Does efavirenz replacement improve neurological function in treated HIV infection?

Abstract

ObjectivesThe contribution of specific antiretroviral drugs to cognitive function in HIV‐infected people remains poorly understood. Efavirenz (EFV) may plausibly cause cognitive impairment. The objective of this study was therefore to determine whether chronic EFV therapy is a modifier of neurocognitive and neurometabolic function in the setting of suppressive highly active antiretroviral therapy.MethodsWe performed an open‐label phase IV controlled trial. Adult subjects who were stable on suppressive EFV therapy for at least 6 months were switched to ritonavir‐boosted lopinavir (LPV/r) with no change in the nucleoside reverse transcriptase inhibitor (NRTI) backbone. The following parameters were assessed before and 10 weeks after therapy switch: cognitive function (by CogState® computerized battery); brain metabolites (by proton magnetic resonance spectroscopy); brain activity [by attentional processing task‐based functional magnetic resonance imaging]; and sleep quantity and quality [by sleep diary, Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale].ResultsSixteen subjects completed the study. Despite most subjects (81%) self‐reporting memory problems at baseline, cognitive function, brain metabolites, and brain activity showed no change at 10 weeks after switch. Sleep quality improved on switch off EFV [mean PSQI (standard deviation): EFV, 8.5 (6.5); LPV/r, 5.8 (5.5); mean difference −0.4; 95% confidence interval −6.0 to −0.7].ConclusionsThis is the first study to assess the effects of chronic EFV therapy on neurological function in a controlled setting. We conclude that EFV withdrawal is unlikely to result in significant modification of neurocognitive function in otherwise stable HIV‐infected people.

Improved Central Nervous System Symptoms in People with HIV without Objective Neuropsychiatric Complaints Switching from Efavirenz to Rilpivirine Containing cART

“…The effect of efavirenz on cognitive function remains controversial, with some observational studies showing an increased rate of cognitive impairment associated with efavirenz use [14] and others showing no changes in cognitive function after efavirenz withdrawal [17,18]. Neurotoxicity data from animal and in vitro studies suggests that efavirenz might have a detrimental effect on human brain cells [29,30,31] and therefore, another reason why some patients might not be showing clinical impairment is because of individual differences in brain reserve.…”

“…In contrast, another randomized controlled trial of people with HIV on efavirenz switching to rilpivirine did not show a significant improvement in cognitive function or patient reported outcomes of depression and anxiety [17]. Similarly, Payne et al showed that switching people with HIV on efavirenz for at least 6 months to a protease inhibitor combination was not associated with changes in cognitive function or brain imaging parameters [18].…”

Neuropsychological changes in efavirenz switch regimens

“…A randomized study conducted by Clifford et al showed that changes in neuropsychological score were comparable between participants randomized to EFV and non-EFV arms, without statistical significance at any time point during 24 weeks of follow-up [12] ; even after extending their observation to 184 weeks, EFV group and non-EFV group had similar changes in neuropsychological score [13] . A small study enrolling 16 subjects demonstrated no significant changes in neurocognitive function after switching EFV to LPV/r-based regimen for 10 weeks, along with brain activity and metabolites (evaluated by proton magnetic resonance spectroscopy and functional magnetic resonance imaging) [7] . These findings are consistent with our analysis.…”

“…However, this study recruited only a small number of subjects and had short follow-up period [6] . Another Phase IV open label study involving 16 subjects who switched off EFV showed that discontinuation of EFV was not associated with improvement in neurocognitive function; however, this study is also limited by its small sample size [7] . Given that EFV is still widely used in many low-and middle-income countries as first-line regimen, it was more important to evaluate the impact of EFV switch on neurocognitive effect with longer follow-up and a larger sample size.…”

Sleep and neuropsychological performance in HIV+ subjects on efavirenz-based therapy and response to switch in therapy

“…Therefore, a better method for assessing possible outcomes of EFV treatment would be to determine whether these parameters improved when EFV-based therapy was discontinued in favor of a non-EFV-containing therapy. In respect to neuropsychological parameters, one small pilot study of 16 subjects reported that EFV discontinuation was unlikely to modify neurocognitive function 17 . Our study similarly found a lack of ready reversal with EFV discontinuation.…”