Background Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma HIV-1 RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used ART regimens in relation to intrathecal immune activation and CNS penetration effectiveness (CPE) rank. Methods Sixty-nine neurologically asymptomatic subjects treated with ART >6 months and plasma HIV-1 RNA <50 copies/ml were cross-sectionally included in the analysis. ART regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analysed with real-time PCR assays. Neopterin was analysed by ELISA. Results Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median (IQR) 121 (54–213) copies/ml. Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. CPE-rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Conclusions Viral escape in CSF is more common than previously reported, suggesting that low-grade CNS infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice.

ObjectiveTo explore whether hospitalized patients with SARS-CoV-2 and neurologic symptoms have evidence of CNS infection, inflammation and injury using CSF biomarker measurements.MethodsWe assessed CSF SARS-CoV-2 RNA along with CSF biomarkers of intrathecal inflammation (CSF white blood cell count, neopterin, β2-microglobulin (β2M) and immunoglobulin G-index), blood-brain-barrier (BBB) integrity (albumin ratio), and axonal injury (CSF neurofilament light chain protein [NfL]) in 6 patients with moderate to severe COVID-19 and neurologic symptoms who had undergone a diagnostic lumbar puncture. Neurologic symptoms and signs included features of encephalopathies (4/6), suspected meningitis (1/6) and dysgeusia (1/6). SARS-CoV-2 infection was confirmed by rtPCR analysis of nasopharyngeal swabs.ResultsSARS-CoV-2 RNA was detected in the plasma of 2 patients (Cycle threshold [Ct] value 35.0–37.0) and in CSF at low levels (Ct 37.2, 38.0, 39.0) in 3 patients in one but not in a second rtPCR assay. CSF neopterin (median, 43.0 nmol/L) and β2-microglobulin (median, 3.1 mg/L) were increased in all. Median IgG-index (0.39), albumin ratio (5.35) and CSF white blood cell count (<3 cells/µL) were normal in all, while CSF NfL was elevated in 2 patients.ConclusionOur results on patients with COVID-19 and neurologic symptoms suggest an unusual pattern of marked CSF inflammation in which soluble markers were increased but white cell response and other immunologic features typical of CNS viral infections were absent. While our initial hypothesis centered on CNS SARS-CoV-2 invasion, we could not convincingly detect SARS-CoV-2 as the underlying driver of CNS inflammation. These features distinguish COVID-19 CSF from other viral CNS infections, and raise fundamental questions about the CNS pathobiology of SARS-CoV-2 infection.