Abstract
The aim of this study is to assess the effect of efavirenz exposure on neurocognitive functioning and investigate plasma neurofilament light (Nfl) as a biomarker for neurocognitive damage. Sub-analysis of the ESCAPE-study, a randomised controlled trial where virologically suppressed, cognitively asymptomatic HIV patients were randomised (2:1) to switch to rilpivirine or continue on efavirenz. At baseline and week 12, patients underwent an extensive neuropsychological assessment (NPA), and serum efavirenz concentration and plasma Nfl levels were measured. Subgroups of elevated (≥ 4.0 mg/L) and therapeutic (0.74 to< 4.0 mg/L) baseline efavirenz concentration were made. Differences between these groups in baseline NPA Z-scores and in delta scores after efavirenz discontinuation were assessed. Nfl level was measured using an ELISA analysis using single molecule array (Simoa) technology. Correlation of plasma NFL with NPA Z-scores was evaluated using a linear mixed model. The elevated group consisted of 6 patients and the therapeutic group of 48. At baseline, the elevated group showed lower composite Z-scores (median − 1.03; IQR 0.87 versus 0.27; 0.79. p 0.02). This effect was also seen on the subdomains verbal (p 0.01), executive functioning (p 0.02), attention (p < 0.01) and speed (p 0.01). In the switch group, the elevated group improved more on composite scores after discontinuing efavirenz (mean 0.58; SD 0.32 versus 0.22; 0.54, p 0.15). No association between plasma Nfl and composite Z-score was found. High efavirenz exposure is associated with worse cognitive functioning compared with patients with therapeutic concentrations. Plasma Nfl is not a suitable biomarker to measure cognitive damage in this group.
Highlights
Antiretroviral agents used to treat infection with human immunodeficiency virus 1 (HIV) have been associated withElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Multiple mechanisms on how efavirenz causes neurotoxicity have been described through in vitro and in vivo studies
In the ESCAPE study, we found that discontinuing efavirenz led to an objective improvement in neurocognitive functioning in a group of asymptomatic people with HIV (Hakkers et al 2019)
We investigate the hypothesis that a high exposure to efavirenz leads to axonal damage and/or neuronal cell death, which can be measured by plasma neurofilament light (Nfl)
Summary
Antiretroviral agents used to treat infection with human immunodeficiency virus 1 (HIV) have been associated with. Besides HIV infection, plasma Nfl has been investigated in neurological conditions such as frontotemporal dementia, multiple sclerosis and Creutzfeldt disease and proven to be useful as a biomarker of neurodegeneration (Rohrer et al 2016; Steinacker et al 2016; Kuhle et al 2017). We investigate the hypothesis that a high exposure to efavirenz leads to axonal damage and/or neuronal cell death, which can be measured by plasma Nfl. emotional functioning) which was previously published (Hakkers et al 2019). Emotional functioning) which was previously published (Hakkers et al 2019) This randomised controlled trial included neurologically asymptomatic, stable (i.e. undetectable viral load), HIV-infected male patients on efavirenz/ emtricitabine/tenofovir (Atripla) for at least 6 months, aged from 25 to 50 years old. All participants signed written informed consent (Hakkers et al 2019)
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