P8. Asymptomatic Cerebrospinal Fluid Viral Escape During ART is Associated with Increased Intrathecal Immune Activation.

Arvid Edén1, Staffan Nilsson2, Lars Hagberg1, Dietmar Fuchs3, Henrik Zetterberg1,4, Bo Svennerholm1, Magnus Gisslén1

Affiliates: 1Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden, 2Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden, 3Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Austria, 4Institute of Neurology, University College London, UK

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Background
Asymptomatic cerebrospinal fluid (CSF) viral escape, where HIV-1 RNA is increased in CSF while suppressed in plasma, has previously been shown to occur infrequently in patients responding well to antiretroviral therapy (ART). However, it is unclear if asymptomatic CSF viral escape is benign or represents an active CNS infection in some patients, and may represent a risk for future neurological injury. We examined the relationship between asymptomatic CSF viral escape and CSF biomarkers of axonal injury (the light subunit of neurofilament protein, NFL) and intrathecal immune activation (neopterin) in a longitudinal cohort of subjects responding well to ART.

Methods
Patients on effective ART ≥6 months with plasma HIV-1 RNA <50 c/ml at inclusion, followed with ≥2 lumbar punctures for CSF analysis were identified from a longitudinal study. Subjects with CNS opportunistic infections or other significant CNS disease were excluded from the analysis. Transient low increases in plasma viral load (“blips”) during the study period were allowed. HIV-1 RNA was analyzed with real-time PCR (Cobas TaqMan v2, Roche) with a lower level of quantification (LLQ) of 20 c/ml. CSF concentrations of NFL and neopterin were measured by ELISA. Mann Whitney U-test or t-test was used for group wise comparisons, and continuous variables were log10 transformed where appropriate for the tests used.

Results
Seventy-five (52 male, 23 female) neuro-asymptomatic patients on ART with in median (IQR) 5 (3-8) available CSF samples were included in the analysis. Median (IQR) treatment time, and time with plasma HIV-1 RNA LLQ was 50 (32-77) c/ml. 42 (56%) patients also had ≥1 transient HIV-1 RNA >20 c/ml (median 44, IQR 29-71 c/ml) in plasma. CSF neopterin was higher in samples with quantifiable CSF RNA (median 7.2, IQR 4.9-10.5 nmol/l) than with CSF RNA <LLQ (median 6.5, IQR 5.2-7.7 nmol/l) (pLLQ.

Conclusion
In this longitudinal analysis, occasional increase in CSF HIV-1 RNA was present in a substantial minority (36%) of patients on ART, although less frequent than in plasma. Asymptomatic CSF viral escape was associated with increased intrathecal immune activation measured by neopterin, but not with neuronal injury measured by NFL, suggesting that increased CSF virus and immune activation does not result in CNS axonal injury in patients on ART, at least not in the short term.