HIV Productively Infects Highly Differentiated and Exhausted CD4+ T Cells During AIDS

Background: Throughout HIV infection, productively infected cells generate billions of viral particles and are thus responsible for body-wide HIV dissemination, but their phenotype during AIDS is unknown. As AIDS is associated with immunological changes, analyzing the phenotype of productively infected cells can help understand HIV production during this terminal stage. Methods: Blood samples from 15 untreated viremic participants (recent infection, n=5; long-term infection, n=5; active opportunistic AIDS-defining disease, n=5) and 5 participants virologically controlled on antiretroviral therapy (ART) enrolled in the Analysis of the Persistence, Reservoir and HIV Latency (APRIL) study (NCT05752318) were analyzed. Cells expressing the capsid protein p24 (p24+ cells) after 18 hours of resting or 24 hours of stimulation (HIV-Flow) revealed productively infected cells from viremic participants or translation-competent reservoir cells from treated participants, respectively. Results: The frequency of productively infected cells tended to be higher during AIDS in comparison with recent and long-term infections (median, 340, 72, and 32/million CD4+ T cells, respectively) and correlated with the plasma viral load at all stages of infection. Altogether, these cells were more frequently CD4low, HLA-ABClow, CD45RA-, Ki67+, PD-1+, with a non-negligible contribution from pTfh (CXCR5+PD-1+) cells, and were not significantly enriched in HIV coreceptors CCR5 nor CXCR4 expression. The comparison markers expression between stages showed that productively infected cells during AIDS were enriched in memory and exhausted cells. In contrast, the frequencies of infected pTfh were lower during AIDS compared to non-AIDS stages. A UMAP analysis revealed that total CD4+ T cells were grouped in 7 clusters and that productive p24+ cells were skewed to given clusters throughout the course of infection. Overall, the preferential targets of HIV during the latest stages seemed to be more frequently highly differentiated (memory, TTD-like) and exhausted cells and less frequently pTfh-like cells. In contrast, translation-competent reservoir cells were less frequent (5/million CD4+ T cells) and expressed more frequently HLA-ABC and less frequently PD-1. Conclusions: In long-term infection and AIDS, productively infected cells were differentiated and exhausted. This could indicate that cells with these given features are responsible for HIV production and dissemination in an immune dysfunction environment occurring during the last stages of infection

Impact clinique de la PCR 16S au CHU de Strasbourg

Médecine InterneRésumé : un diagnostic microbiologique est fondamental pour adapter l’antibiothérapie des patients à la fois pour augmenter les chances de guérison, réduire les effets secondaires et la sélection de bactéries multirésistantes, ce qui est un enjeu actuel de santé publique. La culture standard a des limites et une méthode de biologie moléculaire, la PCR 16S, est une alternative intéressante. Notre étude incluait rétrospectivement 806 PCR 16S. Les résultats confirmaient l’intérêt de cet examen pour la prise en charge des patients suspectés d’infection bactérienne sur différents types de prélèvements habituellement stériles. Cette technique ne semblait pas plus rentable en ce qui concerne l’impact clinique sur l’un ou l’autre des différents types d’échantillons, même si elle semblait plus intéressante sur les liquides de sonication de prothèse. Une PCR 16S positive avait en revanche un impact clinique significativement plus fréquent pour les méningites que pour les endocardites (62% versus 16%, p-0.001). La prise en charge des patients était plus fréquemment modifiée quand une bactérie à croissance difficile était identifiée par la PCR 16S, quand les hémocultures étaient négatives, et surtout quand la culture standard ne permettait pas de diagnostic microbiologique. La PCR 16S pouvait tout de même s’avérer utile quand une bactérie était identifiée par hémoculture ou par culture de l’échantillon. Elle permettait en cas de résultat discordant de mettre en évidence une contamination ou d’identifier plus précisément un pathogène. En cas d’antibiothérapie préalable au prélèvement, la PCR 16S avait un intérêt diagnostic au vu de la fréquence des cultures négatives. Dans un avenir proche, les techniques de séquençage à haut débit devraient considérablement modifier les pratiques de diagnostic moléculaire et remplacer dans certaines situations la PCR 16S, en apportant des informations plus larges que la simple identification microbiologique comme les profils de résistance aux antibiotiques, la présence d’éléments génétiques mobiles ou encore de facteurs de virulence.Summary : Antimicrobial stewardship is to be improved in patients suspected of bacterial infection. Standard cultures can be found wanting leading to unsuitable antibiotic therapy. Polymerase Chain reaction targeting 16S ribosomal DNA (16S PCR) followed by Sanger’s sequencing can identify bacteria from usually sterile sites. We conducted a retrospective study in Strasbourg University Hospital to assess the clinical impact on patient’s management regarding different type of samples of this technique. From 2014 to 2018, 806 16S PCR were included among which 191 were positive. A clinical impact was found in 62/191 patients (32%). The antibiotic treatment was rationalized in 31 patients (50%), extended in 24 patients (39%) and for 7 patients (11%) 16S PCR result lead to an invasive procedure. Among all 16S PCR done, none of the different type of sample was significantly more profitable than another based on the clinical impact (p=0.078). However, a positive 16S PCR on CSF was more likely to change the patient’s management than on cardiac valves (p=0.044). The proportion of clinical impact of a positive 16S PCR was significantly superior when blood cultures were negative (p-0.001), and this difference appeared larger when blood cultures and sample culture were negative (p-0.001). Diagnostic contribution of 16S PCR was higher in patients having efficient antibiotic treatment before sampling (p-0.001). Positive 16S PCR was clinically relevant in 36% discordant result with sample culture (8/22) and 44% discordant result with blood cultures (7/16). In conclusion, 16S PCR is useful on different type of samples on patient’s management especially when no bacterium is identified in culture and for patients with previous antibiotic treatment

Management of a Major Carbapenem-Resistant Acinetobacter baumannii Outbreak in a French Intensive Care Unit While Maintaining Its Capacity Unaltered

We describe bundle measures implemented to overcome a protracted carbapenem-resistant Acinetobacter baumannii (CRAB) outbreak in an 18-bed trauma Intensive Care Unit (ICU) at Strasbourg University Hospital, a tertiary referral center in France. Outbreak cases were defined by a positive CRAB sample with OXA-23 profile during or after ICU say. To sustain the capacity of the busy trauma ICU, infection control bundles were purposely selected to control the outbreak without closing the ICU. During the outbreak, from May 2015 to January 2019, 141 patients were contaminated by CRAB, including 91 colonized and 50 infected patients. The conventional infection and prevention control (IPC) measures implemented included weekly active surveillance of patients’ samples, enhancement of environmental cleaning, interventions to improve hand hygiene compliance and antibiotic stewardship with audits. Supplemental measures were needed, including environmental samplings, health care workers’ (HCWs) hand sampling, chlorhexidine body-washing, relocation of the service to implement Airborne Disinfection System (ADS), replication of crisis cells, replacement of big environmental elements and improvement of HCW organization at the patient’s bedside. The final measure was the cohorting of both CRAB patients and HCW caring for them. Only the simultaneous implementation of aggressive and complementary measures made it possible to overcome this long-lasting CRAB epidemic. Facing many CRAB cases during a rapidly spreading outbreak, combining simultaneous aggressive and complementary measures (including strict patients and HCW cohorting), was the only way to curb the epidemic while maintaining ICU capacity

High Incidence of Acute Kidney Injury in Patients Treated with High-Dose Amoxicillin and Cloxacillin Combination Therapy

High-dose amoxicillin and cloxacillin combination therapy is recommended for the empiric treatment of selected patients with infective endocarditis despite a low level of evidence. The main objective of this study was to evaluate the renal tolerance of high-dose intravenous amoxicillin and cloxacillin combination. We studied 27 patients treated with amoxicillin and cloxacillin (≥100 mg/kg daily) for at least 48 h. The primary endpoint was the occurrence of acute kidney injury (AKI). The median patient age was 68 ± 8 years, and 16 (59%) were male. The indication for this combination therapy was suspected or confirmed endocarditis with no bacterial identification in 22 (81%) patients. The primary endpoint occurred in 16 (59%) patients after initiating this combination therapy within an average of 4.4 ± 3.6 days. Among them, seven (26%) patients developed severe AKI, including four (15%) patients who required hemodialysis. Other risk factors for AKI were identified in all patients, including injection of iodinated contrast media in 21 (78%), acute heart failure in 18 (67%), cardiac surgery in 11 (41%), and aminoglycoside use in 9 (33%) patients. This study reports an incidence of 59% of AKI after initiating amoxicillin and cloxacillin combination therapy in a population at high renal risk

Two Cases of Viral Re-suppression After M184V+R263K Selection on Dolutegravir/Lamivudine Without Treatment Modification

Dolutegravir/lamivudine (DTG/3TC) has a high genetic barrier against the development of human immunodeficiency virus drug resistance. We report 2 cases of R263K + M184V mutations during DTG/3TC failure followed by viral suppression after adherence intervention without treatment change that we attribute to residual drug activity, reduced viral fitness, and robust immune competence

Two Cases of Viral Re-suppression After M184V+R263K Selection on Dolutegravir/Lamivudine Without Treatment Modification

Dolutegravir/lamivudine (DTG/3TC) has a high genetic barrier against the development of human immunodeficiency virus drug resistance. We report 2 cases of R263K + M184V mutations during DTG/3TC failure followed by viral suppression after adherence intervention without treatment change that we attribute to residual drug activity, reduced viral fitness, and robust immune competence

Cefepime vs carbapenems for treating third-generation cephalosporin-resistant AmpC β-lactamase-hyperproducing Enterobacterales bloodstream infections: a multicenter retrospective study

Objectives: AmpC β-lactamase-hyperproducing Enterobacterales (ABLHE) bloodstream infections (BSI) are emerging and leading to therapeutic challenges worldwide. Prescriptions of carbapenems may lead to the emergence of resistance. This study aimed to compare cefepime with carbapenems for the treatment of third-generation cephalosporin-resistant ABLHE BSI. Methods: This retrospective multicenter study included patients with ABLHE BSI from two tertiary hospitals in France, between July 2017 and July 2022. Non-AmpC-producing Enterobacterales, extended-spectrum β-lactamase, and carbapenemase-producing Enterobacterales were excluded. Cefepime was prescribed only in case of minimal inhibitory concentration ≤1 mg/l. The primary outcome was 30-day in-hospital mortality from the date of index blood culture. Secondary outcomes were infection recurrence and treatment toxicity. An inverse probability of treatment weighting approach was used to balance the baseline characteristics between the two groups. Results: We analyzed 164 BSI, which included 77 in the cefepime group and 87 in the carbapenem group. In the weighted cohort, the 30-day mortality rates were similar between the cefepime group (23.3%) and the carbapenem group (19.6%) with a relative risk of 1.19 (95% confidence interval, 0.61-2.33 P = 0.614). No significant difference in recurrence or toxicity was found between the two groups. Conclusion: This study adds evidence in favor of the use of cefepime for treating third-generation cephalosporin-resistant ABLHE BSI in case of minimal inhibitory concentration ≤ 1 mg/l, which could spare carbapenems

Increased risk of severe COVID-19 in hospitalized patients with SARS-CoV-2 Alpha variant infection: a multicentre matched cohort study

International audienceBackground: The impact of the variant of concern (VOC) Alpha on the severity of COVID-19 has been debated. We report our analysis in France.Methods: We conducted an exposed/unexposed cohort study with retrospective data collection, comparing patients infected by VOC Alpha to contemporaneous patients infected by historical lineages. Participants were matched on age (± 2.5 years), sex and region of hospitalization. The primary endpoint was the proportion of hospitalized participants with severe COVID-19, defined as a WHO-scale > 5 or by the need of a non-rebreather mask, occurring up to day 29 after admission. We used a logistic regression model stratified on each matched pair and accounting for factors known to be associated with the severity of the disease.Results: We included 650 pairs of patients hospitalized between Jan 1, 2021, and Feb 28, 2021, in 47 hospitals. Median age was 70 years and 61.3% of participants were male. The proportion of participants with comorbidities was high in both groups (85.0% vs 90%, p = 0.004). Infection by VOC Alpha was associated with a higher odds of severe COVID-19 (41.7% vs 38.5%-aOR = 1.33 95% CI [1.03-1.72]).Conclusion: Infection by the VOC Alpha was associated with a higher odds of severe COVID-19

Incidence of diabetes in HIV-infected patients treated with first-line integrase strand transfer inhibitors: a French multicentre retrospective study

International audienceAbstract Background Integrase strand transfer inhibitors (INSTIs) are increasingly used in patients living with HIV due to their safety, effectiveness and high genetic barrier. However, an association with weight gain has recently been suggested and several cases of diabetes mellitus have been reported with raltegravir and dolutegravir. The long-time metabolic impact of these recent molecules remains unclear. Objectives To assess if an INSTI as a third agent is statistically associated with new-onset diabetes mellitus compared with an NNRTI or a PI. Patients and methods Patients undergoing first-line combined ART (cART) without diabetes at baseline were retrospectively included from the Dat’AIDS French cohort study (ClinicalTrials.gov NCT02898987). Incident diabetes mellitus was defined as a notification of new diabetes in the medical history, a glycated haemoglobin (HbA1c) level superior to 7.5% or the start of a diabetes therapy following the initiation of ART. Results From 2009 to 2017, 19 462 patients were included, among which 265 cases of diabetes mellitus occurred. Multivariate and survival analyses did not highlight an increase in new-onset diabetes in patients undergoing cART with an INSTI as a third agent compared with an NNRTI or a PI. BMI >30 kg/m2, age >37 years old (in survival analysis), black race or Hispanic ethnicity, arterial hypertension and AIDS were associated with a higher proportion of incident diabetes. Conclusions INSTIs were not statistically associated with new-onset diabetes. However, clinicians should remain aware of this possible metabolic comorbidity, particularly in patients with a high BMI and older patients