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Modern antiretroviral therapy (ART) has increased longevity of people with HIV and shifted the age distribution of the HIV pandemic upward toward that of the general population. This positive development has also led to concerns about premature and/or accelerated neurocognitive and physical ageing due to the combined effects of chronic HIV, accumulating comorbidities, adverse effects or possible toxicities of ART and biological ageing. Here we present results of comprehensive assessments over 12 years of 402 people with HIV in the CNS HIV ART Effects Research (CHARTER) programme, who at follow-up were composed of younger ( Over the 12 years, ART use and viral suppression increased in both subgroups as did systemic and psychiatric comorbidities; participants in both subgroups also evidenced neurocognitive decline beyond what is expected in typical ageing. Contrary to expectations, all these adverse effects were comparable in the younger and older CHARTER subgroups, and unrelated to chronological age. Neurocognitive decline was unrelated to HIV disease or treatment characteristics but was significantly predicted by the presence of comorbid conditions, specifically diabetes, hypertension, chronic pulmonary disease, frailty, neuropathic pain, depression and lifetime history of cannabis use disorder. These results are not consistent with premature or accelerated neurocognitive ageing due to HIV itself but suggest important indirect effects of multiple, potentially treatable comorbidities that are more common among people with HIV than in the general population. Good medical management of HIV disease did not prevent these adverse outcomes, and increased attention to a range of comorbid conditions in people with HIV may be warranted in their care.

Background Neurofilament light (NFL) chain concentrations, reflecting axonal damage, are seen in several polyneuropathies but have not been studied in human immunodeficiency virus (HIV) distal sensory polyneuropathy (DSP). We evaluated NFL in cerebrospinal fluid (CSF) and plasma in relation to DSP in people with HIV (PWH) from 2 independent cohorts and in people without HIV (PWoH). Methods Cohort 1 consisted of PWH from the CHARTER Study. Cohort 2 consisted of PWH and PWoH from the HIV Neurobehavioral Research Center (HNRC). We evaluated DSP signs and symptoms in both cohorts. Immunoassays measured NFL in CSF for all and for plasma as well in Cohort 2. Results Cohort 1 consisted of 111 PWH, mean ± SD age 56.8 ± 8.32 years, 15.3% female, 38.7% Black, 49.6% White, current CD4+ T-cells (median, interquartile range [IQR]) 532/µL (295, 785), 83.5% with plasma HIV RNA ≤50 copies/mL. Cohort 2 consisted of 233 PWH of similar demographics to PWH in Cohort 1 but also 51 PWoH, together age 58.4 ± 6.68 years, 41.2% female, 18.0% Black, Hispanic, non-Hispanic White 52.0%, 6.00% White. In both cohorts of PWH, CSF and plasma NFL were significantly higher in both PWH with DSP signs. Findings were similar, albeit not significant, for PWoH. The observed relationships were not explained by confounds. Conclusions Both plasma and CSF NFL were elevated in PWH and PWoH with DSP. The convergence of our findings with others demonstrates that NFL is a reliable biomarker reflecting peripheral nerve injury. Biomarkers such as NFL might provide, validate, and optimize clinical trials of neuroregenerative strategies in HIV DSP.

Background Neurosyphilis (NS) is increasing in prevalence in the U.S. but remains challenging to diagnose, particularly in asymptomatic cases. Uncovering central nervous system (CNS) specific immune pathways may shed light on disease pathogenesis and potential biomarkers. Methods Paired cerebrospinal fluid and blood were collected from participants with syphilis without neurological symptoms from 2013–2019. Participants were categorized as NS if CSF VDRL was positive and matched by RPR and date of enrollment to participants without neurosyphilis (non-NS), defined by VDRL negative and CSF WBC < 5/uL. Paired CSF and plasma were run on a 71-plex chemokine/cytokine array, high-sensitivity (SIMOA) ELISA for markers of neuronal and astrocyte injury, and ELISA for neopterin, a marker of intrathecal macrophage/microglial activation. Comparisons between NS and non-NS were made using T-tests and Wilcoxon rank-sum tests, with p-values adjusted (FDR) for multiple comparisons. Results 24 participants were enrolled with characteristics as in Table 1. HIV status, age, race/ethnicity, and plasma RPR values did not significantly differ by group. Six cytokines were significantly (p< 0.05, FDR < 0.10) different in the CSF in NS compared to non-NS, including MIG/CXCL9, IP-10/CXCL10, macrophage-derive-chemokine (MDC), IL-8/CXCL8 and BCA-1/CXCL13, which was previously recognized as elevated in NS (Figure 1B). Neopterin, but no neuronal or astrocyte markers, was elevated in the CSF of NS versus non-NS (p < 0.001) (Figure 1A). After adjusting for multiple comparisons, there were no significant differences between markers in plasma of NS vs non-NS. Differences between NS and non-NS groups were not affected by HIV status. Conclusion There is a distinct and compartmentalized CNS immune response occurring in individuals with NS, as indicated by elevated markers of CNS inflammation and of key chemoattractants, the CXC family of proteins. Elevation of neopterin, but not neuronal injury markers suggest asymptomatic disease elicits an immune response without incurring neuronal damage. These immune biomarkers can provide insight into neuroinflammatory processes during asymptomatic NS and should be explored as potential CSF biomarkers of NS. Disclosures Magnus Gisslen, MD, PhD, Amgen: Honoraria|AstraZeneca: Advisor/Consultant|AstraZeneca: DSMB membership|Biogen: Honoraria|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Honoraria|GlaxoSmithKline/ViiV: Advisor/Consultant|GlaxoSmithKline/ViiV: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Novo Nordic: Honoraria|Novocure: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Sanofi: Honoraria.

Lumbar puncture is recommended for individuals with syphilis who have neurological symptoms; however, symptoms have poor sensitivity for predicting symptomatic neurosyphilis. Neurofilament light chain (NfL) is a marker for neuroaxonal injury; cerebrospinal fluid concentrations are higher in symptomatic neurosyphilis than in uncomplicated syphilis or asymptomatic neurosyphilis. Serum NfL was quantified in 20 individuals with uncomplicated syphilis, 10 with asymptomatic neurosyphilis and 10 with symptomatic neurosyphilis using an ultrasensitive single-molecule array assay; it was repeated a median of 12.5 months after neurosyphilis therapy. Serum NfL concentration was age-adjusted using a published formula. Age-adjusted serum NfL concentration was significantly higher in symptomatic neurosyphilis compared with each of the other 2 groups. It was above the highest value in uncomplicated syphilis in 1 of 10 participants with asymptomatic neurosyphilis and 3 of 10 with symptomatic neurosyphilis. Serum NfL concentration increased in 1 participant with asymptomatic neurosyphilis with possible treatment failure. If confirmed in a larger study, serum NfL may be a useful adjunct for identifying central nervous system infection by Treponema pallidum .

Although plasma D-dimer levels are high in patients with some types of peripheral neuropathy, this has not been examined in people with HIV (PWH). We tested the hypothesis that higher plasma D-dimer levels would be related to the presence and severity of HIV-associated distal sensory peripheral neuropathy (DSP). Participants in a U.S. research cohort were evaluated using standardized clinical examinations and interviews for findings of DSP and distal neuropathic pain by trained clinicians. D-dimer levels in the two neuropathy groups (0 or 1 versus 2 or more neuropathy signs), were compared using the Wilcoxon rank sum test. Multivariable regression assessed the effects of age and other covariates. Participants were 185 PWH, mean (SD) age 56.2 (8.10), 19.7% females, 56.4% non-White, median nadir and current CD4 lymphocytes 107 (IQR 20, 210) and 567 (348, 817), undetectable plasma HIV RNA 79.9%; and 210 people without HIV (PWoH), mean age 50.6 (15.8) years, 38.6% female, 18.1% non-White. Among PWH, 50 had 0 signs, 47 had 1 and 88 had 2 or more; among PWoH, 149 had 0 signs, 38 had 1 sign, and 23 had 2 or more signs (PWH versus PWoH p = 1.36e-20). Log10 plasma D-dimer levels were higher in PWH than PWoH (2.78±0.233 versus 2.66±0.253, p = 5.20e-6). D-dimer was significantly higher in those with DSP (2 or more DSP signs) compared to those without (p = 0.0017, Wilcoxon rank sum test). In multivariable analyses this relationship was independent of potential confounders. This association persisted in a sensitivity analysis that was limited to only the subset of participants with undetectable plasma HIV RNA (Wilcoxon p = 0.041). In PWoH, d-dimer levels were numerically higher in those with DSP (2.75±0.206 versus 2.65±0.256, p = 0.0604). Neuropathy symptoms (pain, paresthesias) were not significantly related to D-dimer levels. Since DSP is a major cause of disability in PWH, identifying biomarkers such as D-dimer may enable future investigations to assess prognosis or response to therapy.

Human immunodeficiency virus (HIV) infection is potentially associated with premature aging, but demonstrating this is difficult due to a lack of reliable biomarkers. The mitochondrial (mt) DNA "common deletion" mutation (mtCDM) is a 4977-bp deletion associated with aging and neurodegenerative diseases. We examined how mtDNA and mtCDM correlate with markers of neurodegeneration and inflammation in people with and without HIV (PWH and PWOH). Data from 149 adults were combined from two projects involving PWH (n = 124) and PWOH (n = 25). We measured buccal mtDNA and mtCDM by digital droplet PCR and compared them to disease and demographic characteristics and soluble biomarkers in cerebrospinal fluid (CSF) and blood measured by immunoassay. Participants had a median age of 52years, with 53% white and 81% men. Median mtDNA level was 1,332 copies/cell (IQR 1,201-1,493) and median mtCDM level was 0.36 copies × 102/cell (IQR 0.31-0.42); both were higher in PWH. In the best model adjusting for HIV status and demographics, higher mtDNA levels were associated with higher CSF amyloid-β 1-42 and 8-hydroxy-2'-deoxyguanosine and higher mtCDM levels were associated with higher plasma soluble tumor necrosis factor receptor II. The differences in mtDNA markers between PWH and PWOH support potential premature aging in PWH. Our findings suggest mtDNA changes in oral tissues may reflect CNS processes, allowing the use of inexpensive and easily accessible buccal biospecimens as a screening tool for CSF inflammation and neurodegeneration. Confirmatory and mechanistic studies on mt genome alterations by HIV and ART may identify interventions to prevent or treat neurodegenerative complications.