Cerebrospinal Fluid Diffusion of Bictegravir/Emtricitabine/Tenofovir in HIV-Related Central Nervous System Impairment

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Researchers sought to determine the effects and cerebrospinal fluid concentrations of treatment with bictegravir, emtricitabine, and tenofovir in patients with HIV-related central nervous system impairment.

Among patients younger than 51 years of age with HIV-related central nervous system impairment (HCI), first-line treatment with an antiretroviral (ART) regimen of bictegravir, emtricitabine, and tenofovir should be used with caution, according to study results published in the Journal of Antimicrobial Chemotherapy.

In this real-life prospective, observational study conducted in France, researchers evaluated total and unbound cerebrospinal fluid (CSF) concentrations of bictegravir and total CSF concentrations of emtricitabine and tenofovir in a total of 24 patients with HCI.

All plasma and CSF total ART and unbound plasma bictegravir concentrations, separated by ultrafiltration, were measured by quality control-validated assays based on liquid chromatography in tandem with mass spectrometry. “The inhibitory quotient was calculated as the ratio of unbound bictegravir or total emtricitabine and tenofovir CSF concentration to half (or 90%) maximal inhibitory concentration for bictegravir (or emtricitabine and tenofovir),” noted the researchers.

Of the 24 patients enrolled, 15 were men. The median age was 45 years and all patients had at least 1 HCI, with progressive multifocal leukoencephalopathy being the most common (46%), followed by cerebral toxoplasmosis (25%), and HIV encephalitis (13%).

The median CSF concentrations for total and unbound bictegravir were 11.8 ng/mL (range, 0.5-44.9 ng/mL) and 4.4 ng/mL (range, 1.6-9.6 ng/mL), respectively. The unbound bictegravir CSF fraction was 34% (range, 15%-82%) and ART diffusion was 0.45%. The researchers observed an inverse relationship between unbound bictegravir CSF fraction and CSF albumin concentrations (r= ˗0.88; P <.0001).

The median CSF concentrations for total emtricitabine and tenofovir were 84.4 ng/mL (range, 28.6-337.4 ng/mL) and 1.6 ng/mL (range, 0.7-4.3 ng/mL), respectively. Thus, ART diffusion was 57.5% and 8.5%, respectively.

There was a significantly decreased CSF inhibitory quotient for wild-type viruses, with a median of less than 2 for the 3 ART agents: 1.3 for bictegravir, 1.7 for emtricitabine, and 0.5 for tenofovir. Only 3 patients had an inhibitory quotient above unity for the 3 ART agents.

For all 3 ART agents, factors that significantly affected the total (or unbound for bictegravir) CSF concentration were patient age and total plasma concentration. Patients older than 51 years of age had significantly increased CSF concentrations of bictegravir (unbound, P =.0356), emtricitabine (P =.0082), and tenofovir (P =.0413).

Despite all patients having HCI, only 4 had an abnormal blood-brain barrier, defined as an albumin quotient greater than 6.8 in those younger than 45 years of age and greater than 10.2 for those older than 45 years.

Limitations of this study included its small sample size and the heterogeneity of the study population.

Given the low diffusion of bictegravir, emtricitabine, and tenofovir “[this ART regimen] should be used with caution as first-line treatment,” the researchers noted. “Further studies combining virologic, immunologic, and pharmacologic follow-up are needed to determine the best [ART] combination to [decrease] neurocognitive manifestations and [progress] toward an HIV cure,” the researchers concluded.

Disclosure: Some author(s) declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of disclosures.


Gelé T, Chéret A, Gordon AC, et al. Cerebrospinal fluid exposure to bictegravir/emtricitabine/tenofovir in HIV-1-infected patients with CNS impairment. J Antimicrob Chemother. Published online September 11, 2021. doi:10.1093/jac/dkab334