People living with HIV (PLWH) experienced an increased risk of heme malignancies. The place of cellular therapy as consolidation is well established in the general population, but remains to be confirmed in PLWH. Control of HIV has dramatically been improved due to combined antiretroviral therapy, and continuation of the treatment all through the graft procedure resulted in survival and TRM comparable with the general population. So, PLWH with an indication of auto- or allo-graft must be referred as eligible for the procedure. The conditioning regimen depends mainly on the malignancy and comorbidities. In allograft setting, the choice of the donor and the stem cell source must follow standard rules. Moreover, eradication of HIV has been described in patients allografted with a donor homozygous for CCR5 delta 32 mutation, due to a Graft vs. Reservoir effect independent of the myeloablation. If available, the selection of a donor bearing this mutation must be favoured. The antiretroviral therapy must be continued all along the treatment procedure after discussion with an expert for the choice of the antivirals. Prophylaxies against GVHD and management of infectious complications have to be followed according to standard rules.

Les personnes vivant avec le virus de l’immunodéficience humaine (PVVIH) ont un risque accru de développer une hémopathie maligne. La thérapie cellulaire s’est développée comme consolidation dans de nombreuses hémopathies malignes, mais sa place chez les patients vivant avec le VIH reste à définir. Les progrès majeurs réalisés dans le contrôle du VIH grâce aux antirétroviraux permettent la poursuite du traitement tout au long de la greffe, avec des résultats en termes de survie globale et de survie sans progression, ainsi que de TRM, comparable à la population générale. Tout patient vivant avec le VIH avec une indication de greffe doit être considéré comme éligible à la procédure, qui sera réalisée après conditionnement standard pour l’hémopathie considérée et selon les comorbidités. Concernant l’allogreffe, le choix du donneur et de la source cellulaire obéit aux règles standards. De plus, une éradication du VIH a été décrite chez certains patients greffés avec un donneur homozygote pour la mutation CCR5 Δ32, rendant compte d’un effet « Greffe contre réservoir » qui serait indépendant du degré de myéloablation. Si disponible, la sélection d’un donneur homozygote CCR5 delta 32 doit être privilégiée. Le traitement antirétroviral doit être poursuivi tout au long de la procédure après discussion avec un infectiologue expert, les prophylaxies de la GVH et la gestion des complications infectieuses réalisées selon les standards en cours.

Background The composition of the vaginal microbiota is known to be highly structured into five main community state types (CSTs) that are found in all human populations. Several associations between perceived ethnicity and the type of community have been reported but analyses of human genetic data, especially genome wide association studies (GWAS), remain limited and mostly rely on phenotypic traits rather than microbial DNA data. Methods Analysing genotyping data from in 168 women from the PAPCLEAR cohort study in France, we perform a GWAS looking for human genetic polymorphisms associated with vaginal microbiota community composition. For the latter, we use Simpson diversity and community state type (CST) as summary statistics to summarise 16S RNA metabarcoding data. Results We show that inverse Simpson diversity is the trait related to the vaginal microbiota that is best explained by the human genome. Furthermore, we identify several genomic regions associated with variations in this trait and show that the covariates associated with vaginal microbiota composition do not correlate with these genetic variants. Conclusion This is one of the first GWAS to use microbial genetic data instead of symptoms to characterise the vaginal microbiota. However, it remains limited because of the size of our cohort and our results call for more powered studies in terms of participants and genome coverage.

Background To better understand why about 15% of people with human immunodeficiency virus-1 (PWH) on highly active antiretroviral therapy do not restore their CD4 count, we explored the link previously reported between glutamate plasma level and CD4 count.Methods We recruited 44 adults with HIV-1 aviremic under antiretroviral therapy. Their peripheral blood concentrations in glutamate and gamma-aminobutyric acid (GABA) were determined by ELISA. Flow cytometry was used to detect GABA receptor, reactive oxygen species (ROS) produced by monocytes, and programmed T-cell death. DNA-dependent protein kinase (DNA-PK) and p53 phosphorylation were analyzed by western blot. DNA damage was quantified by immunofluorescence.Results We show that (1) some virologic responders present high plasma levels of glutamate and of its derivative, GABA; (2) monocytes express the GABA receptor GABA-B1; (3) GABA-B1 stimulation induces monocytic ROS production; (4) monocytes of PWH with high plasma levels of GABA release high amounts of ROS; and (5) monocyte-derived ROS oxidize the DNA of CD4+ T cells, creating double-strand breaks that activate DNA-PK and p53, and finally apoptosis. The intensity of this cascade of events is inversely correlated with the slope of CD4+ T-cell recovery in treated PWH.Conclusions We propose that DNA damage resulting from ROS produced by GABA-activated monocytes plays a key role in impaired immune restoration. Consequently, GABA-B1 antagonists and/or ROS inhibitors might be a promising therapy for nonimmunologic responders. Furthermore, the same mechanism could be involved in CD4 loss in the natural course of the infection.Clinical Trials Registration NCT04028882. Some PWH present high levels of plasma GABA, resulting in monocytic ROS production, DNA oxidation and apoptosis in CD4+ T cells. The intensity of this cascade is inversely correlated with CD4 recovery under antiretroviral therapy, suggesting a causative link.

Human papillomavirus (HPV) infections drive one in 20 new cancer cases, exerting a particularly high burden on women. Most anogenital HPV infections are cleared in less than two years, but the underlying mechanisms that favour persistence in around 10% of women remain largely unknown. Notwithstanding, it is precisely this information that is crucial for improving treatment, screening, and vaccination strategies. To understand viral and immune dynamics in non-persisting HPV infections, we set up an observational longitudinal cohort study with frequent on-site visits for biological sample collection. We enrolled 189 women aged from 18 to 25 and living in the area of Montpellier (France) between 2016 and 2020. We performed 974 on-site visits for a total of 1,619 months of follow-up. We collected data on virus load, local immune cell populations, local concentrations of cytokines, and circulating antibody titres. Using hierarchical Bayesian statistical modelling to simultaneously analyse the data from 164 HPV infections from 76 participants, we show that in two months after infection, HPV viral load in non-persisting infections reaches a plateau that lasts on average for 13 to 20 months (95% credibility interval) and is then followed by a rapid clearance phase. This first description of the dynamics of HPV infections comes with the identification of immune correlates associated with infection clearance, especially gamma-delta T cells and CXCL10 concentration. A limitation of this study on HPV kinetics is that many infection follow-ups are censored. Furthermore, some immune cell populations are difficult to label because cervical immunity is less well characterised than systemic immunity. These results open new perspectives for understanding the frontier between acute and chronic infections, and for controlling HPV-associated diseases, as well as for research on human cancers of infectious origin. Trial Registration: This trial was registered is registered at ClinicalTrials.gov under the ID NCT02946346. This study has been approved by the Comité de Protection des Personnes (CPP) Sud Méditerranée I (reference number 2016-A00712-49); by the Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé (reference number 16.504); by the Commission Nationale Informatique et Libertés (reference number MMS/ABD/ AR1612278, decision number DR-2016-488), by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (reference 20160072000007).

The vaginal microbiota is known to affect women's health. Yet, there is a notable paucity of high-resolution follow-up studies lasting several months, which would be required to interrogate the long-term dynamics and associations with demographic and behavioural covariates. Here, we present a high-resolution longitudinal cohort study of 125 women, followed for a median duration of 8.6 months, with a median of 11 samples collected per woman. Using a hierarchical Bayesian Markov model, we characterised the patterns of vaginal microbiota community persistence and transition, simultaneously estimated the impact of 16 covariates and quantified individual variability among women. We showed that "optimal" (Community State Type (CST) I, II, and V) and "sub-optimal" (CST III) communities are more stable over time than "non-optimal" (CST IV) ones. Furthermore, we found that some covariates - most notably alcohol consumption - impacted the probability of shifting from one CST to another. We performed counterfactual simulations to confirm that alterations of key covariates, such as alcohol consumption, could shape the prevalence of different microbiota communities in the population. Finally, our analyses indicated that there is a relatively canalised pathway leading to the deterioration of vaginal microbiota communities, whereas the paths to recovery can be highly individualised among women. In addition to providing one of the first insights into vaginal microbiota dynamics over a year, our study showcases a novel application of a hierarchical Bayesian Markov model to clinical cohort data with many covariates. Our findings pave the way for an improved mechanistic understanding of microbial dynamics in the vaginal environment and the development of novel preventative and therapeutic strategies to improve vaginal health.

Persistent infection by high-risk human papillomavirus (HPV) genotypes has been identified as a necessary etiological factor in cervical cancer, with HPV16 alone accounting for approximately 50-60 % of these cases. Fortunately, the vast majority of genital HPV infections clear spontaneously within two years and without causing any symptoms. The mechanisms leading to this clearance, or more precisely absence of HPV detection, remain unclear. Yet, understanding the immunology of HPV clearance could help develop new biomarkers or therapies. Building on a longitudinal study of women with genital HPV infections, we analysed 100 samples using quantitative bulk RNA sequencing (RNA-seq) to identify potential host transcriptomic signatures associated with infection clearance in asymptomatic young women. Using Gene Set Enrichment Analysis (GSEA) to anaylse significantly enriched pathways across infection outcome categories, we found that HPV-positive infections were characterised by downregulation in both antiviral innate and adaptive immune responses. Additionally, amongst the HPV-positive infections, HPV16-positive infections were associated with downregulation of pathways related to the viral life cycle regulation. Furthermore, non-clearing infections were differentiated by adaptive immune response activation, and persistent infections were marked by downregulation of pathways related to tumor necrosis factor (TNF) production and regulation. This work represents one of the first transcriptomics analyses tackling asymptomatic HPV clearance. It suggests that adaptive immunity is the most prominent factor involved in HPV infection clearance and could be potentially used to further address future diagnostic and therapy-related challenges for HPV screening and prevention. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 648963, to SA) and the ExposUM Fellowship (to NT) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The PAPCLEAR study has been approved by the Comité de Protection des Personnes (CPP) Sud Méditerranée I (reference number 2016-A00712-49); by the Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé (reference number 16.504); by the Commission Nationale Informatique et Libertés (reference number MMS/ABD/AR1612278, decision number DR-2016-488), by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (reference 20160072000007), and is registered at ClinicalTrials.gov under the ID [NCT02946346][1]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02946346&atom=%2Fmedrxiv%2Fearly%2F2025%2F10%2F13%2F2025.10.10.25337763.atom

Abstract Background In order to better understand why about 15% of people living with Human Immunodeficiency Virus-1 (PWH) on highly active antiretroviral therapy do not restore their CD4 count, we explored the link previously reported between glutamate plasma level and CD4 count. Methods We recruited fourty-four adults living with HIV-1 aviremic under antiretroviral therapy. Their peripheral blood concentrations in glutamate and GABA were determined by ELISA. Flow cytometry was used to detect GABA receptor, reactive oxygen species (ROS) produced by monocytes, and programmed T cell death. DNA-dependent protein kinase (DNA-PK) and p53 phosphorylation were analyzed by western blot. DNA damage was quantified by immunofluorescence. Results We show that i) some virologic responders present high plasma levels of glutamate and of its derivative, GABA; ii) monocytes express the GABA receptor GABA-B1; iii) GABA-B1 stimulation induces monocytic ROS production; iv) GABA-B1-overexpressing monocytes of PWH with high plasma levels of GABA release high amount of ROS; and v) monocyte-derived ROS oxidise the DNA of CD4+ T cells, creating double-strand breaks which activate DNA-PK and p53, and finally apoptosis. The intensity of this cascade of events is inversely correlated with the slope of CD4+ T cell recovery in treated PWH. Discussion We propose that DNA damage resulting from ROS produced by GABA-activated monocytes plays a key role in impaired immune restoration. Consequently, GABA-B1 antagonists and/or ROS inhibitors might be a promising therapy for non-immunologic responders. Furthermore, the same mechanism could be involved in CD4 loss in the natural course of the infection.

Human papillomaviruses (HPVs) are the most oncogenic viruses known to humans, with 12 high-risk (HR) genotypes causing nearly all cervical cancers. Cytology is commonly used to screen for cervical lesions but is currently being replaced by testing for high-risk HPV (HR HPV). Although HR HPV screening has a higher sensitivity, its specificity is limited, and it is currently advised to repeat the first screening 4 to 6 months later. To increase the sensitivity of the screening triage, other biomarkers have been suggested, including HPV viral load. Indeed, since 1999, several independent studies have found an association between HR HPV viral load in cervical samples and the severity of cervical disease. Here, we further explore the determinants of variations in HPV viral load in genital infections in young adult women. We analysed samples collected in the PAPCLEAR clinical cohort for participants who were infected by HPV genotypes for which we quantified virus load using qPCR targeting 13 genotypes. We developed a Bayesian statistical model estimating the effect of covariates of interest on the HPV viral load. To analyse precisely the viral load difference between HPV genotypes, phylogenetic distances between HPVs were also integrated in the Bayesian model. Our results fail to identify an effect of anti-HPV vaccination, co-infections by multiple HPVs or tobacco smoking on the detected viral load. On the opposite, swabs contained significantly more viral copies than cervical smears. Our results also highlight that most of the viral load variance could be explained at the genotype level (80%) rather than at the individual level (20%). Our model reveals important differences in viral load detected between the different genotypes tested, with HPV16 being the highest and HPV18 the lowest. The impact of phylogenetic signal on viral load was also estimated to be low, except for a cluster comprised of HPV53, HPV66 and HPV56. These results contribute to identifying the main drivers of HPV viral load detected and could help design needed future screening policies. ### Competing Interest Statement JR reports personal fees from Gilead (consulting and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events), Janssen (payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events), Merck (payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events), Theratechnologies (payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events), and ViiV Healthcare (consulting and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events) and support for attending meetings and/or travel from Gilead and Pfizer, outside of the submitted work. All the other authors do not report any conflict of interest. ### Funding Statement This project was funded by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 648963). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The PAPCLEAR cohort study has been approved by the Comite de Protection des Personnes (CPP) Sud Mediterranee I (reference number 2016-A00712-49), the Comite Consultatif sur le Traitement de l'Information en matiere de Recherche dans le domaine de la Sante (reference number 16.504), the Commission Nationale Informatique et Libertes (reference number MMS/ABD/ AR1612278, decision number DR-2016-488), the Agence Nationale de Securite du Medicament et des Produits de Sante (reference 20160072000007), and is registered at [ClinicalTrials.gov][1] under the ID [NCT02946346][2]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study will be made available upon publication in a peer reviewed journal. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02946346&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F17%2F2024.01.17.24301437.atom

Background People living with HIV (PLWH) are at risk of frailty, which is predictive for death. As an overactivity of the immune system is thought to fuel frailty, we characterized the immune activation profiles linked to frailty. Methods We quantified twenty-seven activation markers in forty-six virological responders (four females and forty-two males; median age, 74 years; median duration of infection, 24 years; median duration of undetectability, 13 years), whose frailty was determined according to the Fried criteria. T cell and NK cell activation was evaluated by flow cytometry, using a panel of cell surface markers. Soluble markers of inflammation, and monocyte activation and endothelial activation were measured by ELISA. The participants’ immune activation was profiled by an unsupervised double hierarchical clustering analysis. We used ANOVA p-values to rank immunomarkers most related to Fried score. A Linear Discriminant Analysis (LDA) was performed to link immune activation markers to frailty. Results 41% of the participants were pre-frail, including 24% with a Fried score of 1, and 17% with a Fried score of 2. ANOVA identified the 14 markers of T cell, monocyte, NK cell, endothelial activation, and inflammation the most linked to Fried 3 classes. The LDA performed with these 14 markers was capable of discriminating volunteers according to their Fried score. Two out of the 5 immune activation profiles revealed by the hierarchical clustering were linked to and predictive of pre-frailty. These two profiles were characterized by a low percentage of CD4 T cells and a high percentage of CD8 T cells, activated CD4 T cells, CD8 T cells, and NK cells, and inflammation. Conclusions We identified a particular immune activation profile associated with pre-frailty in PLWH. Profiling participants at risk of developing frailty might help to tailor the screening and prevention of medical complications fueled by loss of robustness. Further studies will indicate whether this frailty signature is specific or not of HIV infection, and whether it also precedes frailty in the general population.

The early administration of appropriate antibiotic therapy is crucial for the survival of patients with bacteremia. Current research focuses on improving analytical times through technology, whereas there have been very few efforts to improve postanalytical times even though they represent 40% of the time between blood taking and appropriate treatment administration. One of the clues is the efficiency and appropriateness of the result communication system. Here, we review all delays in the entire process with the aim of improving time to appropriate treatment administration. We discuss causes for long times to adjust treatment once microbiological results are released. We argue that the pervasive health information system in this organization serves as both a bottleneck and a rigid framework. Finally, we explore how next-generation hospital information systems should be designed to effectively assist the doctors in treating patients with bacteremia.

BACKGROUND:We studied the duration of HPV detection and risk of (re-) detection for 25 HPV genotypes in a cohort of 132 women followed every eight weeks for up to two years between 2016 and 2020. Participants were between 18 and 25 years old at inclusion and half of them were vaccinated against HPV. They were recruited near the University and the STI detection centre in Montpellier, France. METHODS:We used genotype-specific longitudinal data to characterise the dynamics of HPV-detected episodes. We investigated the contribution of viral and host factors to the variations in the duration of HPV detection, and the time before (re-)detection of the same genotype using multivariate Cox regression models with frailty at the patient level. FINDINGS:We detected at least one HPV episode in 74% of the participants and re-detected the same genotype in 47% of them. Covariates related to socio-economic difficulties were associated with a lower risk of detectability loss (hazard ratio 0.45 with a 95% confidence interval, CI, from 0.21 to 0.97). The number of lifetime sexual partners was strongly associated with an increased risk of new positive detection (hazard ratio 2.40 with a 95%CI from 1.07 to 5.39). In contrast, vaccination was associated with a lower risk of displaying incident infections (hazard ratio of 0.64 with a 95%CI from 0.43 to 0.96). CONCLUSION:In the short term, vaccination shows clear signs of protection against new HPV detections, including for some genotypes not targeted by the vaccine, such as HPV31 and HPV51.

Introduction La bithérapie dolutegravir/lamivudine (DTG/3TC) est une combinaison thérapeutique aujourd'hui recommandée en 1ère ligne comme en maintenance. Le faible nombre des échecs virologiques sous ce régime, dans les essais cliniques comme dans les cohortes, rend difficile l'analyse des facteurs associés à leur survenue. La cohorte française Dat'AIDS, du fait de ses effectifs importants, peut répondre à cette question. Matériels et méthodes Dat'AIDS agrège les dossiers informatisés de 89547 personnes vivant avec le VIH (PvVIH) incluant les données démographiques, immuno-virologiques, les évènements liés ou non au VIH/SIDA, ainsi que les lignes thérapeutiques.Dans cette étude rétrospective, nous avons inclus toutes les PvVIH initiant une ligne DTG/3TC pour la première fois avec une charge virale (CV) contrôlée (<50 copies/mL) et ayant ≥ 1 CV ensuite. L'échec virologique (avant/sous DTG/3TC) était défini par la survenue de 2 CV consécutives >50 copies/mL (ou 1 seule >200) au-delà des 6 premiers mois de traitement, sans préjuger du maintien de la ligne thérapeutique.Une analyse de Cox multivariée a évalué les variables d'intérêt (âge, sexe, mode de contamination, origine géographique, nadir CD4, zénith CV, durée du VIH et de l'indétectabilité sous antirétroviraux, échec virologique avant DTG/3TC, mutation M184V/I préalable, sous-type VIH, co-infection HBV/HCV, CD4 et CV au switch) associées à la survenue d'un échec virologique. Un Hazard Ratio (HR)>1 signifie un risque plus élevé d'échec virologique. Résultats Entre 2015 et 2022, 6770 PvVIH initiant en maintenance DTG/3TC ont été incluses : âge moyen (ET) 52 ans (12), sexe ratio H/F = 2,5, médiane indétectabilité 8,5 ans. Parmi eux, 2575 PvVIH avaient déjà eu un échec virologique avant DTG/3TC et 4633 avaient ≥ 1 génotype historique, qui montrait que 516 avaient présenté une M184V/I.Au cours du suivi sous DTG/3TC, médiane 1,4 an (IQR=0,8-2,1), un échec virologique survenait chez 172 PvVIH (2,5%, Intervalle de confiance (IC) à 95% [2,2-2,9]) avec une CV médiane de 1145 cp/mL. À l'échec, 68 génotypes étaient disponibles, montrant des mutations de résistance pour le DTG chez 4 patients et pour le 3TC chez 6 patients. La ligne DTG/3TC était toutefois poursuivie 68 fois avec re-suppression virologique rapide chez 2/3 des PvVIH.Parmi les facteurs indépendamment associés à l'échec virologique sous DTG/3TC, un échec virologique antérieur (152/2575 (5,9%) versus 20/4195 (0,5%) sans échec antérieur ; HR, 26,7 ; IC95% [14,9-40,8]) augmentait le risque, alors que la durée avec le VIH plus longue (0,91 par année ; [0,89-0,93]), le sexe masculin (0,5 ; 0,3-0,7) et les CD4 plus élevés au switch (0,99 ; 0,99-1,00) diminuaient ce risque.Un antécédent de résistance au 3TC sur le génotype historique n'augmentait pas le risque d'échec virologique (p=0,17). Conclusion Ces données françaises de vraie vie confirment l'efficacité et la solidité virologique de la bithérapie DTG/3TC, surtout s'il n'y a pas eu d'échec virologique auparavant.Liens d'intérêts déclarés :Déclaration de liens d'intérêts de Laurent Hocqueloux : Gilead Sciences (participation à des boards, congrès, études cliniques) MSD (participation à des boards, congrès, études cliniques) ViiV Healthcare (participation à des boards, congrès, études cliniques)

The rapid development of mRNA vaccines against SARS-CoV-2 infection significantly reduced the incidence of severe forms of Covid-19 in the elderly and in people with co-morbidities. The loss of efficacy over time and the appearance of Omicron variants has necessitated booster shots and adapting the vaccine mRNAs to the new circulating variants. (c) 2023 Published by Elsevier Masson SAS

Background. A prospective study was extended to the new antiretroviral and monitoring strategies in HIV-infected adults in low-income countries (NAMSAL-ANRS)-12313 trial, a 96-week open-label, multicenter, randomized phase 3 trial comparing dolutegravir (DTG) 50 mg with efavirenz 400 mg (EFV400), both administered with tenofovir disoproxil fumarate and lamivudine (TDF/3TC) as first-line treatment for antiretroviral therapy (ART)-naive people living with human immunodeficiency virus type 1 (HIV). Noninferiority of DTG to EFV400 was demonstrated at 48-week and sustained at 96 weeks. Here, we present results at 192-week.Methods. Previous trial participants were reconsented and followed up on their initial randomization arm (1:1 DTG/TDF/3TC:EFV400/TDF/3TC). Assessments included changes in viral suppression, biological parameters, and new serious adverse events (SAEs).Results. Among the participants enrolled in the trial, 81% (499/613) were analyzed at week 192: 84% (261/310) on DTG/TDF/3TC and 78% (238/303) on EFV400/TDF/3TC. HIV RNA suppression was maintained in 69% (214/310) on DTG/TDF/3TC-based and 62% (187/303) on EFV400/TDF/3TC-based regimens (difference, 7.3% [95% confidence interval, -.20 to 14.83]; P = .057). Five (DTG/TDF/3TC = 2; EFV400/TDF/3TC = 3) new viral failures (World Health Organization definition) without related resistance DTG mutations and 24 new SAEs were observed (DTG/TDF/3TC = 13; EFV400/TDF/3TC = 11). Mean weight gain was +9.4 kg on DTG/TDF/3TC and +5.9 kg on EFV400/TDF/3TC. The percentage of participants with obesity increased from 6.9% to 27.7% on DTG/TDF/3TC (P < .0001) and from 8.3% to 16.7% on EFV400/TDF/3TC (P = .0033).Conclusions. Four-year follow-up of people with HIV on DTG- and EFV400-based regimens showed long-term efficacy and safety of both ARTs, markedly among participants on DTG/TDF/3TC with high baseline viral load. However, unexpected substantial weight gain over time was prominent among participants on DTG/TDF/3TC, which should be closely monitored.

L'isavuconazole est un agent antifongique triazole de développement récent recommandé comme traitement de première ligne pour l'aspergillose pulmonaire invasive. Avec l'avènement de la pandémie de COVID-19, des cas d'aspergillose pulmonaire associée à la COVID-19 (CAPA) ont été décrits avec une prévalence allant de 5 à 30%. Nous avons développé et validé un modèle pharmacocinétique de population (PKpop) des concentrations plasmatiques d'isavuconazole chez les patients hospitalisés en unités de soins intensifs et réanimation atteints de CAPA La modélisation non linéaire à effets mixtes à l'aide du logiciel Monolix a été utilisé pour l'analyse pharmacocinétique de 65 concentrations plasmatiques minimales provenant de 18 patients. Les paramètres pharmacocinétiques ont été estimés au mieux avec un modèle à un compartiment. A partir du modèle validé des simulations de hautes posologies ont été évaluées par des simulations de Monte carlo. La moyenne des concentrations plasmatiques d'isavuconazole était de 1,87 [1,29-2,25] mg/L malgré une dose d'attaque prolongée (72 h pour un tiers des patients) et une dose d'entretien moyenne de 300 mg par jour. La modélisation pharmacocinétique a montré que le traitement d'épuration extra-rénal (EER) était significativement associé à une sous exposition, expliquant une partie de la variabilité de la clairance. Les simulations de Monte Carlo ont suggéré que le schéma posologique recommandé ne permettait pas d'atteindre la valeur minimale cible de 2 mg/L en temps voulu (72 h). Il s'agit du premier modèle pharmacocinétique populationnel sur l'isavuconazole développé pour les patients en soins intensifs atteints de CAPA, qui souligne la nécessité d'une surveillance thérapeutique de l'isavuconazole, notamment pour les patients sous EER. Aucun lien d'intérêt

The efficacy and rapid adaptability of vaccines based on messenger RNA (mRNA) was demonstrated during the Covid-19 pandemic. The clinical development is at an advanced stage compared to other respiratory viruses (influenza virus, respiratory syncytial virus). Many viruses responsible for serious epidemics in tropical regions are potential targets for mRNA vaccines. mRNA-vaccine platforms are one of the tools capable of responding to the emergence of new infectious diseases. (c) 2023 Published by Elsevier Masson SAS

Les vaccins basés sur l’ARN messager (ARNm) ont démontré leur efficacité et leur rapide adaptabilité dans le contexte de la pandémie de Covid-19. Leur développement clinique est très avancé vis-à-vis d’autres virus respiratoires (virus de la grippe, virus respiratoire syncytial). De nombreux virus responsables d’épidémies graves en régions tropicales sont des cibles potentielles des vaccins à ARNm. Les plateformes vaccinales à ARNm font partie des outils de réponse à l’émergence d’une infection à germe nouveau. © 2023 Publié par Elsevier Masson SAS mRNA vaccines: perspectives in infectiology. The efficacy and rapid adaptability of vaccines based on messenger RNA (mRNA) was demonstrated during the Covid-19 pandemic. The clinical development is at an advanced stage compared to other respiratory viruses (influenza virus, respiratory syncytial virus). Many viruses responsible for serious epidemics in tropical regions are potential targets for mRNA vaccines. mRNA-vaccine platforms are one of the tools capable of responding to the emergence of new infectious diseases. © 2023 Published by Elsevier Masson SAS