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BACKGROUND AND AIMS A cytokine storm drives the pathogenesis of severe coronavirus disease (COVID-19) and several biomarkers with different mechanisms of action have been linked to mortality. Chronic kidney disease (CKD) emerged as a very common risk factor for severe COVID-19. Indeed, CKD patients are at increased risk of premature death from many causes, including, but not limited to, cardiovascular disease (CVD) and infections. In this study, we aimed to investigate the associations between the growth differentiation factor 15 (GDF-15), an established cardiovascular and inflammatory biomarker and outcomes in CKD patients hospitalized for COVID-19. METHOD A retrospective study on COVID-19 hospitalized subjects in the acute phase of the disease. A broad range of cytokines (CD25, IL-18, TNF-α, TNF RI, TNF RII, GDF-15, IL-7, LIF, IL-6, CHITINASE3_LIKE1, RAGE and Pentraxin-3) were assessed in plasma (Luminex, ELISA) collected upon hospitalization. A total of 77 subjects were divided into two groups according to their estimated glomerular filtration rate (eGFR, by CKD-EPI formula), ≥45 mL/min (n = 44), or ˂45 mL/min (n = 33). RESULTS We found no statistical differences between the two groups in terms of demographic features. Among comorbidities, we found a higher percentage of patients with diabetes in the eGFR < 45 group. Likewise, the serum tests upon admission showed in the eGFR < 45 group a higher value of neutrophilic count. Upon hospital admission, the patient groups were comparable in terms of symptoms, time from symptom onset to admission and death or discharge, radiological evidence of pneumonia and respiratory parameters and time of hospitalization. Furthermore, there were no statistical differences between medical therapy during hospitalization, need for respiratory support with Continuous Positive Airways Pressure or Non-Invasive Mechanical Ventilation, or death rather than discharge as the clinical outcome. Serum levels of 20 different compounds were measured in COVID-19 patients admitted to the hospital 4–5 days after the onset of symptoms. Interestingly, we found that patients with lower renal function (eGFR < 45 mL/min) had a significant increase of GDF-15, CD-25 and RAGE and, furthermore, higher serum levels of these molecules were detected in non-survivor patients and in those who needed ventilation. Also, TNFα, TNFR I, TNFR II, IL-7 and LIF had a significant increase in patients with eGFR < 45 mL/min with more elevated levels in non-survivor patients. In univariate analysis low and mid-low GDF-15 quartiles (4.45 ng/mL) were associated with higher mortality risk (Figure 1). Independent association between GDF-15 quartiles and mortality risk was confirmed in Cox model adjusted for eGFR, age, fever, dyspnoea and P/F [hazard ratio (HR) 2.28, 95% confidence interval (CI) 1.53–3.39, P < 0.0001) The strength of association between GDF-15 quartiles and mortality risk was increased in patients with eGFR < 45 mL/min/1.73 m2 (HR 2.53, CI 1.34–4.79) compared with the other eGFR group (HR 1.99, CI 1.17–3.39) (Table 1). CONCLUSION Our results demonstrate that GDF-15 is an independent predictor of COVID-19 mortality in CKD patients. Given the reported increase of this cytokine with age and its possible mechanistic role in various pathological conditions, our findings suggest that GDF-15 signalling pathway inhibitors may be included as possible therapeutic candidates for COVID-19 in CKD.

Objectives Our primary aim was to study diabetes mellitus (DM) arising during combination ART (cART) and to attempt to identify associations between these cases and triglycerides (TRG) and the TRG to HDL-cholesterol (TRG/HDL) ratio. Our secondary aim was to analyse the association between DM development and hepatic fibrosis. Methods This was a retrospective cohort study. Patients from the Icona Foundation study initiating first-line cART between 1997 and 2013 were selected and observed until new-onset DM or most recent clinical follow-up. The predictive value of TRG and TRG/HDL ratio levels on DM was evaluated using multivariable Poisson regression models. Results Three-thousand, five-hundred and forty-six patients (males, 73.7%; median age, 38 years; median BMI, 23.1 kg/m2; and hepatitis C virus antibody positive, 22.1%) were included. Of these, 80 developed DM over 13 911 person-years of follow-up (PYFU), corresponding to 5.7 cases per 1000 PYFU (95% CI = 4.6–7.1). At multivariable analysis, latest TRG/HDL ratio, when high, was associated with significant increases in DM risk [relative risk (RR) = 1.63; 95% CI = 1.32–2.01 per 10 points higher], while current TRG, in contrast, was associated with new-onset DM only at crude analysis. Advanced liver fibrosis (defined as fibrosis-4 index >3.25) was also shown to be an independent risk factor for DM (RR = 2.91; 95% CI = 1.10–7.72). Conclusions High TRG/HDL ratio predicted risk of new-onset DM, independently of other traditional risk factors. Furthermore, our findings suggest that advanced hepatic fibrosis, estimated using the fibrosis-4 score, could provide an additional predictor for DM.

ObjectivesOur aim was to investigate the durability of different initial regimens in patients starting ART with CD4+ counts 5 log10 copies/mL.MethodsThis was a retrospective study of HIV-infected patients prospectively followed in the ICONA cohort. Those who started ART with boosted protease inhibitors (bPIs), NNRTIs or integrase strand transfer inhibitors (InSTIs), with CD4+ 5 log10 copies/mL, were included. The primary endpoint was treatment failure (TF), a composite endpoint defined as virological failure (VF, first of two consecutive HIV-RNA >50 copies/mL after 6 months of treatment), discontinuation of class of the anchor drug or death. Independent associations were investigated by Poisson regression analysis in a model including age, gender, mode of HIV transmission, CDC stage, HCV and HBV co-infection, pre-treatment HIV-RNA, CD4+ count and CD4+/CD8+ ratio, ongoing opportunistic disease, fibrosis FIB-4 index, estimated glomerular filtration rate, haemoglobin, platelets, neutrophils, calendar year of ART initiation, anchor drug class (treatment group) and nucleos(t)ide backbone.ResultsA total of 1195 patients fulfilled the inclusion criteria: 696 started ART with a bPI, 315 with an InSTI and 184 with an NNRTI. During 2759 person-years of follow up, 642 patients experienced TF. Starting ART with bPIs [adjusted incidence rate ratio (aIRR) (95% CI) 1.62 (1.29–2.03) versus starting with NNRTIs; P ConclusionsIn patients starting ART with 5 log10 HIV-RNA copies/mL, the durability of regimens based on InSTIs was longer than that of NNRTI- and bPI-based regimens.

BACKGROUND: Using data from the COHERE collaboration, we investigated whether primary prophylaxis for pneumocystis pneumonia (PcP) might be withheld in all patients on antiretroviral therapy (ART) with suppressed plasma human immunodeficiency virus (HIV) RNA (≤400 copies/mL), irrespective of CD4 count. METHODS: We implemented an established causal inference approach whereby observational data are used to emulate a randomized trial. Patients taking PcP prophylaxis were eligible for the emulated trial if their CD4 count was ≤200 cells/µL in line with existing recommendations. We compared the following 2 strategies for stopping prophylaxis: (1) when CD4 count was >200 cells/µL for >3 months or (2) when the patient was virologically suppressed (2 consecutive HIV RNA ≤400 copies/mL). Patients were artificially censored if they did not comply with these stopping rules. We estimated the risk of primary PcP in patients on ART, using the hazard ratio (HR) to compare the stopping strategies by fitting a pooled logistic model, including inverse probability weights to adjust for the selection bias introduced by the artificial censoring. RESULTS: A total of 4813 patients (10 324 person-years) complied with eligibility conditions for the emulated trial. With primary PcP diagnosis as an endpoint, the adjusted HR (aHR) indicated a slightly lower, but not statistically significant, different risk for the strategy based on viral suppression alone compared with the existing guidelines (aHR, .8; 95% confidence interval, .6-1.1; P = .2). CONCLUSIONS: This study suggests that primary PcP prophylaxis might be safely withheld in confirmed virologically suppressed patients on ART, regardless of their CD4 count.

The incidence of and predictors of acquired immunodeficiency syndrome-defining malignancies (ADMs) and nonADM (NADMs) were evaluated in a large Italian cohort. The incidence of ADM and NADM was 5.0 cases per 1000 personyears of follow-up (95% confidence interval, 4.3-5.8 cases per 1000 person-years of follow-up) and 2.4 cases per 1000 person-years of follow-up (95% confidence interval, 1.9-3.1 cases per 1000 person-years of follow-up), respectively. Lower current CD4 cell count was an independent predictor of developing malignancies, with the association being stronger for ADM than for NADM. © 2010 by the Infectious Diseases Society of America. All rights reserved.

Background: The human immunodeficiency virus (HIV) epidemic in Ukraine has been driven by a rapid rise among people who inject drugs, but recent studies have shown an increase through sexual transmission. Methods: Protease and reverse transcriptase sequences from 876 new HIV diagnoses (April 2013–March 2015) in Kiev were linked to demographic data. We constructed phylogenetic trees for 794 subtype A1 and 64 subtype B sequences and identified factors associated with transmission clustering. Clusters were defined as ≥2 sequences, ≥80% local branch support, and maximum genetic distance of all sequence pairs in the cluster ≤2.5%. Recent infection was determined through the limiting antigen avidity enzyme immunoassay. Sequences were analyzed for transmitted drug resistance mutations. Results Thirty percent of subtype A1 and 66% of subtype B sequences clustered. Large clusters (maximum 11 sequences) contained mixed risk groups. In univariate analysis, clustering was significantly associated with subtype B compared to A1 (odds ratio [OR], 4.38 [95% confidence interval {CI}, 2.56–7.50]); risk group (OR, 5.65 [95% CI, 3.27–9.75]) for men who have sex with men compared to heterosexual males; recent, compared to long-standing, infection (OR, 2.72 [95% CI, 1.64–4.52]); reported sex work contact (OR, 1.93 [95% CI, 1.07–3.47]); and younger age groups compared with age ≥36 years (OR, 1.83 [95% CI, 1.10–3.05] for age ≤25 years). Females were associated with lower odds of clustering than heterosexual males (OR, 0.49 [95% CI, .31–.77]). In multivariate analysis, risk group, subtype, and age group were independently associated with clustering (P < .001, P = .007, and P = .033, respectively). Eighteen sequences (2.1%) indicated evidence of transmitted drug resistance. Conclusions Our findings suggest high levels of transmission and bridging between risk groups.

Background There are few data concerning the risk of specific opportunistic diseases in patients with and without hepatitis C virus (HCV) infection. We evaluated the correlation between the occurrence of different AIDS-defining illnesses (ADIs) and chronic HCV infection or HCV-related liver cirrhosis in a large Italian cohort of human immunodeficiency virus (HIV)-infected subjects. Methods Subjects were stratified into 2 groups: patients without HCV coinfection and with persistently normal aminotransferase levels and patients with HCV coinfection. The patients with HCV coinfection were stratified according to the diagnosis of liver cirrhosis. The incidences of new ADIs were calculated as the number of events per 1000 person-years of follow-up. The rates in the 2 groups were compared using a Poisson regression model adjusted for potential confounders. Results We observed a total of 496 ADIs among 5397 patients with 25,105 person-years of follow-up (50% tested positive for HCV). HCV coinfection was associated with increased risk of developing an ADI (adjusted relative rate [ARR], 2.61; 95% confidence interval [CI], 1.88-3.61), specifically bacterial infection (ARR, 3.15; 95% CI, 1.76-5.67), HIV-related disease (ARR, 2.68; 95% CI, 1.03-6.97), and mycotic disease (ARR, 3.87; 95% CI, 2.28-6.59) but not non-Hodgkin lymphoma (ARR, 0.88; 95% CI, 0.22-3.48). The rate of mycotic infection, bacterial infection, toxoplasmosis, and HIV-related ADI among patients with cirrhosis were significantly higher than that among HIV-monoinfected patients, and the risk was greater than that estimated for HCV antibody-positive patients without cirrhosis. Conclusions HIV-related bacterial and mycotic infections are strongly associated with positive HCV serostatus and HCV-related cirrhosis. Clinicians should take into account these data when making decisions on initiation of antiretroviral therapy for HCV-coinfected individuals.

Concerns have arisen about possible effects of protease inhibitors (PIs) on cardiac conductivity. We found no significant association between current or recent PI exposure and sudden death or nonhemorrhagic stroke (adjusted rate ratio, 1.22; 95% confidence interval, .95-1.57), whereas cumulative exposure to PIs was associated with an increased risk (adjusted rate ratio, 1.06 per year of exposure; 95% confidence interval, 1.01-1.11).

Background. The impact of human immunodeficiency virus (HIV)‐associated tuberculosis on CD4 T-cell count response to combined antiretroviral therapy (cART) is poorly investigated. Methods. A collaborative analysis including HIV-infected patients prospectively enrolled in 4 Italian clinical cohorts was conducted. Patients were grouped according to Centers for Disease Control and Prevention stage at the start of cART as having tuberculosis, having AIDS but not tuberculosis (nontuberculosis AIDS), and not having AIDS (AIDS free). Time to CD4 T-cell count of at least 100, 200, and 300 cells/lL above pre-cART levels and to CD4 T-cell count of .500 cells/lL were major end points. Survival analysis with time-fixed and time-dependent covariates was used. Results. A total of 6528 patients were eligible; 125 patients (2%) had tuberculosis, 1062 (16%) had nontuberculosis AIDS, and 5341 (82%) were AIDS free. Patients with tuberculosis had a significantly reduced chance of CD4 T-cell count increase compared with AIDS-free patients as well as those with nontuberculosis AIDS, regardless of the primary outcome considered for a given value of confounders measured at baseline (eg, for .200 cells/lL above baseline; relative hazard, 0.71; P 5 .02), although it was no longer significant after further adjustment for current level of viral load suppression (relative hazard, 0.80; P 5 .11). There was a trend for reduced virological response in patients treated concomitantly for tuberculosis and HIV infection compared with those who were treated separately in time (P 5 .09). Conclusions. HIV-infected patients starting cART with a tuberculosis diagnosis showed an impaired immune recovery to cART compared with AIDS-free patients and those with nontuberculosis AIDS. It seems to be driven mainly by a delay in achieving viral suppression. Whether this may be due to interactions between antituberculosis drugs and antiretrovirals needs to be investigated.

BACKGROUND. The risk of myocardial infarction (MI) in patients with human immunodeficiency virus (HIV) infection has been assessed in 13 anti-HIV drugs in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. METHODS. Poisson regression models were adjusted for cardiovascular risk factors, cohort, calendar year, and use of other antiretroviral drugs and assessed the association between MI risk and cumulative (per year) or recent (current or in the past 6 months) use of antiretroviral drugs, with >30,000 person-years of exposure. RESULTS. Over 178,835 person-years, 580 patients developed MI. There were no associations between use of tenofovir, zalcitabine, zidovudine, stavudine, or lamivudine and MI risk. Recent exposure to abacavir or didanosine was associated with an increased risk of MI. No association was found between MI risk and cumulative exposure to nevirapine, efavirenz, nelfinavir, or saquinavir. Cumulative exposure to indinavir and lopinavir-ritonavir was associated with an increased risk of MI (relative rate [RR] per year, 1.12 and 1.13, respectively). These increased risks were attenuated slightly (RR per year, 1.08 [95% confidence interval {CI}, 1.02-1.14] and 1.09 [95% CI, 1.01-1.17], respectively) after adjustment for lipids but were not altered further after adjustment for other metabolic parameters. CONCLUSIONS. Of the drugs considered, only indinavir, lopinavir-ritonavir, didanosine, and abacavir were associated with a significantly increased risk of MI. As with any observational study, our findings must be interpreted with caution (given the potential for confounding) and in the context of the benefits that these drugs provide.

Up to 30% of human immunodeficiency virus (HIV)-infected patients who are receiving long-term highly active antiretroviral therapy do not exhibit a marked increase in the CD4(+) T cell count, despite achieving complete suppression of the HIV load. These patients are referred to as "immunological nonresponders." When treating immunological nonresponders, the practicing clinician has several questions, including questions about the clinical risk associated with persistent immunodeficiency and about possible approaches to treatment that would provide clinical and immunological benefits. However, tentative answers to these questions require investigations of the mechanisms that underlie the lack of immune recovery, because only the deepest comprehension of the immunological gaps underlying functional defects will allow administration of highly targeted and efficacious treatment strategies. The aim of our review is to provide a thorough assessment of the clinical implications of a lack of increase in the CD4(+) T cell count in immunological nonresponders, to examine the immunological gaps limiting recovery of the CD4(+) T cell count, and to note possible therapeutic avenues, which may offer clinicians guidance regarding how to most efficaciously treat these critical patients.

Recently, it was shown that cirrhotic patients without human immunodeficiency virus (HIV) infection had low CD4 cell counts and normal CD4 cell percentages, suggesting that, for HIV-infected persons, the CD4 cell percentage might be a more accurate marker of disease progression than the absolute CD4 cell count. In cirrhotic HIV-infected persons in the Italian Cohort of Antiretroviral-Naive Patients, the absolute CD4 cell count seemed to be better predictor of the risk of developing an acquired immunodeficiency syndrome-defining illness than the CD4 cell percentage.

Objectives: The correlation between subclinical hypothyroidism [thyroid stimulating hormone (TSH) >4 mIU/L with normal free triiodothyroxine and free thyroxine levels], HIV infection and HAART is still unclear. Patients and methods: To evaluate the predictive factors of subclinical hypothyroidism in an HIVinfected population, we identified three groups of subjects: G1, subjects on stable highly active antiretroviral therapy (HAART) (for at least 1 year) at baseline and at month 24 (n = 97); G2, subjects naive at both baseline and month 24 (n = 47); G3, subjects starting HAART at baseline (n = 46). Results: The three groups were comparable with respect to age, gender, body weight and prevalence of HCV infection. At baseline, subclinical hypothyroidism was detected in 14 subjects in G1 (14.4%), 5 in G2 (10.6%) and 4 in G3 (8.7%) (P = 0.18) and these were excluded from the analysis. At month 24, 15 subjects had developed subclinical hypothyroidism: 4 in G1 (4.8%), 3 in G2 (7.1%) and 8 in G3 (19.0%). In the multivariable analysis, the higher increase in total cholesterol was predictive of subclinical hypothyroidism (RR: 1.53 for each additional 10 mg/dL, 95% CI 1.23-1.90; P < 0.01); other variables, which were statistically significant in the univariate analysis, such as G3 group, body weight and higher increase in CD4+ cell count and in triglyceride serum levels were not confirmed to be associated with TSH alterations. Conclusions: The occurrence of subclinical hypothyroidism in HIV-positive patients seems to be related to the increase in total cholesterol serum levels occurring after HAART initiation. Thyroid function should be monitored in all HIV-infected subjects, especially in those starting HAART. © The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c), as well as the TC:HDL-c ratio, were compared in patients receiving different antiretroviral therapy regimens. Patients receiving first-line regimens including protease inhibitors (PIs) had higher TC and TG levels and TC : HDL-c ratios than did antiretroviral-naive patients; patients receiving 2 PIs had higher levels of each lipid. Ritonavir-containing regimens were associated with higher TC and TG levels and TC : HDL-c ratios than were indinavir-containing regimens; however, receipt of nelfinavir was associated with reduced risk of lower HDL-c levels, and receipt of saquinavir was associated with lower TC : HDL-c ratios. Patients receiving nonnucleoside reverse-transcriptase inhibitors had higher levels of TC and LDL-c than did antiretroviral-naive patients, although the risk of having lower HDL-c levels was lower than that in patients receiving a single PI. Efavirenz was associated with higher levels of TC and TG than was nevirapine.

A nested polymerase chain reaction (PCR) was evaluated for the detection of cytomegalovirus (CMV) DNA in cerebrospinal fluid (CSF). CSF and serum samples from 19 AIDS patients with intracerebral CMV infection diagnosed at autopsy were retrospectively examined. As controls, CSF and serum samples from 15 AIDS patients with only extracerebral CMV involvement at autopsy, from 10 AIDS patients without CMV infection at autopsy, and from 10 anti-human immunodeficiency virus-negative patients without ongoing CMV infection, were studied. CMV DNA was detected from patients with intracerebral CMV infection in 9 of 9, 5 of 6, and 1 of 4 CSF samples collected, respectively, 1-30, 30-90, and 90-300 days before death. Twelve of 13 sera from these patients were CMV PCR-positive. None of the control patients had CMV DNA in CSF. PCR was positive in 6 of 8 sera from AIDS patients with only extracerebral CMV infection and in serum from 1 AIDS patient without CMV involvement at autopsy. CMV PCR on CSF is highly sensitive and specific. It should be considered a rapid and reliable diagnostic method for CMV infection of the central nervous system. © 1992 the University of Chicago.

The immunovirological outcome of lopinavir/ritonavir was evaluated in 70 antiretroviral-experienced HIV patients; at baseline, median CD4+ cell count was 218 cells/mm(3) and median plasma viraemia 4.58 log(10) copies/mL. After 12 months, we observed an increase in CD4+ cell count to 322 cells/mm(3) (P = 0.0001) and a decrease in plasma viraemia to 2.35 log(10) copies/mL (P = 0.0001). Four patients discontinued lopinavir/ritonavir during observation. Among metabolic parameters, only triglyceride concentrations increased during treatment (P = 0.02). Twenty-six patients had a genotypic resistance test at baseline; four had > or =6 mutations known to reduce susceptibility to lopinavir/ritonavir. Undetectable plasma viraemia was obtained only in patients with < or =5 mutations (61.9%).

International audience; Many questions about the long-term effects of combination antiretroviral therapy (cART) on clinical outcomes in people living with HIV (PLWH) and their impact on health systems remain unanswered. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) was formed in 2005 to pool and harmonize existing longitudinal data on people living with HIV in Europe, to answer key research questions that could not be addressed adequately by individual cohorts. Key research questions include long-term prognosis, rare outcomes, and variations across patient groups, settings and health systems. COHERE uses the HIV Cohorts Data Exchange Protocol, a standardized and validated method of data structure and transfer, to compile data from over 40 cohorts of PLWH residing in Europe, representing 331 481 individuals, including 2808 children (

SUMMARY Interferon-gamma (IFN-γ) induces de novo expression of IgG Fc receptor type I (FcRI) on neutrophils and significantly raises the level of these receptors on monocytes. Since increased concentrations of IFN-γ have been observed in sera from patients with HIV infection, FcRI expression might also be increased on these subjects' phagocytes. FcRI expression was assessed by indirect immunofluorescence staining of phagocytes in whole blood from 40 healthy controls and 55 HIV+ subjects, 24 belonging to CDC class III and 31 to CDC class IV; 42 were intravenous drug abusers (IVDA) and 13 were homosexual men. Plasma levels of IFN-γ were measured using a modified immunoradiometric assay. The mean linear fluorescence intensity, used as a relative measure of receptor expression, was significantly higher on unseparated neutrophils from HIV+ subjects in CDC classes III (P

Purpose of the study The association between abacavir exposure and cardiovascular disease (CVD) in HIV-infected patients is currently intensely debated. Recently, the D:A:D Study Group described increased myocardial infarction risk in patients with current/recent abacavir exposure, while repository data from GlaxoSmithKline clinical trials failed to find any association. Given the association between lymphocyte hyperactivation and CVD, and the major role of T-cell hyperactivation in HIV/AIDS, the purpose of our study was to investigate T-cell immunephenotype and proinflammatory cytokines kinetics in HIV-infected patients receiving abacavir-containing regimens.