Risk factors for central venous catheter-related infections in surgical and intensive care units. The Central Venous Catheter-Related Infections Study Group.

To identify avoidable risk factors for central venous catheter (CVC) infections in patients undergoing short-term catheterization

Signals were broadly positive for months, but never definitive: the tocilizumab story

BACKGROUND: Most COVID-19 treatment guidelines currently recommend tocilizumab in combination with dexamethasone in critically ill patients who are exhibiting rapid respiratory decompensation. OBJECTIVES: To produce a critical review and summary of the pathway which led to the repurposing of tocilizumab for COVID-19 treatment, from in vitro observations to guidelines recommendations. SOURCES: All studies evaluating the effectiveness of tocilizumab to treat COVID-19 disease published over July 2020-July 2021. CONTENT: Two large methodologically well conducted observational studies, the TESEO and the STOP COVID cohorts, showed a reduction in the risk of invasive mechanical ventilation or death in patients treated with tocilizumab as compared to standard of care in 2020. Concomitantly and up to February 2021 a number of small sample size randomized trials (RCTs) were showing discrepant results. These RCTs had a number of issues: small sample size, various designs and inclusion criteria and different dosages of tocilizumab used. The confidence interval of the meta-analytic estimate for the RCT results was consistent with the hypothesis of no efficacy of tocilizumab. In our opinion, this was mainly because the meta-analysis included small and heterogeneous studies. These results led to a delay in the inclusion of tocilizumab in guidelines which occurred only in the summer of 2021. IMPLICATIONS: Although observational studies are unable to control for unmeasured confounding, they can be put together quickly during a pandemic and promptly provide important information. The large sample size allows us to investigate effect measure modifiers and better target interventions. It is key that the effect size is somewhat large (RR>2), all sources of bias are properly accounted for and the direct evidence is weighted against these factors. It appears to us that for tocilizumab, not having dismissed the results of carefully designed and analysed observational studies in 2020 could have prevented many deaths over those months

Relevance of Interleukin-6 and D-Dimer for Serious Non-AIDS Morbidity and Death among HIV-Positive Adults on Suppressive Antiretroviral Therapy

Background: Despite effective antiretroviral treatment (ART), HIV-positive individuals are at increased risk of serious non-AIDS conditions (cardiovascular, liver and renal disease, and cancers), perhaps due in part to ongoing inflammation and/or coagulation. To estimate the potential risk reduction in serious non-AIDS conditions or death from any cause that might be achieved with treatments that reduce inflammation and/or coagulation, we examined associations of interleukin-6 (IL-6), D-dimer, and high-sensitivity C-reactive protein (hsCRP) levels with serious non-AIDS conditions or death in 3 large cohorts. Methods: In HIV-positive adults on suppressive ART, associations of IL-6, D-dimer, and hsCRP levels at study entry with serious non-AIDS conditions or death were studied using Cox regression. Hazard ratios (HR) adjusted for age, gender, study, and regression dilution bias (due to within-person biomarker variability) were used to predict risk reductions in serious non-AIDS conditions or death associated with lower “usual” levels of IL-6 and D-dimer. Results: Over 4.9 years of mean follow-up, 260 of the 3766 participants experienced serious non-AIDS conditions or death. IL-6, D-dimer and hsCRP were each individually associated with risk of serious non-AIDS conditions or death, HR = 1.45 (95% CI: 1.30 to 1.63), 1.28 (95% CI: 1.14 to 1.44), and 1.17 (95% CI: 1.09 to 1.26) per 2x higher biomarker levels, respectively. In joint models, IL-6 and D-dimer were independently associated with serious non-AIDS conditions or death, with consistent results across the 3 cohorts and across serious non-AIDS event types. The association of IL-6 and D-dimer with serious non-AIDS conditions or death was graded and persisted throughout follow-up. For 25% lower “usual” IL-6 and D-dimer levels, the joint biomarker model estimates a 37% reduction (95% CI: 28 to 46%) in the risk of serious non-AIDS conditions or death if the relationship is causal. Conclusions: Both IL-6 and D-dimer are independently associated with serious non-AIDS conditions or death among HIV-positive adults with suppressed virus. This suggests that treatments that reduce IL-6 and D-dimer levels might substantially decrease morbidity and mortality in patients on suppressive ART. Clinical trials are needed to test this hypothesis

Efficacy and tolerability of switching to a dual therapy with darunavir/ritonavir plus raltegravir in HIV-infected patients with HIV-1 RNA <= 50 cp/mL

Background: Nucleos(t)ide reverse transcriptase inhibitors (NRTI) toxicity may represent a threat for long-term success of combined antiretroviral therapy. Some studies have suggested a possible improvement of NRTI-related toxicity after switching to NRTI-sparing regimens. Objectives: We aimed to explore the efficacy and tolerability of switching to darunavir/ritonavir (DRV/r) plus raltegravir (RAL) while having a viral load (VL) ≤50 copies/mL in the clinical setting. Study design: Treatment-experienced HIV 1-infected patients enrolled in the ICONA Foundation Study cohort were included if they switched their current regimen to DRV/r + RAL with a HIV-RNA ≤50 copies/mL. Different definitions of virological failure (VF) and treatment failure (TF) were employed. Kaplan–Meier curves and Cox regression models were performed to estimate time to event probability. Results: We included 72 HIV-infected patients, 22 (31%) of these were female, 31 (43%) men who have sex with men (MSM) amd 15 (21%) had hepatitis co-infections. Median age was 44 (IQR: 35-50) years amd CD4 count was 389 (IQR 283-606) cells/mmc. Median follow-up time for TF was 24 (IQR 9–31) months. Twenty-five discontinuations occurred (60% simplifications); only 2 (8%) were toxicity-driven (lipid elevations). The probability of VF (confirmed VL >50 copies/mL) was estimated at 7% [95% confidence interval (CI) 1–13%] by 12 and 9% (95% CI 2–16%) by 24 months. When considering TF, we found a probability of stop/intensification/single VL > 200 copies/mL of 13% (95% CI 1–17%) and 22% (95% CI 11–33%) by 12 and 24 months. Female gender (adjusted relative hazard, ARH = 0.10; 95% CI 0.01–0.74; p = 0.024) and older age (AHR = 0.50 per 10 years older; 95% CI 0.25–0.99; p = 0.045) were associated with a lower risk of TF. A previous PI failure was strongly associated with TF (AHR = 52.6, 95% CI 3.6–779; p = 0.004). Conclusions: DRV/r + RAL is a valuable NRTI-sparing option, especially in female and older patients, with a relatively low risk of VF and good tolerability after 2 years since start in an ART-experienced population. However, previous PI-failure should be a limiting factor for this strategy

Incidence and Progression to Cirrhosis of New HCV infections in Persons Living with HIV.

OBJECTIVE: To estimate the incidence of HCV seroconversion and the risk of severe fibrosis/cirrhosis in HCV seroconverters among persons with HIV. METHODS: We analyzed data on 4,059 persons with HIV enrolled in a cohort study in Italy. RESULTS: Incidence rate of seroconversion was 0.6/100 person-years overall, and drug users and men-who-have-sex-with-men were at highest risk. The cumulative risk of progression to severe fibrosis/cirrhosis was 30% by 10 years after seroconversion. CONCLUSIONS: New HCV infections have a rapidly progressive course in this population. Persons with HIV and HCV superinfection should be prioritized for treatment with anti-HCV direct-acting antivirals

Time spent with HIV-RNA ≤ 200 copies/ml in a cohort of people with HIV during the U=U era

Objective: Zero risk of linked HIV transmission in sero-discordant couples when the HIV-infected partner had viral load (VL) <200 copies/mL (‘U status’) was found in observational studies. We aimed at estimating the proportion of time in which ‘U status’ was maintained and identifying factors associated with the risk of losing it. / Design: Observational cohort study. / Methods: We included participants in the ICONA cohort who had reached an established ‘U status’ (VL≤200 copies/mL for >6 months) as of December 2010. The outcome was the number of person-days of follow up (PDFU) above a VL>200 copies/ml, relative to the total number of PDFU observed. A logistic regression model was used to identify factors independently associated with the risk of losing ‘U status’. / Results: 8,241 persons living with HIV were included in the analysis who contributed 12,670,888 PDFU. Of these, 1,648 (20%) were female, 768 (9%) were people who inject drugs (PWID), and 2,066 (25%) were foreing-born. The median of VL measurements was 9 (IQR: 4–15). Overall, only 3.1% of PDFU were observed when VL was >200 copies/mL. The proportion of PDFU with VL>200 cp/ml was higher than average in females (5.3%), unemployed (5.4%), PWID (4.7%), and in people with>3 previous virologic failures (6.3%). These variables were significant predictors of losing ‘U status’ in the multivariable logistic regression. / Conclusions: Our results reinforce the validity of the U=U message in real-world setting. However, we identified subsets of our study population at higher risk of losing the ‘U status’ for whom additional efforts are needed

Triglyceride/HDL ratio and its impact on the risk of diabetes mellitus development during ART

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/m(2); 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 &gt;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