Cerebrospinal Fluid Viral Load Across the Spectrum of Untreated Human Immunodeficiency Virus Type 1 (HIV-1) Infection: A Cross-Sectional Multicenter Study.

BACKGROUND: The aim of this large multicenter study was to determine variations in cerebrospinal fluid (CSF) HIV-RNA in different phases of untreated human immunodeficiency virus type 1 (HIV-1) infection and its associations with plasma HIV-RNA and other biomarkers. METHODS: Treatment naive adults with available CSF HIV-RNA quantification were included and divided into groups representing significant disease phases. Plasma HIV-RNA, CSF white blood cell count (WBC), neopterin, and albumin ratio were included when available. RESULTS: In total, 1018 patients were included. CSF HIV-RNA was in median (interquartile range [IQR]) 1.03 log10 (0.37-1.86) copies/mL lower than in plasma, and correlated with plasma HIV-RNA (r = 0.44, P < .01), neopterin concentration in CSF (r = 0.49, P < .01) and in serum (r = 0.29, P < .01), CSF WBC (r = 0.34, P < .01) and albumin ratio (r = 0.25, P < .01). CSF HIV-RNA paralleled plasma HIV-RNA in all groups except neuroasymptomatic patients with advanced immunodeficiency (CD4 < 200) and patients with HIV-associated dementia (HAD) or opportunistic central nervous system (CNS) infections. Patients with HAD had the highest CSF HIV-RNA (in median [IQR] 4.73 (3.84-5.35) log10 copies/mL). CSF > plasma discordance was found in 126 of 972 individuals (13%) and varied between groups, from 1% in primary HIV, 11% in neuroasymptomatic groups, up to 30% of patients with HAD. CONCLUSIONS: Our study confirms previous smaller observations of variations in CSF HIV-RNA in different stages of HIV disease. Overall, CSF HIV-RNA was approximately 1 log10 copies/mL lower in CSF than in plasma, but CSF discordance was found in a substantial minority of subjects, most commonly in patients with HAD, indicating increasing CNS compartmentalization paralleling disease progression.

Relapse of Symptomatic Cerebrospinal Fluid HIV Escape.

PURPOSE OF REVIEW: Symptomatic cerebrospinal fluid (CSF) HIV escape defines the presence of neurological disease in combination antiretroviral therapy (cART)-treated persons due to HIV replication in CSF despite systemic suppression or to higher viral replication in CSF than in plasma. The aim was to search for cases of recurrent symptomatic CSF escape and to define their characteristics. RECENT FINDINGS: By review of the literature, we identified symptomatic CSF escape relapses in three patients who had shown clinical remission of a first escape episode following cART optimization. By examination of our cohort of 21 patients with symptomatic CSF escape, we identified five additional patients. In the latter, viral escape relapsed over a median follow-up of 108 months because of low adherence or upon treatment simplification of a previously optimized regimen. cART reoptimization based on resistance profile and potential drug neuropenetration and efficacy led to relapse resolution with no further episodes after a median follow-up of 50 months from relapse. The observation that CSF escape may relapse highlights the importance of long-term neuro-suppressive regimens after a first episode and supports the role of the brain as a reservoir for HIV.

Increasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19.

We conducted an observational cohort study in adult patients consecutively admitted for the respiratory illness Covid-19 to our hub hospital from March 9 to April 7, 2020. The high observed rate of venous thromboembolism prompted us to increase the prophylactic doses of enoxaparin from 40 mg daily up to 1 mg/kg twice daily in patients admitted to intensive care units (ICU), 0.7 mg/kg twice daily in high-intensity of care wards and 1 mg/kg daily in low-intensity of care wards. Patients on high enoxaparin doses were compared to those who received prophylaxis with the standard dosage. Efficacy endpoints were mortality, clinical deterioration, and the occurrence of venous thromboembolism, safety endpoint was the occurrence of major bleeding. Of 278 patients with Covid-19, 127 received prophylaxis with high enoxaparin doses and 151 with standard dosage. At 21 days, the incidence rate of death and clinical deterioration were lower in patients on higher doses than in those on the standard dosage (hazard ratio 0.39, 95% confidence interval 0.23-0.62), and the incidence of venous thromboembolism was also lower (hazard ratio 0.52, 95% confidence interval 0.26-1.05). Major bleeding occurred in four of 127 patients (3.1%) on the high enoxaparin dosage. In conclusion, in the cohort of patients with Covid-19 treated with high enoxaparin dosages we observed a 60% reduction of mortality and clinical deterioration and a 50% reduction of venous thromboembolism compared to standard dosage prophylaxis. However, 3% of patients on high enoxaparin dosages had non-fatal major bleeding.

The symptomatology of cerebrospinal fluid HIV RNA escape: a large case-series.

OBJECTIVE: To characterize the clinical, laboratory and radiological characteristics of persons with HIV (PWH) presenting with cerebrospinal fluid (CSF) HIV RNA escape. DESIGN: Retrospective case review of PWH presenting with symptomatic CSF HIV RNA escape at seven tertiary HIV clinical sites in the United Kingdom and Italy. METHOD: PWH with symptomatic CSF HIV RNA escape episodes were identified and data obtained from medical records. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in unquantifiable plasma HIV RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV RNA was quantifiable. The onset of clinical symptoms was classified as acute (<2 weeks-6 months), or chronic (>6 months) and differences in presentation in those with CSF HIV RNA below and above 1000 copies/ml determined. RESULTS: We identified 106 PWH with CSF HIV RNA escape (65 male); 68 (64%) PWH had acute presentations and 38 (36%) had chronic presentations. Cognitive decline (n = 54; 50.9%), confusion (n = 20; 18.9%) and headache (n = 28; 26.4%) were the most common presentations, with cognitive decline being more common in PWH who presented chronically compared with PWH who presented acutely (73.7% vs. 35.3%, P = 0.0002). Sixty PWH had CSF HIV RNA at least 1000 copies/ml and presented more frequently with confusion (n = 15/60; 25.0%) compared with PWH with CSF HIV RNA less than 1000 copies/ml at presentation (n = 5/46; 10.9%; P = 0.03). CONCLUSION: Cognitive decline, confusion and headache are the most frequent presenting symptoms of CSF HIV RNA escape and their relative frequency varied according to symptom onset and CSF HIV RNA concentration.

The ADAMTS13-von Willebrand factor axis in COVID-19 patients.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is characterized by an increased risk of thromboembolic events, with evidence of microthrombosis in the lungs of deceased patients. OBJECTIVES: To investigate the mechanism of microthrombosis in COVID-19 progression. PATIENTS/METHODS: We assessed von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin-cofactor (VWF:RCo), VWF multimers, VWF propeptide (VWFpp), and ADAMTS13 activity in a cross-sectional study of 50 patients stratified according to their admission to three different intensity of care units: low (requiring high-flow nasal cannula oxygenation, n = 14), intermediate (requiring continuous positive airway pressure devices, n = 17), and high (requiring mechanical ventilation, n = 19). RESULTS: Median VWF:Ag, VWF:RCo, and VWFpp levels were markedly elevated in COVID-19 patients and increased with intensity of care, with VWF:Ag being 268, 386, and 476 IU/dL; VWF:RCo 216, 334, and 388 IU/dL; and VWFpp 156, 172, and 192 IU/dL in patients at low, intermediate, and high intensity of care, respectively. Conversely, the high-to-low molecular-weight VWF multimers ratios progressively decreased with increasing intensity of care, as well as median ADAMTS13 activity levels, which ranged from 82 IU/dL for patients at low intensity of care to 62 and 55 IU/dL for those at intermediate and high intensity of care. CONCLUSIONS: We found a significant alteration of the VWF-ADAMTS13 axis in COVID-19 patients, with an elevated VWF:Ag to ADAMTS13 activity ratio that was strongly associated with disease severity. Such an imbalance enhances the hypercoagulable state of COVID-19 patients and their risk of microthrombosis.

A Mobile Application for Exercise Intervention in People Living with HIV.

PURPOSE: This study aimed to assess 16-wk improvements of physical fitness, metabolic, and psychological parameters in people living with HIV (PLWH) exercising with the support of a smartphone application, as compared with a control group exercising without application. METHODS: This was a randomized, open-label, pilot study enrolling PLWH in a 16-wk protocol consisting of moderate physical activity three times per week, which included an initial coach-supervised period of 4 wk, followed by 12 wk where participants trained independently. Participants were allocated to either an experimental group that trained using a smartphone application (APP) or a control group that practiced following a hard copy training program (No-APP). At baseline (BL) and after 16 wk (W16), patients were assessed for cardiorespiratory fitness, body composition, blood lipid profile, and POMS. RESULTS: Forty-eight PLWH were screened and 38 were eligible: 20 were allocated to the APP group and 18 to the No-APP group. Two APP and two No-APP participants were lost to follow-up. Intention-to-treat analysis showed a W16 improvement from BL of ≥15% V˙ O2peak in 13 (72%) of 18 in APP, but only in 3 (19%) of 16 in No-APP participants (P = 0.025). Significant W16 improvements were observed in APP, but not in No-APP participants, in V˙O2peak; fat mass and fat-free mass percent; total cholesterol, LDL cholesterol, and triglycerides; vigor; and total mood by POMS. Accordingly, significant percent change differences between the APP and the No-APP groups were observed in V˙O2peak; fat and fat-free mass percent; total cholesterol, LDL cholesterol, and triglycerides; and depression, vigor, anger, and total mood by POMS. CONCLUSIONS: Exercising using a smartphone application improved cardiorespiratory fitness, body composition, cholesterol profiles, and psychological outcomes in PLWH.

Symptomatic cerebrospinal fluid escape.

: Cerebrospinal fluid (CSF) viral escape is defined by detectable HIV-RNA in CSF despite undetectable or lower-than-CSF level in plasma of patients receiving combination antiretroviral therapy (cART). This condition may occasionally be associated with neurological problems, consisting of new and progressive cognitive decline and/or focal symptoms and signs, defining the 'symptomatic CSF escape'. Brain MRI usually shows diffuse white matter hyperintensities that recall the presentation of HIV encephalopathy in the precART era. However, patients develop symptomatic CSF escape with relatively high CD4 cell counts and suppressed or low systemic virus replication. In addition, the frequent CSF pleocytosis and the pathological demonstration of CD8 T-cell brain infiltrates in some cases of symptomatic escape indicate that inflammation is an important component in the pathogenesis of this condition. Low nadir CD4 cells are common, likely reflecting the establishment of a HIV reservoir in the central nervous system (CNS). CSF escape seems to result from reactivation of CNS infection when cART potency is lowered, because of low patient's adherence, drug resistance, or use of drug combinations that are poorly effective in the CNS and cART optimization is key to revert escape and neurological disease in the great majority of cases.

Metabolomic Profiling in Individuals with a Failing Kidney Allograft.

BACKGROUND: Alteration of certain metabolites may play a role in the pathophysiology of renal allograft disease. METHODS: To explore metabolomic abnormalities in individuals with a failing kidney allograft, we analyzed by liquid chromatography-mass spectrometry (LC-MS/MS; for ex vivo profiling of serum and urine) and two dimensional correlated spectroscopy (2D COSY; for in vivo study of the kidney graft) 40 subjects with varying degrees of chronic allograft dysfunction stratified by tertiles of glomerular filtration rate (GFR; T1, T2, T3). Ten healthy non-allograft individuals were chosen as controls. RESULTS: LC-MS/MS analysis revealed a dose-response association between GFR and serum concentration of tryptophan, glutamine, dimethylarginine isomers (asymmetric [A]DMA and symmetric [S]DMA) and short-chain acylcarnitines (C4 and C12), (test for trend: T1-T3 = p<0.05; p = 0.01; p<0.001; p = 0.01; p = 0.01; p<0.05, respectively). The same association was found between GFR and urinary levels of histidine, DOPA, dopamine, carnosine, SDMA and ADMA (test for trend: T1-T3 = p<0.05; p<0.01; p = 0.001; p<0.05; p = 0.001; p<0.001; p<0.01, respectively). In vivo 2D COSY of the kidney allograft revealed significant reduction in the parenchymal content of choline, creatine, taurine and threonine (all: p<0.05) in individuals with lower GFR levels. CONCLUSIONS: We report an association between renal function and altered metabolomic profile in renal transplant individuals with different degrees of kidney graft function.