The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people

OBJECTIVES: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-κ, FLC-λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. METHODS: A nested matched case–control study was carried out within the EuroSIDA cohort, including 73 HIV-positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and > 2 years prior to diagnosis were investigated. RESULTS: Two-fold higher levels of FLC-κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-λ emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). CONCLUSIONS: FLC-κ, FLC-λ and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Association between consumption of antibiotics, infection control interventions and Clostridioides difficile infections: Analysis of six-year time-series data in a tertiary-care hospital in Greece

Background: To investigate the association between Clostridioides difficile infection (CDI), antibiotic use, and infection control interventions, during an antibiotic stewardship program (ASP) implemented in a tertiary-care hospital in Greece from 2013 to 2018. Methods: Analysis was applied for the following monthly indices: 1. consumption of antibiotics; 2. use of hand hygiene disinfectant solutions; 3. percentage of isolations of patients either with multidrug-resistant (MDR) bacteria, or CDI, or admitted from another hospital; and 4. percentage of patients with CDI divided into two groups: community-acquired CDI (CACDI) and hospital-associated CDI (HACDI) (onset ≤72 h and >72 h after admission, respectively). Results: During the study, a significant reduction in CACDI rate from 0.3%/admissions [95% CI 0.1–0.6] to 0.1%/admissions [95% CI 0.0–0.3] (p-value = 0.035) was observed in adults ICU, while CDI rates were stable in the rest of the hospital. Antibiotic consumption showed a significant reduction in total hospital, from 91.7 DDDs [95% CI 89.7–93.7] to 80.1 DDDs [95% CI 79.1–81.1] (p-value<0.001), except adults ICU. Non-advanced antibiotics correlated with decreased CDI rates in Adults Clinic Departments and ICU. Isolation of patients one and two months earlier correlated with decreased CACDI rates per 20% [95% CI 0.64–1.00, p-value = 0.046] and HACDI per 23% [95% CI 0.60–1.00, p-value = 0.050] in Adults Clinic Departments. Consumption of disinfectant solutions current month correlated with decreased rate for CACDI per 33% [95% CI 0.49–0.91, p-value = 0.011] and HACDI per 38% [95% CI 0.40–0.98, p-value = 0.040] in total Hospital Clinics. Conclusion: Rational antibiotic prescribing during ASP along with multipronged intervention strategy focusing on hand hygiene and patient isolation measures prevent and control CDI outbreaks in the hospital setting. © 2022 Australasian College for Infection Prevention and Contro

Central-line-associated bloodstream infections, multi-drug-resistant bacteraemias and infection control interventions: a 6-year time-series analysis in a tertiary care hospital in Greece

Background: Central-line-associated bloodstream infections (CLABSIs) are serious healthcare-associated infections with substantial morbidity and hospital costs. Aim: To investigate the association between the incidence of CLABSIs, the implementation of specific infection control measures, and the incidence of multi-drug-resistant (MDR) bacteraemias in a tertiary care hospital in Greece from 2013 to 2018. Methods: Analysis was applied for the following indices, calculated monthly: CLABSI rate; use of hand hygiene disinfectants; isolation rate of patients with MDR bacteria; and incidence of bacteraemias [total Gram-negative carbapenem-resistant Acinetobacter baumanii, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Klebsiella pneumoniae; and/or Gram-positive meticillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci]. Findings: The total number of bacteraemias from carbapenem-resistant Gram-negative pathogens was significantly correlated with an increased CLABSI rate for all (total) hospital departments [incidence rate ratio (IRR) 1.17, 95% confidence interval (CI) 1.05–1.31, P=0.006] and the adult intensive care unit (ICU) (IRR 1.37, 95% CI 1.07–1.75, P=0.013). In the adult ICU, every increase in the incidence of each resistant Gram-negative pathogen was significantly correlated with a decreased CLABSI rate (carbapenem-resistant A. baumanii: IRR 0.59, 95% CI 0.39–0.90, P=0.015; carbapenem-resistant K. pneumoniae: IRR 0.48, 95% CI 0.25–0.94, P=0.031; carbapenem-resistant P. aeruginosa: IRR 0.54, 95% CI 0.33–0.89, P=0.015). The use of hand disinfectants was correlated with a decreased CLABSI rate 1–3 months before the application of this intervention for all (total) hospital departments (IRR 0.80, 95% CI 0.69–0.93, P=0.005), and for scrub disinfectants in the current month for the adult ICU (IRR 0.34, 95% CI 0.11–1.03, P=0.057). Isolation of patients with MDR pathogens was not associated with the incidence of CLABSIs. Conclusion: Hand hygiene was associated with a significant reduction in the incidence of CLABSIs at the study hospital. Time-series analysis is an important tool to evaluate infection control interventions. © 2022 The Healthcare Infection Societ

Daptomycin use in patients with osteomyelitis: A preliminary report from the EU-CORESM database

Background: Osteomyelitis is a complex and heterogeneous group of infections that require surgical and antimicrobial interventions. Because treatment failure or intolerance is common, new treatment options are needed. Daptomycin has broad Gram-positive activity, penetrates bone effectively and has bactericidal activity within biofilms. This is the first report on clinical outcomes in patients with osteomyelitis from the multicentre, retrospective, non-interventional European Cubicin® Outcomes Registry and Experience (EU-CORESM), a large database on real-world daptomycin use. Patients and methods: In total, 220 patients were treated for osteomyelitis; the population was predominantly elderly, with predisposing baseline conditions such as diabetes and chronic renal/cardiac diseases. Results: Most patients (76%) received prior antibiotic treatment, and first-line treatment failure was the most frequent reason to start daptomycin. Common sites of infection were the knee (22%) or hip (21%), and the most frequently isolated pathogens were Staphylococcus aureus (33%) and coagulase-negative staphylococci (32%). Overall, 52% of patients had surgery, 55% received concomitant antibiotics and 29% received a proportion of daptomycin therapy as outpatients. Clinical success was achieved in 75% of patients. Among patients with prosthetic device-related osteomyelitis, there was a trend towards higher success rates if the device was removed. Daptomycin was generally well tolerated. Conclusions: This analysis suggests that daptomycin is an effective and well-tolerated treatment option for osteomyelitis and highlights the importance of optimal surgical intervention and appropriate microbiological diagnosis for clinical outcomes

Long‐term effectiveness of recommended boosted protease inhibitor‐based antiretroviral therapy in Europe

The aim of the study was to evaluate the long-term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)-, darunavir/ritonavir (DRV/r)-, and lopinavir/ritonavir (LPV/r)-containing regimens. Data were analysed for 5678 EuroSIDA-enrolled patients starting a DRV/r-, ATZ/r- or LPV/r-containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART-naïve subjects (8%) at ritonavir-boosted protease inhibitor (PI/r) initiation; (2) ART-experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV-1 RNA copies/mL; and (3) ART-experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan-Meier and multivariable Cox models were used to compare risks of failure by PI/r-based regimen. The main analysis was performed with intention-to-treat (ITT) ignoring treatment switches. The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log-rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART-naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment-experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r-based ART. Although confounding by indication and calendar year cannot be completely ruled out, in ART-experienced subjects the long-term effectiveness of DRV/r-containing regimens appears to be greater than that of ATZ/r and LPV/

Evolution of epidemiological characteristics of infective endocarditis in Greece

Objective: The clinical profile, management and outcome of infective endocarditis (IE) may be influenced by socioeconomic issues. Methods: A nationwide prospective study evaluated IE during the era of deep economic crisis in Greece. Epidemiological data and factors associated with 60-day mortality were analyzed through descriptive statistics, logistic and Cox-regression models. Results: Among 224 patients (male 72.3%, mean age 62.4 years), Staphylococcus aureus (n = 62; methicillin-resistant S. aureus (MRSA) 33.8%) predominated in the young without impact on mortality (p = 0.593), whilst Enterococci (n = 36) predominated in the elderly. Complications of IE were associated with mortality: heart failure [OR 2.415 (95% CI: 1.159–5.029), p = 0.019], stroke [OR 3.206 (95% CI: 1.190–8.632), p = 0.018] and acute kidney injury [OR 2.283 (95% CI: 1.085–4.805), p = 0.029]. A 60-day survival benefit was solely related to cardiac surgery for IE during hospitalization [HR 0.386 (95% CI: 0.165–0.903), p = 0.028] and compliance with antimicrobial treatment guidelines [HR 0.487 (95% CI: 0.259–0.916), p = 0.026]. Compared with a previous country cohort study, history of rheumatic fever and native valve predisposition had declined, whilst underlying renal disease and right-sided IE had increased (p < 0.0001); HIV infection had emerged (p = 0.002). No difference in rates of surgery and outcome was assessed. Conclusions: A country-wide survey of IE highlighted emergence of HIV, right-sided IE and predominance of MRSA in the youth during a severe socioeconomic crisis. Compliance with treatment guidelines promoted survival. © 2021 The Author