Changes in cerebrospinal fluid proteins across the spectrum of untreated and treated chronic HIV-1 infection.

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers contributed by uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of CSF proteins in HIV-associated dementia (HAD) and neurosymptomatic CSF escape (NSE). These reveal a complex but coherent picture of CSF protein changes with highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of systemic HIV-1 progression that included two common patterns, designated as lymphoid and myeloid patterns, related to principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will supplement this report to provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, advancing the mechanistic understanding of HIV-1-related CNS pathobiology.

The longitudinal characterization of immune responses in COVID-19 patients reveals novel prognostic signatures for disease severity, patients' survival and long COVID.

Introduction: SARS-CoV-2 pandemic still poses a significant burden on global health and economy, especially for symptoms persisting beyond the acute disease. COVID-19 manifests with various degrees of severity and the identification of early biomarkers capable of stratifying patient based on risk of progression could allow tailored treatments. Methods: We longitudinally analyzed 67 patients, classified according to a WHO ordinal scale as having Mild, Moderate, or Severe COVID-19. Peripheral blood samples were prospectively collected at hospital admission and during a 6-month follow-up after discharge. Several subsets and markers of the innate and adaptive immunity were monitored as putative factors associated with COVID-19 symptoms. Results: More than 50 immunological parameters were associated with disease severity. A decision tree including the main clinical, laboratory, and biological variables at admission identified low NK-cell precursors and CD14+CD91+ monocytes, and high CD8+ Effector Memory T cell frequencies as the most robust immunological correlates of COVID-19 severity and reduced survival. Moreover, low regulatory B-cell frequency at one month was associated with the susceptibility to develop long COVID at six months, likely due to their immunomodulatory ability. Discussion: These results highlight the profound perturbation of the immune response during COVID-19. The evaluation of specific innate and adaptive immune-cell subsets allows to distinguish between different acute and persistent COVID-19 symptoms.

A Digital Platform for Home-Based Exercise Prescription for Older People with Sarcopenia.

Digital therapeutics refers to smartphone applications, software, and wearable devices that provide digital solutions to improve healthcare delivery. We developed a digital platform to support the GYM (Grow Your Muscle) study, an ongoing 48-week randomized, controlled trial on reduction of sarcopenia through a home-based, app-monitored physical exercise intervention. The GYM platform consists of a smartphone application including the exercise program and video tutorials of body-weight exercises, a wearable device to monitor heart rate during training, and a website for downloading training data to remotely monitor the exercise. The aim of this paper is to describe the platform in detail and to discuss the technical issues emerging during the study and those related to usability of the smartphone application through a retrospective survey. The main technical issue concerned the API level 33 upgrade, which did not enable participants using the Android operating systems to use the wearable device. The survey revealed some problems with viewing the video tutorials and with internet or smartphone connection. On the other hand, the smartphone application was reported to be easy to use and helpful to guide home exercising. Despite the issues encountered during the study, this digital-supported physical exercise intervention could provide useful to improve muscle measures of sarcopenia.

Serum and CSF biomarkers in asymptomatic patients during primary HIV infection: a randomized study.

It is debated whether central nervous system involvement begins during acute HIV infection in persons without meningitis/encephalitis and if specific antiretroviral drugs or combinations would be beneficial. Neurologically asymptomatic participants enrolled in a randomized and controlled study comparing three combination antiretroviral regimens (tenofovir alafenamide/emtricitabine plus dolutegravir, darunavir or both) during primary HIV infection were enrolled. Serum and cerebrospinal fluid (CSF) were collected at baseline, 12 and 48 (serum only) weeks after treatment initiation. Single Molecule Array was used to measure neurofilament light chain (NFL), total tau protein (Tau), Brain-Derived Neurotrophic Factor (BDNF), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase (UCH-L1). We assessed the longitudinal change in biomarkers over time as well as the change in the prevalence of serum NFL concentrations above previously published age-adjusted cut-offs (7 pg/mL if 5-18 years, 10 pg/mL if 18-51 years, 15 pg/mL if 51-61 years, 20 pg/mL if 61-70 years and 35 pg/mL if >70 years). Serum was available from 47 participants at all time points while CSF was in 13 and 7 participants (baseline/W12). We observed a significant direct serum-to-CSF correlation for NFL (rho = 0.692, p = 0.009), GFAP (rho = 0.659, p = 0.014) and BDNF (rho = 0.587, p = 0.045). Serum (rho = 0.560, p = 0.046) and CSF NFL (rho = 0.582, p = 0.037) concentrations were directly associated with CSF HIV RNA levels. We observed a significant decrease over time in serum NFL (p = 0.006) and GFAP (p = 0.006) but not in the other biomarkers. No significant difference was observed among the treatment arms. At baseline, serum and CSF age-adjusted NFL levels were above age-adjusted cut-offs in 23 (48.9%) and 4 participants (30.8%); considering serum NFL, this proportion was lower at weeks 12 (31.9%, p = 0.057) and 48 (27.7%, p = 0.13). A relevant proportion of neurologically asymptomatic participants had abnormal CSF and serum NFL levels during primary HIV infection. NFL and GFAP decreased in serum following combination antiretroviral therapy without significant differences among the treatment arms.

Changes in Cerebrospinal Fluid Proteins across the Spectrum of Untreated and Treated Chronic HIV-1 Infection.

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers that included uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of the CSF proteins in HIV-associated dementia ( HAD ) and neurosymptomatic CSF escape ( NSE ). These reveal a complex but coherent picture of CSF protein changes that includes highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of neuroasymptomatic systemic HIV-1 progression, including two common patterns, designated as lymphoid and myeloid patterns, related to the principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, and further the mechanistic understanding of HIV-1-related CNS pathobiology.

Biomarkers for progressive multifocal leukoencephalopathy: emerging data for use of JC virus DNA copy number in clinical trials.

Progressive multifocal leukoencephalopathy is a rare but devastating demyelinating disease caused by the JC virus (JCV), for which no therapeutics are approved. To make progress towards addressing this unmet medical need, innovations in clinical trial design are needed. Quantitative JCV DNA in CSF has the potential to serve as a valuable biomarker of progressive multifocal leukoencephalopathy disease and treatment response in clinical trials to expedite therapeutic development, as do neuroimaging and other fluid biomarkers such as neurofilament light chain. Specifically, JCV DNA in CSF could be used in clinical trials as an entry criterion, stratification factor, or predictor of clinical outcomes. Insights from the investigation of candidate biomarkers for progressive multifocal leukoencephalopathy might inform approaches to biomarker development for other rare diseases.

Otitis in Patients With Community-Acquired Bacterial Meningitis: A Nationwide Prospective Cohort Study.

BACKGROUND: Otitis is commonly associated with community-acquired bacterial meningitis, but the role of ear surgery as treatment is debated. In this study, we investigated the impact of otitis and ear surgery on outcome of adults with community-acquired bacterial meningitis. METHODS: We analyzed episodes of adults with community-acquired bacterial meningitis from a nationwide prospective cohort study in the Netherlands, between March 2006 and July 2021. RESULTS: A total of 2548 episodes of community-acquired bacterial meningitis were evaluated. Otitis was present in 696 episodes (27%). In these patients the primary causative pathogen was Streptococcus pneumoniae (615 of 696 [88%]), followed by Streptococcus pyogenes (5%) and Haemophilus influenzae (4%). In 519 of 632 otitis episodes (82%) an ear-nose-throat specialist was consulted, and surgery was performed in 287 of 519 (55%). The types of surgery performed were myringotomy with ventilation tube insertion in 110 of 287 episodes (38%), mastoidectomy in 103 of 287 (36%), and myringotomy alone in 74 of 287 (26%). Unfavorable outcome occurred in 210 of 696 episodes (30%) and in 65 of 696 episodes was fatal (9%). Otitis was associated with a favorable outcome in a multivariable analysis (odds ratio 0.74; 95% confidence interval [CI] .59-.92; P = .008). There was no association between outcome and ear surgery. CONCLUSIONS: Otitis is a common focus of infection in community-acquired bacterial meningitis in adults, with S. pneumoniae being the most common causative pathogen. Presence of otitis is associated with a favorable outcome. Ear surgery's impact on the outcome of otogenic meningitis patients remains uncertain.

Strategies to target the central nervous system HIV reservoir.

PURPOSE OF THE REVIEW: The central nervous system (CNS) is an hotspot for HIV persistence and may be a major obstacle to overcome for curative strategies. The peculiar anatomical, tissular and cellular characteristics of the HIV reservoir in the CNS may need to be specifically addressed to achieve a long-term HIV control without ART. In this review, we will discuss the critical challenges that currently explored curative strategies may face in crossing the blood-brain barrier (BBB), targeting latent HIV in brain-resident myeloid reservoirs, and eliminating the virus without eliciting dangerous neurological adverse events. RECENT FINDINGS: Latency reversing agents (LRA), broadly neutralizing monoclonal antibodies (bNabs), chimeric antigen receptor (CAR) T-cells, and adeno-associated virus 9-vectored gene-therapies cross the BBB with varying efficiency. Although brain penetration is poor for bNAbs, viral vectors for in vivo gene-editing, certain LRAs, and CAR T-cells may reach the cerebral compartment more efficiently. All these approaches, however, may encounter difficulties in eliminating HIV-infected perivascular macrophages and microglia. Safety, including local neurological adverse effects, may also be a concern, especially if high doses are required to achieve optimal brain penetration and efficient brain cell targeting. SUMMARY: Targeting the CNS remains a potential problem for the currently investigated HIV curing strategies. In vivo evidence on CNS effectiveness is limited for most of the investigated strategies, and additional studies should be focused on evaluating the interplay between the cerebral HIV reservoir and treatment aiming to achieve an ART-free cure.

Alterations in glutamate, arginine, and energy metabolism characterize cerebrospinal fluid and plasma metabolome of persons with HIV-associated dementia.

OBJECTIVES: HIV-associated dementia (HAD) is the most severe clinical expression of HIV-mediated neuropathology, and the processes underlying its development remain poorly understood. We aimed to exploit high-dimensional metabolic profiling to gain insights into the pathological mechanisms associated to HAD. DESIGN: In this cross-sectional study, we utilized metabolomics to profile matched cerebrospinal fluid (CSF) and plasma samples of HAD individuals ( n  = 20) compared with neurologically asymptomatic people with HIV (ASYM, n  = 20) and healthy controls (NEG, n  = 20). METHODS: Identification of plasma and CSF metabolites was performed by liquid-chromatography or gas-chromatography following a validated experimental pipeline. The resulting metabolic profiles were analyzed by machine-learning algorithms, and altered pathways were identified by comparison with KEGG pathway database. RESULTS: In CSF, HAD patients displayed an imbalance in glutamine/glutamate ratio, decreased levels of isocitrate and arginine, and increased oxidative stress when compared with ASYM or NEG. These changes were confirmed in matched plasma samples, which in addition revealed an accumulation of eicosanoids and unsaturated fatty acids in HAD individuals. Pathway analysis in both biological fluids suggested that alterations in several metabolic processes, including protein biosynthesis, glutamate and arginine metabolism, and energy metabolism, in association to a perturbed eicosanoid metabolism in plasma, may represent the metabolic signature associated to HAD. CONCLUSION: These findings show that HAD may be associated with metabolic modifications in CSF and plasma. These preliminary data may be useful to identify novel metabolic biomarkers and therapeutic targets in HIV-associated neurological impairment.

Failure of Digital Device Performance in Monitoring Physical Exercise in a Pilot Study in Sedentary Persons with HIV.

Digital devices have gained popularity in the last 10 years as a tool for exercise prescription, the monitoring of daily physical activity, and nutrition for the management of a health-related parameter. Therefore, the aim of this study was to assess the effectiveness of the use of digital devices to monitor exercise data in sedentary persons with HIV who exercise following an individualized activity pacing (AP) protocol on cardiorespiratory fitness body composition, blood lipid profile, and psychological parameters. Twenty-four PLWH were enrolled in an 18-week randomized, open-label, pilot AP exercise protocol. All participants were monitored by a Health Band connected to a mobile app that transmitted the data to a server. At week 3, they were randomized either in an experimental group (EG), in which an open device configuration enabled them to receive training data feedback (n = 12), or continued with no data feedback (control group, n = 12). The primary endpoint was improvement from the baseline of 15% of steady-state oxygen consumption (V˙O2) during a 6-min walking test. Technical issues occurred when pairing the health band with the app, which prevented EG participants from regularly receiving data feedback, and with data transmission to the server, which enabled only 40% monitoring of the total training days. Consequently, the study outcomes could not be compared between the two groups, and participants also lost confidence in the study. However, 19 out of 24 participants completed the AP program. Overall, only 6 (32%) improved steady-state V˙O2, with no significant changes at W18 from the baseline. Significant reductions were observed of BMI (p = 0.040), hip circumference (p = 0.027), and total-(p = 0.049) and HDL-cholesterol (p = 0.045). The failure of digital device performance substantially affected study procedures, monitoring, and participants' engagement, and likely limited the potential benefits of the AP exercise program.

Exploring the Association between Delirium and Malnutrition in COVID-19 Survivors: A Geriatric Perspective.

Older individuals face an elevated risk of developing geriatric syndromes when confronted with acute stressors like COVID-19. We assessed the connection between in-hospital delirium, malnutrition, and frailty in a cohort of COVID-19 survivors. Patients aged ≥65, hospitalized in a tertiary hospital in Milan for SARS-CoV-2 pneumonia, were enrolled and screened for in-hospital delirium with the 4 'A's Test (4AT) performed twice daily (morning and evening) during hospital stay. Malnutrition was assessed with the malnutrition universal screening tool (MUST) at hospital admission and with the mini-nutritional assessment short-form (MNA-SF) one month after hospital discharge. Frailty was computed with the frailty index one month after hospital discharge. Fifty patients (median age 78.5, 56% male) were enrolled. At hospital admission, 10% were malnourished. The 13 patients (26%) who developed delirium were frailer (7 vs. 4), experienced a higher in-hospital mortality (5 vs. 3), and were more malnourished one month after discharge (3 of the 4 patients with delirium vs. 6 of the 28 patients without delirium who presented at follow up). The 4AT scores correlated with the MNA-SF scores (r = -0.55, p = 0.006) and frailty (r = 0.35, p = 0.001). Frailty also correlated with MUST (r = 0.3, p = 0.04), MNA-SF (r = -0.42, p = 0.02), and hospitalization length (r = 0.44, p = 0.001). Delirium, malnutrition, and frailty are correlated in COVID-19 survivors. Screening for these geriatric syndromes should be incorporated in routine clinical practice.

Major revision version 12.0 of the European AIDS Clinical Society guidelines 2023.

BACKGROUND: The European AIDS Clinical Society (EACS) guidelines were revised in 2023 for the 19th time, and all aspects of HIV care were updated. KEY POINTS OF THE GUIDELINES UPDATE: Version 12.0 of the guidelines recommend the same six first-line treatment options for antiretroviral treatment (ART)-naïve adults as versions 11.0 and 11.1: tenofovir-based backbone plus an unboosted integrase inhibitor or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. The long-acting section has been expanded in the ART and drug-drug interaction (DDI) panels. Tables for preferred and alternative ART in children and adolescents have been updated, as has the section on prevention of vertical transmission, particularly with new guidance for breastfeeding. A new DDI table has been included for the ART and anti-infective drugs used for opportunistic infections, sexually transmitted infections, and other infectious conditions; lenacapavir has been included in all DDI tables. New sections on alcohol use and patient-reported outcome measures (PROMs) have been included in the comorbidity panel, in addition to updates on many relevant topics, such as new resource guidance for deprescribing in people with HIV. Other sections, including travel, cognitive impairment, cancer screening, sexual health, and diabetes have also been revised extensively. The algorithm for the management of acute hepatitis C virus infection has been removed, as current guidelines recommend immediate treatment of all people with recently acquired hepatitis C virus. Updates on vaccination for hepatitis B virus and recommendations for simplification to tenofovir-free two-drug regimens in people with isolated anti-hepatitis B core antibodies are provided. In the opportunistic infections and COVID-19 panel, guidance on the management of COVID-19 in people with HIV has been updated according to the most up-to-date evidence, and a new section on monkeypox has been added. CONCLUSIONS: In 2023, the EACS guidelines were updated extensively and now include several new sections. The recommendations are available as a free app, in interactive web format, and as a pdf online.

High-dose anakinra in addition to standard of care including corticosteroids in patients with severe COVID-19 treated with non-invasive ventilation.

Management of COVID-19 patients experiencing persisting respiratory failure despite corticosteroids remains challenging. Data on high-dose intravenous anakinra (HD-ANK) in this context are lacking. We aimed to investigate the impact of HD-ANK on mortality in COVID-19 patients progressing to non-invasive ventilation (NIV) while receiving corticosteroids. We retrospectively analyzed the impact of HD-ANK on 28-day mortality in individuals hospitalized with COVID-19 necessitating NIV after corticosteroid initiation. A total of 256 patients were identified: 146 received standard-of-care only (SOC), and 110 received HD-ANK+SOC. The groups were well-balanced at baseline. In-hospital mortality at 28 days did not differ between the two groups. HD-ANK is not beneficial in patients with severe COVID-19 deteriorating despite corticosteroids.

Cognitive impairment in people living with HIV: consensus recommendations for a new approach.

Current approaches to classifying cognitive impairment in people living with HIV can overestimate disease burden and lead to ambiguity around disease mechanisms. The 2007 criteria for HIV-associated neurocognitive disorders (HAND), sometimes called the Frascati criteria, can falsely classify over 20% of cognitively healthy individuals as having cognitive impairment. Minimum criteria for HAND are met on the basis of performance on cognitive tests alone, which might not be appropriate for populations with diverse educational and socioeconomic backgrounds. Imprecise phenotyping of cognitive impairment can limit mechanistic research, biomarker discovery and treatment trials. Importantly, overestimation of cognitive impairment carries the risk of creating fear among people living with HIV and worsening stigma and discrimination towards these individuals. To address this issue, we established the International HIV-Cognition Working Group, which is globally representative and involves the community of people living with HIV. We reached consensus on six recommendations towards a new approach for diagnosis and classification of cognitive impairment in people living with HIV, intended to focus discussion and debate going forward. We propose the conceptual separation of HIV-associated brain injury - including active or pretreatment legacy damage - from other causes of brain injury occurring in people living with HIV. We suggest moving away from a quantitative neuropsychological approach towards an emphasis on clinical context. Our recommendations are intended to better represent the changing profile of cognitive impairment in people living with HIV in diverse global settings and to provide a clearer framework of classification for clinical management and research studies.

Biotypes of Central Nervous System Complications in People With Human Immunodeficiency Virus: Virology, Immunology, and Neuropathology.

Despite viral suppression with antiretroviral therapy (ART), people with human immunodeficiency virus (HIV) continue to experience central nervous system (CNS) complications, primarily in the form of mild cognitive impairment and mental health disorders (eg, depression, anxiety, other neuropsychiatric problems). The multifactorial pathogenesis and heterogeneity of mechanisms likely underlying CNS complications must be addressed in the development of preventive interventions and effective treatments. The biotyping approach has previously been useful to define phenotypes of other CNS diseases based on underlying mechanisms and could be translated to the field of neuroHIV. The purpose of the Biotype Workshop series, and the Virology, Immunology and Neuropathology Working Group in particular, is to capitalize on current and new technologies and guide future research efforts using the wealth of available immunological, virologic, and neuropathological data collected from people with HIV on and off ART.

Inflammation burden score in multidrug-resistant HIV-1 infection.

OBJECTIVES: Four-class drug-resistant (4DR) people living with HIV (PLWH) are a fragile population with a high burden of disease. No data on their inflammation and T-cell exhaustion markers are currently available. METHODS: Inflammation, immune activation and microbial translocation biomarkers were measured through ELISA in 30 4DR-PLWH with HIV-1 RNA ≥ 50 copies/mL, 30 non-viremic 4DR-PLWH and 20 non-viremic non-4DR-PLWH. Groups were matched by age, gender and smoking habit. T-cell activation and exhaustion markers were assessed by flow cytometry in 4DR-PLWH. An inflammation burden score (IBS) was calculated from soluble marker levels and associated factors were estimated through multivariate regression. RESULTS: The highest plasma biomarker concentrations were observed in viremic 4DR-PLWH, the lowest ones in non-4DR-PLWH. Endotoxin core immunoglobulin G showed an opposite trend. Among 4DR-PLWH, CD38/HLA-DR and PD-1 were more expressed on CD4+ (p = 0.019 and 0.034, respectively) and CD8+ (p = 0.002 and 0.032, respectively) cells of viremic compared to non-viremic subjects. An increased IBS was significantly associated with 4DR condition, higher values of viral load and a previous cancer diagnosis. CONCLUSIONS: Multidrug-resistant HIV infection is associated with a higher IBS, even when viremia is undetectable. Therapeutic approaches aimed to reduce inflammation and T-cell exhaustion in 4DR-PLWH need to be investigated.

Long-acting drugs: people's expectations and physicians' preparedness. Are we readying to manage it? An Italian survey.

To evaluate patients' expectations regarding long-acting antiretroviral agents and preferences about where to receive them. Multicenter cross-sectional survey-based study. Through an online survey, we asked people living with human immunodeficiency virus to judge their relationship with daily antiretroviral therapy (ART) and to give their opinion about long-acting drugs. We also collected data regarding the age of the patients, their site of follow-up, time since the diagnosis, and compliance to ART. Two hundred forty-two patients aged 18 to 79 years were included in the study: 58 (24%) females, 182 (75.2%) males, and 2 (0.8%) male-to-female transgenders. 81.8% of the said population had a good relationship with ART. 33.6% of them consider daily ART an obligation and a restriction to their freedom. One hundred forty-three (59.1%) patients already knew about long-acting drugs before our interview, and 215 (88.8%) patients were interested in it. One hundred fifty-six (64.4%) interviewees said they would still be interested in hospital-available injective long-acting drugs, although 57.9% of the patients would rather receive them at home. The data emerging from our survey reveal that around 90% of the people living with HIV are interested in changing their actual treatment with a long-acting one. Moreover, for the first time to our knowledge, such a high number of patients showed an enthusiastic response to the new opportunity to be treated directly at home. The introduction of these new drugs could be revolutionary and represents an important step toward treatment simplification.