Leukocyte Count and Coronary Artery Disease Events in People With Human Immunodeficiency Virus: A Longitudinal Study

BACKGROUND: People with human immunodeficiency virus (HIV; PWH) have increased cardiovascular risk. Higher leukocyte count has been associated with coronary artery disease (CAD) events in the general population. It is unknown whether the leukocyte-CAD association also applies to PWH. METHODS: In a case-control study nested within the Swiss HIV Cohort Study, we obtained uni- and multivariable odds ratios (OR) for CAD events, based on traditional and HIV-related CAD risk factors, leukocyte count, and confounders previously associated with leukocyte count. RESULTS: We included 536 cases with a first CAD event (2000-2021; median age, 56 years; 87% male; 84% with suppressed HIV RNA) and 1464 event-free controls. Cases had higher latest leukocyte count before CAD event than controls (median [interquartile range], 6495 [5300-7995] vs 5900 [4910-7200]; P 11 000/µL) was uncommon (4.3% vs 2.1%; P = .01). In the highest versus lowest leukocyte quintile at latest time point before CAD event, participants had univariable CAD-OR = 2.27 (95% confidence interval, 1.63-3.15) and multivariable adjusted CAD-OR = 1.59 (1.09-2.30). For comparison, univariable CAD-OR for dyslipidemia, diabetes, and recent abacavir exposure were 1.58 (1.29-1.93), 2.19 (1.59-3.03), and 1.73 (1.37-2.17), respectively. Smoking and, to a lesser degree, alcohol and ethnicity attenuated the leukocyte-CAD association. Leukocytes measured up to 8 years before the event were significantly associated with CAD events. CONCLUSIONS: PWH in Switzerland with higher leukocyte counts have an independently increased risk of CAD events, to a degree similar to traditional and HIV-related risk factors

Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 years.

BACKGROUND Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). We aimed to make a long-term comparison of epigenetic ageing dynamics in people with HIV during untreated HIV infection and during suppressive ART. METHODS In this longitudinal study, conducted over 17 years in HIV outpatient clinics in Switzerland, we applied 5 established epigenetic age estimators (epigenetic clocks) in peripheral blood mononuclear cells (PBMCs) in Swiss HIV Cohort Study participants before or during suppressive ART. All participants had a longitudinal set of PBMC samples available at four timepoints (T1-T4). T1 and T2 had to be 3 years or longer apart, as did T3 and T4. We assessed epigenetic age acceleration (EAA) and a novel rate of epigenetic ageing. FINDINGS Between March 13, 1990, and Jan 18, 2018, we recruited 81 people with HIV from the Swiss HIV Cohort Study. We excluded one participant because a sample did not meet quality checks (transmission error). 52 (65%) of 80 patients were men, 76 (95%) were white, and the median patient age was 43 (IQR 37·5-47) years. Per year of untreated HIV infection (median observation 8·08 years, IQR 4·83-11·09), mean EAA was 0·47 years (95% CI 0·37 to 0·57) for Horvath's clock, 0·43 years (0·3 to 0·57) for Hannum's clock, 0·36 years (0·27 to 0·44) for SkinBlood clock, and 0·69 years (0·51 to 0·86) for PhenoAge. Per year of suppressive ART (median observation 9·8 years, IQR 7·2-11), mean EAA was -0·35 years (95% CI -0·44 to -0·27) for Horvath's clock, -0·39 years (-0·50 to -0·27) for Hannum's clock, -0·26 years (-0·33 to -0·18) for SkinBlood clock, and -0·49 years (-0·64 to -0·35) for PhenoAge. Our findings indicate that people with HIV epigenetically aged by a mean of 1·47 years for Horvath's clock, 1·43 years for Hannum's clock, 1·36 years for SkinBlood clock, and 1·69 years for PhenoAge per year of untreated HIV infection; and 0·65 years for Horvath's clock, 0·61 years for Hannum's clock, 0·74 years for SkinBlood clock, and 0·51 years for PhenoAge, per year of suppressive ART. GrimAge showed some change in the mean EAA during untreated HIV infection (0·10 years, 0·02 to 0·19) and suppressive ART (-0·05 years, -0·12 to 0·02). We obtained very similar results using the rate of epigenetic ageing. Contribution of multiple HIV-related, antiretroviral, and immunological variables, and of a DNA methylation-associated polygenic risk score to EAA was small. INTERPRETATION In a longitudinal study over more than 17 years, epigenetic ageing accelerated during untreated HIV infection and decelerated during suppressive ART, highlighting the importance of limiting the duration of untreated HIV infection. FUNDING Swiss HIV Cohort Study, Swiss National Science Foundation, and Gilead Sciences

Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 years

BACKGROUND: Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). We aimed to make a long-term comparison of epigenetic ageing dynamics in people with HIV during untreated HIV infection and during suppressive ART. METHODS: In this longitudinal study, conducted over 17 years in HIV outpatient clinics in Switzerland, we applied 5 established epigenetic age estimators (epigenetic clocks) in peripheral blood mononuclear cells (PBMCs) in Swiss HIV Cohort Study participants before or during suppressive ART. All participants had a longitudinal set of PBMC samples available at four timepoints (T1-T4). T1 and T2 had to be 3 years or longer apart, as did T3 and T4. We assessed epigenetic age acceleration (EAA) and a novel rate of epigenetic ageing. FINDINGS: Between March 13, 1990, and Jan 18, 2018, we recruited 81 people with HIV from the Swiss HIV Cohort Study. We excluded one participant because a sample did not meet quality checks (transmission error). 52 (65%) of 80 patients were men, 76 (95%) were white, and the median patient age was 43 (IQR 37·5-47) years. Per year of untreated HIV infection (median observation 8·08 years, IQR 4·83-11·09), mean EAA was 0·47 years (95% CI 0·37 to 0·57) for Horvath's clock, 0·43 years (0·3 to 0·57) for Hannum's clock, 0·36 years (0·27 to 0·44) for SkinBlood clock, and 0·69 years (0·51 to 0·86) for PhenoAge. Per year of suppressive ART (median observation 9·8 years, IQR 7·2-11), mean EAA was -0·35 years (95% CI -0·44 to -0·27) for Horvath's clock, -0·39 years (-0·50 to -0·27) for Hannum's clock, -0·26 years (-0·33 to -0·18) for SkinBlood clock, and -0·49 years (-0·64 to -0·35) for PhenoAge. Our findings indicate that people with HIV epigenetically aged by a mean of 1·47 years for Horvath's clock, 1·43 years for Hannum's clock, 1·36 years for SkinBlood clock, and 1·69 years for PhenoAge per year of untreated HIV infection; and 0·65 years for Horvath's clock, 0·61 years for Hannum's clock, 0·74 years for SkinBlood clock, and 0·51 years for PhenoAge, per year of suppressive ART. GrimAge showed some change in the mean EAA during untreated HIV infection (0·10 years, 0·02 to 0·19) and suppressive ART (-0·05 years, -0·12 to 0·02). We obtained very similar results using the rate of epigenetic ageing. Contribution of multiple HIV-related, antiretroviral, and immunological variables, and of a DNA methylation-associated polygenic risk score to EAA was small. INTERPRETATION: In a longitudinal study over more than 17 years, epigenetic ageing accelerated during untreated HIV infection and decelerated during suppressive ART, highlighting the importance of limiting the duration of untreated HIV infection

Novel insights in S. aureus response to hydrogen peroxide

S. aureus est un pathogène humain qui peut être responsable d’infections sévères voire mortelles. Les dérivés réactifs de l’oxygène sont des molécules hautement toxiques produites par les neutrophiles qui jouent un rôle crucial dans la défense de l’hôte contre cette bactérie. En effet, en l’absence de production de dérivés réactifs de l’oxygène, comme c’est le cas dans la maladie granulomateuse septique, les patients sont plus susceptibles aux infections sévères à S. aureus que la population générale. Cependant, S. aureus possède un système de défense complexe contre les dérivés réactifs de l’oxygène neutralisant les effets toxiques de ces molécules et permettant la réparation rapide des dommages cellulaires. Par conséquent, les mécanismes pour lesquels les dérivés réactifs de l’oxygène sont si importants dans la défense de l’hôte contre ce pathogène sont peu clairs. Ce travail explore les effets du peroxyde d’hydrogène (H2O2), un dérivé réactif de l’oxygène produit par les neutrophiles, sur l’expression des gènes de S. aureus et la manière dont cela affecte le fitness de la bactérie. Nous avons également développé un screen à haut débit pour étudier les gènes importants dans la résistance contre H2O2

VIH/sida - VIH au temps du Covid-19 : rencontre de deux pandémies

The current COVID-19 pandemic is the main topic of news worldwide by its magnitude and consequences across the entire planet. From a medical point of view, several risk factors for developing severe illness have been reported in the literature, notably an immunosuppressed status. For people living with HIV, several questions have been raised concerning not only their vulnerability, but also in relation to an eventual protection conferred by antiretroviral therapy. This article will address these two pandemics by looking at the potential impact of SARS-CoV-2 on people living with HIV and, in parallel, exploring similarities and differences in terms of treatment, potential for recovery, prevention and their impact on clinical research. We review also future novel therapies for the treatment of HIV.La pandémie de Covid-19 est le sujet d’actualité mondial tant par son ampleur que par ses immenses conséquences. Du point de vue médical, plusieurs facteurs de risque de développer une maladie sévère ont été établis dans la littérature, et l’immunosuppression en fait partie. Concernant les personnes vivant avec le VIH, plusieurs questions se sont posées : sont-elles plus vulnérables à l’acquisition de SARS-CoV-2, ou à une maladie Covid-19 sévère ? Ou au contraire sont-elles protégées par les antirétroviraux ? Cet article aborde ces deux pandémies et recherche des similitudes et des différences en termes de traitement, de guérison, de prévention et de recherche clinique. Nous décrivons brièvement quelques-uns des traitements antirétroviraux les plus innovants

Infection par le virus Varicella zoster chez l'adulte: au-delà du zona ?

Chickenpox is a generally benign condition during childhood, but it can cause severe complications when affecting teenage or adult patients. Immunodeficiency and pregnancy are risk factors for disseminated disease with pulmonary, neurological and/or hepatic involvement. Reinfection may be more frequent than previously thought, and management is identical to that of primary infection. The most common manifestation of viral reactivation is shingles, but it can also cause meningitis and vasculopathy, as well as disseminated herpes zoster in the immunocompromised patient. In this article, we will review the clinical manifestations and management of VZV infection in adults

Staphylococcus aureus, phagocyte NADPH oxidase and chronic granulomatous disease

Dysfunction of phagocytes is a relevant risk factor for staphylococcal infection. The most common hereditary phagocyte dysfunction is chronic granulomatous disease (CGD), characterized by impaired generation of reactive oxygen species (ROS) due to loss of function mutations within the phagocyte NADPH oxidase NOX2. Phagocytes ROS generation is fundamental to eliminate pathogens and to regulate the inflammatory response to infection. CGD is characterized by recurrent and severe bacterial and fungal infections, with Staphylococcus aureus as the most frequent pathogen, and skin and lung abscesses as the most common clinical entities. Staphylococcus aureus infection may occur in virtually any human host, presumably because of the many virulence factors of the bacterium. However, in the presence of functional NOX2, staphylococcal infections remain rare and are mainly linked to breaches of the skin barrier. In contrast, in patients with CGD, S. aureus readily survives and frequently causes clinically apparent disease. Astonishingly, little is known why S. aureus, which possesses a wide range of antioxidant enzymes (e.g. catalase, SOD), is particularly sensitive to control through NOX2. In this review, we will evaluate the discovery of CGD and our present knowledge of the role of NOX2 in S. aureus infection

Maladies infectieuses

What's new in infectious diseases in 2020 ? This year has been marked by the COVID-19 pandemic, prompting a review of the current knowledge on SARS-CoV-2 and its management in this article. The results of the Swiss project « PIRATE » indicate non-inferiority between CRP-guided antibiotic durations or fixed 7-day durations and 14-day durations for Gram-negative bacteremia. A Mongolian study did not show any benefit of vitamin D substitution in protecting children from tuberculosis. Baloxavir, a new antiviral against the flu, has been approved by Swissmedic. Finally, new American recommendations for therapeutic monitoring of vancomycin and universal screening for hepatitis C virus have been published

Rapid Progression of Kidney Dysfunction in People Living With HIV: Use of Polygenic and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Risk Scores.

In people with human immunodeficiency virus (PWH), it is unknown whether genetic background associates with rapid progression of kidney dysfunction (ie, estimated glomerular filtration rate [eGFR] decrease of >5mL/min/1.73m2 per year for ≥3 consecutive years). We obtained univariable and multivariable hazard ratios (HR) for rapid progression, based on the clinical D:A:D chronic kidney disease (CKD) risk score, antiretroviral exposures, and a polygenic risk score based on 14 769 genome-wide single nucleotide polymorphisms in white Swiss HIV Cohort Study participants. We included 225 participants with rapid progression and 3378 rapid progression-free participants. In multivariable analysis, compared to participants with low D:A:D risk, participants with high risk had rapid progression (HR = 1.82 [95% CI, 1.28-2.60]). Compared to the first (favorable) polygenic risk score quartile, participants in the second, third, and fourth (unfavorable) quartiles had rapid progression (HR = 1.39 [95% CI, 0.94-2.06], 1.52 [95% CI, 1.04-2.24], and 2.04 [95% CI, 1.41-2.94], respectively). Recent exposure to tenofovir disoproxil fumarate was associated with rapid progression (HR = 1.36 [95% CI, 1.06-1.76]). An individual polygenic risk score is associated with rapid progression in Swiss PWH, when analyzed in the context of clinical and antiretroviral risk factors