolled into EFV-based arms and who had extended follow-up on EFV with known baseline performance. NP performance was evaluated with NPZ3 (a composite score from Trailmaking A and B and Digit Symbol tests), patient status was evaluated with a symptom questionnaire, Pittsburgh Sleep Index, CES-Depression Scale, and an anxiety rating interview.

The investigators found that in 117 pts treated with EFV-based therapy for 184wks, the median NPZ3 score improved from baseline by +0.56 (P<0.001). Median score changes in components of NPZ3 were +0.81, +0.39, and +0.49 on the Trailmaking A, Trailmaking B, and Digit Symbol tests, respectively (all p-values<0.001).

Median change in overall symptom scores was unchanged (median=0, p-value=0.42), while presumptive EFV-associated symptoms increased slightly (median=+1, p-value=0.03). Median change of bad dream sleep scores and anxiety increased slightly (p = 0.0002 and p = 0.03, respectively), while global depression and global sleep scores at 184 weeks were unchanged. Analysis including all 163 subjects on long-term EFV-based therapy yielded similar results.

Based on these data, the authors conclude: “Neuropsychological performance improvement from baseline was maintained over 3 years in HIV-infected subjects taking EFV-based therapy. Overall sleep and affect was unchanged by long-term EFV-based treatment. EFV-based treatment was generally well-tolerated, but minimal increases from baseline in NP symptoms, bad dreams and anxiety could be detected in those remaining on long-term therapy.”

02/07/06

Reference
D Clifford et al. A5097s:  Long-term Neuropsychological Effects of Efavirenz-Based Treatment for HIV.  13^th Conference on Retroviruses and Opportunistic Infections. Denver, CO. February 5-8, 2006. Abstract  773.