Wild-Type AmpC Beta-Lactamase-Producing Enterobacterales Are a Risk Factor for Empirical Treatment Failure in Patients with Bloodstream Infection.

Introduction: Beta-lactamases are frequently prescribed for Gram-negative bloodstream infections (BSIs). However, chromosomally encoded AmpC-producing Enterobacterales (AE) could overproduce beta-lactamases when exposed to third-generation cephalosporins (3GCs), with a risk of clinical failure. There are few available in vivo data on the subject. Our goal was to assess the potential role of AE as a predictive factor for clinical failure in patients with BSIs. Materials and Methods: We retrospectively analyzed patients admitted to Cannes hospital between 2021 and 2022 for BSIs due to Enterobacterales. Patient demographics, comorbidities, and main clinical and laboratory parameters during hospitalization were collected. The risk factors for clinical instability after 48 h or death, as well as for ineffective initial empirical therapy, were assessed using univariate and multivariate analyses. Results: From January 2021 to December 2022, 101 subjects were included (mean age 79 years, 60% men, 97% with comorbidities, 17% with healthcare-associated infection, 13% with septic shock, 82% with qPitt severity score < 2, 58% with urinary tract infection, and 18% with AE). Septic shock [adjusted odds ratio (ORadj) = 5.30, 95% confidence interval (CI): 1.47-22.19, p = 0.014] and ineffective initial empirical therapy [ORadj 5.54, 95% CI: 1.95-17.01, p = 0.002] were independent predictive factors for clinical instability or death. Extended-spectrum beta-lactamases [ORadj 9.40, 95% CI: 1.70-62.14, p = 0.012], AE group [ORadj 5.89, 95% CI: 1.70-21.40, p = 0.006], and clinical instability or death [ORadj 4.71, 95% CI: 1.44-17.08, p = 0.012] were independently associated with ineffective empirical therapy. Conclusions: Infection with AE was associated with treatment failure. Empirical therapy may result in failure if restricted to 3GC.

Immune response to BNT162b2 SARS-CoV-2 vaccine in patients living with HIV: The COVIH-DAPT study.

Introduction: Data on immune response to SARS-CoV-2 vaccine in patients living with HIV (PLWH) over a period longer than 3 months are currently limited. We measured the immune response after BNT162b2 vaccination against SARS-CoV-2 in this population. Methods: We prospectively enrolled PLWH on successful antiretroviral therapy, initiating vaccination with two doses of the BNT162b2 SARS-CoV-2 vaccine administered at six-week interval. SARS-CoV-2 humoral and cellular responses and lymphocyte cell subsets were recorded at inclusion and 6 weeks (W6), 3 months (M3) and 6 months (M6) later. Humoral, humoral strong and cellular responders were defined by IgG titers >10, ≥264BAU/mL and IFN-γ T cell release, respectively. Results: Nineteen subjects without SARS-CoV-2 infection were included (74% men, mean age 51 years, CD4 nadir 399/mm3). All subjects were humoral responders, their antibody titer peak reached at M3. Strong responders' rates were 63% and 21% at M3 and M6, respectively. CD19+CD10+ B cells had increased significantly at W6 then decreased at M3, while CD19+CD27+ B cells remained unchanged. Rates of patients with a cellular response increased from 39% at W6 to 69% at M6. Cellular responders had significantly higher CD3+, CD4+ and CD8+ Effector Memory cells at inclusion (p=0.048, p=0.024, p=0.012, respectively) and CD4+ Terminally Differentiated Effector Memory cells at M3 (p=0.044). Discussion: PLWH have a robust immune response after SARS-CoV-2 vaccination, but a rapid decline in humoral response from 3 months onwards, due to a blunted memory B cell response. Analysis of lymphocyte subsets may help identify optimal times for vaccine boosters.

Treatment of long-term catheter-related bloodstream infections with short-course Daptomycin lock and systemic therapy associated with Taurolidine-lock: A multicenter experience.

PURPOSE: Few studies describe the efficacy of antibiotic lock therapy (ALT) in long-term catheter-related bloodstream (CRBSI) infections. We applied local protocols combining Daptomycin (DPT) and Taurolidine ALT, associated with systemic antibiotic treatment (SAT), for conservative management of coagulase-negative Staphylococci (CoNS) CRBSI. METHODS: Patients admitted for CoNS-associated CRBSI and treated with DPT and Taurolidine as ALT were retrospectively analyzed. Success was defined as catheter retention 30 days after ending treatment. Catheter removal within 30 days was considered as failure. RESULTS: From April 2018 to September 2021, 22 subjects with CoNS-associated-CRBSI were included (95% with cancer, mean age 64 years, 59% male). Staphylococcus epidermidis was isolated in 82% of cases. Mean duration of DPT was 3.9 and 3 days as ALT and SAT, respectively. SAT also included Rifampin for 3 days. Taurolidine ALT was started on day 4 and was combined with oral SAT, that is, either Linezolid or Tedizolid. Mean duration of Taurolidine was 10.5 days, while total antibiotic treatment lasted 13.5 days. Clinical success and failure rates were 95% and 5%, respectively. DISCUSSION: Short course DPT as ALT, combined with SAT and Taurolidine ALT, allowed high rates of conservative management of catheters in case of CoNS-associated-CRBSI.

Accurate Detection of SARS-CoV-2 by Next-Generation Sequencing in Low Viral Load Specimens.

As new SARS-CoV-2 variants emerge, there is an urgent need to increase the efficiency and availability of viral genome sequencing, notably to detect the lineage in samples with a low viral load. SARS-CoV-2 genome next-generation sequencing (NGS) was performed retrospectively in a single center on 175 positive samples from individuals. An automated workflow used the Ion AmpliSeq SARS-CoV-2 Insight Research Assay on the Genexus Sequencer. All samples were collected in the metropolitan area of the city of Nice (France) over a period of 32 weeks (from 19 July 2021 to 11 February 2022). In total, 76% of cases were identified with a low viral load (Ct ≥ 32, and ≤200 copies/µL). The NGS analysis was successful in 91% of cases, among which 57% of cases harbored the Delta variant, and 34% the Omicron BA.1.1 variant. Only 9% of cases had unreadable sequences. There was no significant difference in the viral load in patients infected with the Omicron variant compared to the Delta variant (Ct values, p = 0.0507; copy number, p = 0.252). We show that the NGS analysis of the SARS-CoV-2 genome provides reliable detection of the Delta and Omicron SARS-CoV-2 variants in low viral load samples.

Correlation between CD4/CD8 ratio and neurocognitive performance during early HIV infection.

INTRODUCTION: CD4/CD8 ratio is a marker of immune activation in HIV infection and has been associated with neurocognitive performance during chronic infection, but little is known about the early phases. The aim of this study was to examine the relationship between blood CD4/CD8 ratio and central nervous system endpoints in primary HIV infection (PHI) before and after antiretroviral treatment (ART). METHODS: This was a retrospective analysis of the Primary Infection Stage CNS Events Study (PISCES) cohort. We longitudinally assessed blood and cerebrospinal fluid (CSF) markers of inflammation, immune activation and neuronal injury, and neuropsychological testing performance (NPZ4, an average of three motor and one processing speed tests, and a summarized total score, NPZ11, including also executive function, learning and memory) in ART-naïve participants enrolled during PHI. Spearman correlation and linear mixed models assessed the relationships between the trajectory of CD4/CD8 ratio over time and neurocognitive performance, blood and CSF markers of immune activation and neuronal injury. RESULTS: In all, 109 PHI participants were enrolled. The mean CD4/CD8 ratio decreased with longer time from infection to starting treatment (p < 0.001). Every unit increase in NPZ4 score was independently associated with a 0.15 increase in CD4/CD8 ratio (95% CI: 0.002-0.29; p = 0.047), whereas no correlation was found between CD4/CD8 ratio and NPZ11. Among the cognitive domains, only a change in processing speed was correlated with CD4/CD8 ratio over time (p = 0.03). The trajectory of the CD4/CD8 ratio was negatively correlated with change in CSF neurofilament light chain (p = 0.04). CONCLUSIONS: The trajectory of CD4/CD8 ratio was independently associated with motor/psychomotor speed performance, suggesting that immune activation is involved in brain injury during the early stages of the infection.

Inflammatory Markers after Switching to a Dual Drug Regimen in HIV-Infected Subjects: A Two-Year Follow-Up.

Objective: Immunadapt is a study evaluating the impact of combination antiretroviral treatment (cART) simplification on immune activation. We previously showed that switching to dual therapies could be associated six months later with macrophage activation. Followup continued up to 24 months after treatment simplification. Materials and Methods: Immunadapt is a prospective single arm study of successfully treated subjects simplifying cART from triple to dual regimens. Before cART change, at 6 months, and between 18 and 24 months following the switch, we measured IP-10, MCP-1, soluble CD14 (sCD14), soluble CD163 (sCD163), and lipopolysaccharide binding protein. Patients were stratified according to lower or greater likelihood of immune activation (CD4 nadir < 200, previous AIDS-defining event or very-low-level viremia during follow-up). Variables were compared using matched Wilcoxon tests. Results: From April 2019 to September 2021, 14 subjects were included (mean age 60 years, 12 men, 26 years since HIV infection, CD4 nadir 302 cells/mm3, 18 years on cART, 53 months on last cART). Twenty-one months following the switch, all but one subject maintained their viral load < 50 cp/mL. One subject had two viral blips. For the entire population, the sCD163 values increased significantly from baseline (+36%, p = 0.003) and from 6 months after the switch. The other markers did not change. After 6 months, the sCD163 increase was more pronounced in subjects with greater likelihood of immune activation (+53% vs. +19%, p = 0.026) Conclusions: cART simplification to dual therapy was associated with macrophage activation despite successful virological control after almost two years' follow-up. This was more pronounced in those at risk of immune activation.

Prevalence and Main Clinical Characteristics of Fully Vaccinated Patients Admitted to Hospital for Delta Variant COVID-19.

Objectives: The Delta variant of the novel beta coronavirus responsible for the current coronavirus pandemic (COVID-19) spread across Europe during the summer of 2021. Little is known of vaccine efficacy on this variant. Our aim was to study the prevalence and clinical characteristics of fully vaccinated subjects admitted to hospital for Delta variant COVID-19. Methods: We identified patients admitted to Cannes hospital for Delta-variant-related Covid-19 infection from July to September 2021. Their main demographic parameters, inflammatory markers, and clinical characteristics were recorded. Differences between fully vaccinated subjects and unvaccinated or incompletely vaccinated individuals were analyzed. Results: We included 126 patients (57% male, mean age 64 years, mean delay since symptoms onset 7.8 days). Among admitted patients, 94 (75%) were not vaccinated, 11 (8%) incompletely so and 21 (17%) were fully vaccinated. Fully vaccinated patients were older (77 vs. 61 vs. 62 years, p = 0.003), with fewer days since symptoms onset (5.9 vs. 8.0 vs. 9.3 days, p = 0.035) than unvaccinated or incompletely vaccinated patients, respectively. Severe pneumonia was less frequent among completely vaccinated subjects (67 vs. 84 vs. 100%, p = 0.038), while rates of transfer to the ICU, mechanical ventilation or death did not differ. Thirteen fully vaccinated patients underwent a thoracic CT scan, revealing involvement of lung parenchyma in four of them. Discussion: Prevalence of hospitalization for Delta-variant COVID-19 in fully vaccinated subjects was low and, despite their age and comorbid conditions, these patients had a high rate of favorable outcome.

Switching to a Dual-Drug Regimen in HIV-Infected Patients Could Be Associated With Macrophage Activation?

Objectives: The aim of this study was to evaluate the effect on immune activation of switching from a triple-drug to a dual-drug regimen in HIV-1 infected patients on successful combination antiretroviral treatment (cART). Immunadapt is a prospective study evaluating the impact of cART simplification on immune activation. Methods: We prospectively collected blood samples in HIV-1 infected patients on stable and successful cART switching from triple to dual regimens as a simplifying strategy. We compared immune activation markers: high sensitivity CRP, IL-1, IL-6, IL-8, IP-10, MCP-1, TNF-alpha, soluble CD14 (sCD14), soluble CD163 (sCD163), lipopolysaccharide binding protein, and D-dimer before cART change and at least 6 months after the switch. Patients were stratified according to low or high risk factors of immune activation (low CD4 nadir, previous AIDS-defining condition or very-low-level viremia during follow-up). Results: From April 2019 to May 2020, 20 subjects were included (mean age 57 years, 25 years since HIV infection, CD4 666 cells/mm3, CD8 766 cells/mm3, CD4/CD8 0.94, CD4 nadir 326 cells/mm3, 15% with AIDS, 18 years on cART, 6 cART regimens received, current cART duration: 56 months). Fourteen patients were prescribed Dolutegravir + Rilpivirine and six received Dolutegravir + Lamivudine. After 6.9 months, a significant sCD163 increase (+ 25.5% vs. + 0.5%, p = 0.02) was observed in subjects with high risk factors, despite maintaining a viral load <50 cp/ml. Conclusion: cART simplification in favor of dual therapy is associated with macrophage activation in patients at risk of immune activation despite sustained virological control. Risk factors should thus be considered before generalizing such strategies.

Patients Admitted for Variant Alpha COVID-19 Have Poorer Outcomes than Those Infected with the Old Strain.

OBJECTIVES: The variant alpha COVID-19 rapidly spread across Europe in early 2021. While this variant's increased infectivity has been proven, little is known of its clinical presentation and outcomes compared to the old strain. METHODS: We identified patients admitted to the Cannes General Hospital for variant alpha-related COVID-19 infection from January to April 2021. Their main demographic parameters, inflammatory markers and clinical characteristics were recorded. Patients admitted from October to December 2020 for 20E (EU1) COVID-19 were selected as controls. Differences between groups were analyzed. RESULTS: We included 157 patients (mean age 73 years; 58% men; mean delay of symptoms 6.9 days). Comorbidities were present in 92% (mainly hypertension, diabetes and obesity or overweight). The prevalence of comorbidities did not differ between groups. In 28% of cases, patients either died or required transfer to the Intensive Care Unit (ICU). The cause of death or of transfer to the ICU was presumably associated with severe pneumonia. Variant alpha COVID-19 had 3.8-fold higher risk of death or transfer to the ICU compared to the old strain. DISCUSSION: Patients infected with variant alpha COVID-19, despite similar background characteristics, had a higher risk of unfavorable outcomes than those infected with the old strain, suggesting increased virulence related to this variant.

Brief Report: Frailty in Aging People Living With HIV: A Matched Controlled Study.

BACKGROUND: We compared the prevalence of frailty among aging people living with HIV (PLHIV) with people without HIV from the ANS EP58 HAND 55-70 Study. METHODS: Cross-sectional multicentric study which consecutively included 200 PLHIV and 1000 people without HIV from the French national CONSTANCES cohort, matched on age, sex, and education level. PLHIV were aged 55-70 years, with a HIV viral load < 50 copies/mL and a lymphocyte T-CD4 level > 200 cells/µL for the last 24 and 12 months, respectively. We measured frailty (>2 items) and prefrailty (one or 2 items) using a proxy of the 5-item Fried score. Multivariate logistic regression was performed to assess the association between HIV and frailty/prefrailty, adjusting for demographic, social, behavioral, and comorbidity confounders. RESULTS: Outcome measures were available for 192 PLHIV and 822 people without HIV. The median age was 62 years, and 84.9% were men. Among PLHIV, the median CD4 cell count was 645.5 cells/µL. Prevalence of frailty/prefrailty was 5.73%/57.3% in PLHIV vs. 1.73%/52.2% in people without HIV, respectively. HIV was associated with prefrailty/frailty [odds ratio = 1.89; 95% confidence interval = 1.37 to 2.61), but after adjusting for social and behavioral factors and comorbidities, HIV was not significantly associated with prefrailty/frailty (odds ratio = 1.24; 95% confidence interval: = 0.84 to 1.81). In PLHIV only, frailty/prefrailty was associated with depressive symptomatology, kidney disease, and time since HIV infection. CONCLUSIONS: Prevalence of frailty is increased in aging PLHIV with well-controlled HIV disease, but other factors than HIV are predominant, particularly depression and comorbidities.

Procalcitonin and C-Reactive Protein/Procalcitonin Ratio as Markers of Infection in Patients With Solid Tumors.

Objectives: The roles of procalcitonin (PCT) and C-reactive protein (CRP) in febrile cancer patients is currently unclear. Our aim was to assess these in febrile patients with solid tumors and to identify cut-off values for ruling out infection. Methods: We retrospectively evaluated patients with solid tumors admitted to hospital due to fever. They were divided into those with Fever with microbiologically documented infection (FMDI), Fever with clinically documented infection (FCDI) and Tumor-related fever (TRF). PCT and CRP levels were compared. Receiver-operating curves were plotted to define the best cut-off values for discriminating between infection-related and cancer-related fever. Results: Between January 2015 to November 2018, 131 patients were recorded (mean age 68 years, 67% male, 86% with metastasis). Patients with FMDI or FCDI had significantly higher baseline levels of PCT and lower CRP/PCT than those with TRF. A PCT cut-off value of 0.52 ng/mL for discriminating between infection and cancer-associated fever yielded 75% sensitivity, 55% specificity, 77% positive predictive value (PPV), and 52% negative predictive value (NPV). A CRP/PCT ratio with a cut-off value of 95 showed 56% sensitivity, 70% specificity, 79% NPV, and 44% PPV. Discussion: PCT is a sensitive marker of sepsis or localized infection in patients with solid tumors, but its specificity is poor. The CRP/PCT ratio improves specificity, thus providing a reliable means of ruling out infection for values above 95.

Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV.

Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date. Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide. Design, Setting, and Participants: This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019. Main Outcomes and Measures: Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status. Results: After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] ß = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] ß = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] ß = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] ß = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004). Conclusions and Relevance: In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.

Validation of a rapid and easy-to-perform screening test for neurocognitive impairment in HIV+ patients.

OBJECTIVE: Information Processing Speed (IPS) is one of the earliest cognitive domains impaired in both multiple sclerosis (MS) and HIV-infected patients. Our aim was to study whether the Computerized Speed Cognitive Test (CSCT), an ultra-rapid tool which detects IPS impairment and is already used in MS subjects, could also be useful to screen for HIV-associated neurocognitive disorders (HAND). METHODS: The Neuracog study was an open-label prospective trial conducted in Nice and Cannes hospitals. Each patient performed a wide range of neuropsychological (NP) tests. Patients were defined as no-HAND or HAND. Groups were compared to measure sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CSCT for detecting HAND. RESULTS: Eighty-six subjects were included (26 women, 60 men, mean age: 53.1 years). HAND was diagnosed in 67/86 patients. The CSCT z-score showed a highly significant difference between the no-HAND and the HAND groups (No HAND mean: -0.1, SD: 1.0 versus HAND mean: -1.1, SD: 1.6; p = .002). The sensitivity, specificity, PPV and NPV were 81%, 53%, 86% and 43%, respectively. CONCLUSIONS: The CSCT is an easy-to-perform test allowing detection of mild forms of HAND, to be considered among screening tools for neurocognitive impairment.

Increased Prevalence of Neurocognitive Impairment in Aging People Living With Human Immunodeficiency Virus: The ANRS EP58 HAND 55-70 Study.

BACKGROUND: There are limited data on the comparative prevalence of neurocognitive impairment (NCI) in aging people living with human immunodeficiency virus (PLHIV) and people not living with HIV. METHODS: This was a cross-sectional study of PLHIV randomly matched by age (±4 years), gender, and education with 5 HIV-uninfected individuals from the CONSTANCES cohort. PLHIV were fluent in French and sequentially included during routine outpatient visits if aged 55-70 years, with HIV viral load <50 copies/mL, and lymphocyte T-CD4 level ≥200 cells/µL in the past 24 and 12 months, respectively. The primary outcome was NCI as defined by the Frascati criteria. Multivariate normative comparison (MNC) and -1.5 standard deviations in ≥2 neurocognitive domains were secondary outcomes of NCI. RESULTS: Two hundred PLHIV were matched with 1000 controls. Median age was 62 years, and 85% were men. In PLHIV, the median T-CD4 lymphocyte level was 650 cells/µL, and median nadir T-CD4 lymphocyte level was 176 cells/µL. NCI was found in 71 (35.5%) PLHIV and in 242 (24.2%) controls (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.25, 2.41). After adjusting for confounders, HIV remained significantly associated with NCI (OR, 1.50; 95% CI, 1.04, 2.16). Adjusted results were similar with NCI defined by MNC (ORMNC, 2.95; 95% CI, 1.13, 3.50) or -1.5 SD (OR-1.5, 2.24; 95% CI, 1.39, 3.62). CONCLUSIONS: In this matched study of aging individuals, HIV was significantly associated with an increased risk of NCI after adjusting for major confounders. Results were confirmed with more stringent NCI classifications. CLINICAL TRIALS REGISTRATION: NCT02592174.

Erratum to 'HMGB1/anti-HMGB1 antibodies define a molecular signature of early stages of HIV-Associated Neurocognitive Disorders (HAND)'.

[This corrects the article DOI: 10.1016/j.heliyon.2017.e00245.].

HMGB1/anti-HMGB1 antibodies define a molecular signature of early stages of HIV-Associated Neurocognitive Isorders (HAND).

BACKGROUND: HIV-associated neurocognitive disorders (HAND) persist in the post-HAART era, characterized by asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorders (MND). High mobility group box 1 (HMGB1) is a non-histone chromosomal protein widely expressed in the nucleus of all eukaryotic cells, including brain cells, which acts as a potent proinflammatory cytokine when actively secreted from immune cells. Recent reports suggested that HMGB1 acts on microglial cells to promote neuroinflammation. In this study, our aim was to determine whether HMGB1 is involved in HAND, but also to identify early new markers of neurological impairment in HIV-infected patients. METHODS: CSF and serum were collected from 103 HIV-1-infected patients enrolled in Neuradapt, a prospective study of the prevalence of HAND in HIV-1 infected patients at Nice University Hospital. Stored fluids were assessed for immunological, virological, and brain metabolite parameters. In addition to HIV RNA and DNA measurements, expression of T-cell surface markers of activation (CD38 and HLA-DR) was analyzed on whole blood. Concentration of 27 cytokines and chemokines was measured using multiplex bead assays on serum and CSF. Concentration of HMGB1 and anti-HMGB1 IgG autoantibodies were also measured on the same samples. Changes in cerebral metabolites N-acetyl aspartate (NAA), Choline (Cho) and creatinine (Cr) were assessed by magnetic resonance microscopy (MRS). RESULTS: Clinical, virological and immunological characteristics were comparable between HAND (n = 30) and no HAND (n = 73) patients, except the absolute numbers of CD8+ T cells, which were higher in patients with HAND. Among the 29 molecules tested, only 4 of them were significantly upregulated in the CSF from HAND patients as compared to healthy donors i.e. HMGB1, anti-HMGB1 IgG antibodies, IP-10 and MCP1. CSF HMGB1 levels were positively correlated with HIV-1 DNA in aviremic HAND patients, suggesting a positive impact of HMGB1 on HIV reservoirs. Moreover, in contrast to NAA/Cr and Cho/NAA ratios, circulating anti-HMGB1 IgG antibody levels could discriminate patients with no HAND from patients with no HAND and a single deficit (average ROC-AUC = 0.744, p = 0.03 for viremic patients), thus enabling the identification of a very early stage of neurocognitive impairment. CONCLUSION: We report that brain injury in chronically HIV-infected patients on stable HAART is strongly associated with persistent CNS inflammation, which is correlated with increased levels of HMGB1 and anti-HMGB1 IgG in the CSF. Moreover, we identified circulating anti-HMGB1 IgG as a very early biomarker of neurological impairment in patients without HAND. These results might have important implication for the identification of patients who are at high risk of developing neurological disorders.

Short-course daptomycin lock and systemic therapy for catheter-related bloodstream infections: a retrospective cohort study in cancer patients with surgically implanted devices.

PURPOSE: Few in vivo studies have been reported describing efficacy and duration of antibiotic lock therapy (ALT) with daptomycin (DPT) for long-term catheter-related bloodstream infections (CRBSI) due to coagulase-negative staphylococci (CoNS). We retrospectively analysed the efficacy of short-course ALT with DPT in combination with systemic treatment (ST) for CoNS-associated CRBSI in our hospital. METHODS: Patients admitted for CoNS-associated CRBSI and treated with DPT as ALT and ST were retrospectively analysed. Success was defined as preservation of the catheter device 30 days after ending treatment. Catheter removal within 30 days of discontinuing treatment, for either microbiological documentation of CRBSI relapse or re-occurrence of unexplained fever, was considered as failure. RESULTS: Among 7610 patients admitted to the Departments of Internal Medicine/Infectious Diseases and Pneumology in Cannes from January 2013 to November 2015, we identified 28 episodes of CoNS-associated CRBSI. Seven patients died of cancer during follow-up. Thus, 21 episodes were analysed among 20 patients (median age 67 years, 12 males, all treated for neoplasia and carrying a port-a-cath® device). Staphylococcus epidermidis was the main agent responsible for CRBSI. Median duration of systemic and ALT DPT was 3 days, in combination with rifampin for 4 days and then generally followed by a switch to oral drugs, most frequently cotrimoxazole or linezolid, to achieve 14 median days of treatment. Clinical success and failure rates were 76% and 24%, respectively. CONCLUSIONS: Short-course DPT as ALT, combined with 14 days of ST, allowed conservative management of CoNS-associated CRBSI in surgically implanted-catheters in three-fourth of cases.

A decreasing CD4/CD8 ratio over time and lower CSF-penetrating antiretroviral regimens are associated with a higher risk of neurocognitive deterioration, independently of viral replication.

Persistent immune activation is one of the suspected causes of HIV-associated neurocognitive disorders (HAND) in cART era. The CD4/CD8 ratio has been recently showed as a marker of immune activation and HAND. Our aim was to analyze if a decrease in the CD4/CD8 ratio over time could have an impact on neurocognitive deterioration. Randomly selected HIV-infected patients were followed for neuropsychological (NP) testing during a period of almost 2 years. Tests were adjusted for age, gender, and education. Patients were divided into 5 groups: normal tests (NT), neuropsychological deficit (ND, one impaired cognitive domain), asymptomatic neurocognitive disorders (ANI), mild neurocognitive disorders (MND), and HIV-associated dementia (HAD). Risk factors for neurocognitive deterioration were analyzed. Two hundred fifty-six patients underwent NP tests and 94 participated in the follow-up. The groups were comparable. Upon neuropsychological re-testing, six patients showed clinical improvement, 30 had worsened, and 58 were stable, resulting in 42 patients presenting with HAND (45 %). The majority of HAND cases consisted of ANI (26 %) and MND (16 %). In patients whose NP performance worsened, CPE 2010 score was lower at inclusion (7.13 vs 8.00, p = 0.003) and CD4/CD8 decrease more frequent (60 vs 31 %, p = 0.008) than in those who were stable or improved. Multivariate analysis confirmed these results. A decreasing CD4/CD8 ratio during a longitudinal follow-up of randomly selected HIV-infected patients and lower CSF-penetrating regimens were independently associated with cognitive decline. Monitoring trends in CD4/CD8 ratio could contribute to identifying patients at higher risk of neurocognitive deterioration.