Impact of hormonal therapy on HIV-1 immune markers in cis women and gender minorities.

BACKGROUND: Although sex hormones are recognized to induce immune variations, the effect of hormonal therapy use on immunity is only poorly understood. Here, we quantified how hormonal therapy use affects HIV-1 immune markers in cis women (CW) and trans women and non-binary people (TNBP) with HIV. METHODS: We considered CD4, CD8 and lymphocyte measurements from cis men (CM), CW and TNBP in the Swiss HIV Cohort Study. We modelled HIV-1 markers using linear mixed-effects models with an interaction between 'gender' (CW, TNBP) and 'hormonal therapy use' (yes/no). Models were adjusted on age, ethnicity, education level, time since start of antiretroviral therapy and use of intravenous drugs. We assessed the inflammatory effect of hormonal therapy use in 31 TNBP using serum proteomics measurements of 92 inflammation markers. RESULTS: We included 54 083 measurements from 3092 CW and 83 TNBP, and 147 230 measurements from 8611 CM. Hormonal therapy use increased CD4 count and CD4:CD8 ratio in TNBP more than in CW (pinteraction = 0.02 and 0.007, respectively). TNBP with hormonal therapy use had significantly higher CD4 counts [median = 772 cells/µL, interquartile range (IQR): 520-1006] than without (617 cells/µL, 426-892). This was similar to the effect of CW versus CM on CD4 T cells. Hormonal therapy use did not affect serum protein concentrations in TNBP. CONCLUSION: This study highlights the potential role of hormonal therapy use in modulating the immune system among other biological and social factors, especially in TNBP with HIV.

[Vaccination updates for the elderly]. / Mise à jour des vaccins chez les personnes âgées.

The number of elderly people is constantly increasing in Switzerland. This population is often at higher risk of infections and concomitant decompensation of underlying comorbidities, in particular cardiac or respiratory diseases. Vaccines are some of the most effective preventive measures for limiting morbidity and mortality related to some of those infections, such as influenza or shingles. In order to improve vaccination coverage, it is essential to inform the patients of the benefits of vaccination, and to plan a catch-up vaccination consultation. The goal of this article is to offer a practical guide for the general practitioner detailing vaccines for the elderly recommended in Switzerland.

Le nombre de personnes âgées est en constante augmentation en Suisse. Celles-ci sont souvent plus à risque de présenter des infections et de façon concomitante une décompensation de leurs comorbidités, notamment cardiaques et respiratoires. La vaccination est l'une des mesures préventives efficaces pour limiter la morbimortalité associée à certaines de ces infections, comme la grippe ou le zona. Afin d'améliorer la couverture vaccinale, il est primordial d'informer les patients sur les bénéfices de la vaccination et de prévoir une consultation dédiée à une mise à jour vaccinale. Le but de cet article est d'offrir un guide pratique pour le médecin de famille sur les différents vaccins recommandés chez la personne âgée.

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 < .01), but leukocytosis (>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.

Telomere Length Declines in Persons With Human Immunodeficiency Virus Before Antiretroviral Therapy Start but Not After Viral Suppression: A Longitudinal Study Over >17 Years.

BACKGROUND: In people with human immunodeficiency virus (PWH), long-term telomere length (TL) change without/with suppressive antiretroviral therapy (ART) and the contribution of genetic background to TL are incompletely understood. METHODS: We measured TL change in peripheral blood mononuclear cells by quantitative polymerase chain reaction in 107 Swiss HIV Cohort Study participants with longitudinal samples available both before and during suppressive ART. We applied mixed-effects multilevel regression to obtain uni-/multivariable estimates for longitudinal TL dynamics including age, sex, and CD4/CD8 ratio. We assessed the effect of (1) individual antiretrovirals and (2) an individual TL-polygenic risk score ([TL-PRS] based on 239 single-nucleotide polymorphisms) on TL in 798 additional participants from our previous longitudinal studies. RESULTS: During untreated human immunodeficiency virus (HIV) infection (median observation, 7.7; interquartile range [IQR], 4.7-11] years), TL declined significantly (median -2.12%/year; IQR, -3.48% to -0.76%/year; P = .002). During suppressive ART (median observation, 9.8; IQR, 7.1-11.1 years), there was no evidence of TL decline or increase (median + 0.54%/year; IQR, -0.55% to + 1.63%/year; P = .329). The TL-PRS contributed to TL change (global P = .019) but particular antiretrovirals did not (all P > .15). CONCLUSIONS: In PWH, TL is associated with an individual PRS. Telomere length declined significantly during untreated chronic HIV infection, but no TL change occurred during suppressive ART.

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.

BACKGROUND: 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). METHODS: 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. RESULTS: 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]). DISCUSSION: An individual polygenic risk score is associated with rapid progression in Swiss PWH, when analyzed in the context of clinical and antiretroviral risk factors.

Coronary Artery Disease-Associated and Longevity-Associated Polygenic Risk Scores for Prediction of Coronary Artery Disease Events in Persons Living With Human Immunodeficiency Virus: The Swiss HIV Cohort Study.

BACKGROUND: Coronary artery disease (CAD) is in part genetically determined. Aging is accentuated in people with human immunodeficiency virus (HIV) (PLWH). It is unknown whether genetic CAD event prediction in PLWH is improved by applying individual polygenic risk scores (PRSs) and by considering genetic variants associated with successful aging and longevity. METHODS: In the Swiss HIV Cohort Study participants of self-reported European descent, we determined univariable and multivariable odds ratios (ORs) for CAD events, based on traditional CAD risk factors, adverse antiretroviral exposures, and different validated genome-wide PRSs. PRSs were built from CAD-associated single-nucleotide polymorphisms (SNPs), longevity-associated SNPs, or both. RESULTS: We included 269 patients with CAD events between 2000 and 2017 (median age, 54 years; 87% male; 82% with suppressed HIV RNA) and 567 event-free controls. Clinical (ie, traditional and HIV-related) risk factors and PRSs, built from CAD-associated SNPs, longevity-associated SNPs, or both, each contributed independently to CAD events (P < .001). Participants with the most unfavorable clinical risk factor profile (top quintile) had an adjusted CAD-OR of 17.82 (95% confidence interval [CI], 8.19-38.76), compared with participants in the bottom quintile. Participants with the most unfavorable CAD-PRSs (top quintile) had an adjusted CAD-OR of 3.17 (95% CI, 1.74-5.79), compared with the bottom quintile. After adding longevity-associated SNPs to the CAD-PRS, participants with the most unfavorable genetic background (top quintile) had an adjusted CAD-OR of 3.67 (95% CI, 2.00-6.73), compared with the bottom quintile. CONCLUSIONS: In Swiss PLWH, CAD prediction based on traditional and HIV-related risk factors was superior to genetic CAD prediction based on longevity- and CAD-associated PRS. Combining traditional, HIV-related, and genetic risk factors provided the most powerful CAD prediction.

[HIV in the time of COVID-19 : the meeting between two pandemics]. / 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.

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 «â€…PIRATE ¼ 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.

Que dire des nouveautés en maladies infectieuses en 2020 ? L'année a été marquée évidemment par la pandémie du Covid-19, motivant une revue dans cet article, des connaissances actuelles sur le SARS-CoV-2 et de sa prise en charge. Les résultats du projet suisse PIRATE ont montré une non-infériorité pour les bactériémies Gram négatif entre une antibiothérapie de 7 jours ou guidée par la CRP face à une durée de 14 jours. Une étude mongolienne n'a pas permis de montrer le bénéfice d'une substitution en vitamine D chez les enfants sur l'incidence de la tuberculose. Le baloxavir, un nouvel antiviral contre la grippe, a été approuvé par Swissmedic. Et enfin, des nouvelles recommandations américaines sur le monitoring thérapeutique de la vancomycine et sur le dépistage universel de l'hépatite C ont été publiées.

[Varicella Zoster infections in adults: beyond shingles?]. / 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.

First report of uncommon mycobacteria in post LASIK keratitis: Mycobacterium wolinskyi.

Laser assisted in situ keratomileusis (LASIK) surgery is the leading and most performed refractive surgery nowadays. A possible complication of LASIK surgery is infectious keratitis which can lead to disastrous corneal damage and result in permanent loss of vision. LASIK procedures have become increasingly accessible, and the demand for refractive surgery has risen among patients, challenging the medical field to improve the prevention of post-operative infections. Nevertheless, a wide range of pathogens have been described as responsible for post-LASIK keratitis. However, non-tuberculous mycobacterial keratitis remains an infrequent occurrence and is poorly described in the literature. To the best of our knowledge, this is the first ever reported case of post-LASIK keratitis caused by Mycobacterium wolinskyi. We describe the clinical and microbial characteristics, leading to its challenging treatment choice.

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.

Hydrogen Peroxide Affects Growth of S. aureus Through Downregulation of Genes Involved in Pyrimidine Biosynthesis.

Reactive oxygen species (ROS) play a crucial role in the cellular defense against S. aureus, as evidenced by the importance of this pathogen in patients lacking the ROS-generating phagocyte NADPH oxidase NOX2. ROS concentrations required to kill S. aureus in vitro are much higher than those found in the phagosome. We therefore hypothesized that sublethal ROS concentrations may play a role in S. aureus gene dysregulation and investigated the in vitro transcriptomic response of S. aureus to sublethal concentrations of hydrogen peroxide (H2O2). A striking observation of these experiments was a coordinated and massive downregulation of genes involved in pyrimidine metabolism. Using transposon insertion mutants, we demonstrated that deletion of carA, a gene involved in pyrimidine synthesis, led to a significant growth defect and to an increased sensitivity of S. aureus to added H2O2. The phenotype of the carA mutant could be reversed through supplementation with the pyrimidine precursor uracil, or with a multicopy vector encoding carA. As opposed to the impact of ROS on extracellular survival, carA deletion did not affect the intracellular survival in neutrophils. Our results raise the possibility that ROS-dependent downregulation of pyrimidine metabolism might be a survival strategy of S. aureus, allowing colonization through intracellular survival, while decreasing the risk of killing the host through dampened extracellular growth.

Mammalian NADPH Oxidases.

Reactive oxygen species (ROS) are highly reactive oxygen derivatives. Initially, they were considered as metabolic by-products (of mitochondria in particular), which consistently lead to aging and disease. Over the last decades, however, it became increasingly apparent that virtually all eukaryotic cells possess specifically ROS-producing enzymes, namely, NOX NADPH oxidases. In most mammals, there are seven NOX isoforms: three closely related isoforms, NOX1, 2, 3, which are activated by cytoplasmic subunits; NOX4, which appears to be constitutively active; and the EF-hand-containing Ca2+-activated isoforms NOX5 and DUOX1 and 2. Loss-of-function mutations in NOX genes can lead to serious human disease. NOX2 deficiency leads to primary immune deficiency, while DUOX2 deficiency presents as congenital hypothyroidism. Nox-deficient mice provide important tools to explore the physiological functions of various NADPH oxidases as a loss of function in Nox2, Nox3, and Duox2 leads to a spontaneous phenotype. The genetic absence of Nox1, Nox4, and Duox1 does not result in an obvious mouse phenotype (the NOX5 gene is absent in rodents and can therefore not be studied using knockout mice). Since the discovery of the NOX family at the turn of the millennium, much progress in understanding the biochemistry and the physiology of NOX has been made; however many questions remain unanswered to date. This chapter is an overview of our present knowledge on mammalian NOX/DUOX enzymes.

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.