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Blood-Brain Barrier Impairment in Patients Living with HIV: Predictors and Associated Biomarkers
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7 April 2021 - Giulia Caligaris 1,* , Mattia Trunfio 1 , Valeria Ghisetti 2, Jessica Cusato 1 , Marco Nigra 3, Cristiana Atzori 4, Daniele Imperiale 1, Stefano Bonora 1, Giovanni Di Perri 1 and Andrea Calcagno 1

Despite the substantial changes resulting from the introduction of combination antiretroviral therapy (cART), the prevalence of HIV-associated neurocognitive disorders (HAND) remains substantial. Blood-brain barrier impairment (BBBi) is a frequent feature in people living with HIV (PLWH) and it may persist despite effective antiretroviral treatment. A cross-sectional study was performed in PLWH who underwent lumbar puncture for clinical reasons or research protocols and several cerebrospinal fluid biomarkers were studied. BBBi was defined as cerebrospinal fluid-to-serum albumin ratio (CSAR) >6.5 (<40 years) or >8 (>40 years). We included 464 participants: 147 cART-naïve and 317 on cART. Male sex was prevalent in both groups (72.1% and 72.2% respectively); median age was 44 (38-52) years in naïve and 49 (43-57) years in treated subjects.
BBBi was observed in 35.4% naïve and in 22.7% treated participants; the use of integrase inhibitors was associated with a lower prevalence (18.3 vs. 30.9%, p = 0.050). At multivariate binary logistic regression (including age and sex) nadir CD4 cell count (p = 0.034), presence of central nervous system (CNS) opportunistic infections (p = 0.024) and cerebrospinal fluid (CSF) HIV RNA (p = 0.002) in naïve participants and male sex (p = 0.021), a history of CNS opportunistic infections (p = 0.001) and CSF HIV RNA (p = 0.034) in treated patients were independently associated with BBBi. CSF cells and neopterin were significantly higher in participants with BBBi. BBBi was prevalent in naïve and treated PLWH and it was associated with CSF HIV RNA and neopterin. Systemic control of viral replication seems to be essential for BBB integrity while sex and treatment influence need further studies.
Finally, the mechanism that underlies BBB impairment and HAND is not totally clear. HAND could be a direct consequence of the BBB breakdown by different mechanisms, such as an increased permeability, that allow an increasing entry of virus to CNS [36], or a higher neurotoxicity, caused by an increased drug concentration [37]; furthermore BBB disruption may reflect astrocytes and neurons alteration [8,28]. This is beyond the aim of the current study since we did not specifically analyze the link between BBB integrity and neurocognition.
At multivariate binary logistic regression (including age and sex) we identified nadir CD4 cell count (p = 0.034, for 100 cells/uL increase aOR 1.401, 95% CI 1.026-1.912), presence of CNS opportunistic infections (p = 0.024, aOR 4.193, 95% CI 1.207-14.565) and CSF HIV RNA (p = 0.002, aOR for 1 Log10 increase 1.798, 95% CI 1.245-2.595) in naïve participants.
Aside from the aforementioned factors, we included the use of INSTI in the multivariate model for cART-treated participants: male sex (p = 0.021, aOR 3.230, 95% CI 1.191-8.755), a history of CNS opportunistic infections (p = 0.001, aOR 5.439, 95% CI 2.054-14.405) and CSF HIV RNA (p = 0.034, aOR for 1 Log10 increase 1.336, 95% CI 1.022-1.747) were independently associated with BBBi.
5. Conclusions
BBB impairment is a common finding in PLWH affected by neurological or neurocognitive disorders either with or without suppressive cART. Indeed, BBB plays a critical role in CNS physiology and in neurological disorders, such as neurodegenerative disorders.
We observed higher levels of HIV RNA and neopterin in the CSF of study participants with BBBi, highlighting the significant role of inflammation in the pathogenesis of BBBi. Aside from virological control, female sex was found to be protective: further studies are needed to confirm this finding and to understand thelong-term consequences of an impaired BBB in PLWH.

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