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BackgroundGlenzocimab is a novel antithrombotic agent which targets platelet glycoprotein VI (GPVI) and does not induce haemorrhage. SARS-CoV-2 triggers a prothrombotic state and lung injury whose mechanisms include coagulopathy, endothelial dysfunction, and inflammation with dysregulated platelets.Methods and patientsGARDEN was a randomised double-blind, exploratory phase II study of glenzocimab in SARS-CoV-2 respiratory failure (NCT04659109). PCR+ adults in Brazil and France (7 centres) were randomized to standard-of-care (SOC) plus glenzocimab (1000 mg/dayx3 days) or placebo, followed for 40 days. Primary efficacy endpoint was clinical progression at Day 4. All analyses concerned the intention-to-treat population.ResultsBetween December 2020 and August 2021, 61 patients received at least one dose (30 glenzocimab vs 32 placebo) and 58 completed the study (29 vs 29). Clinical progression of COVID-19 ARDS was not statistically different between glenzocimab and placebo arms (43.3% and 29.0%, respectively; p = 0.245). Decrease in the NEWS-2 category at D4 was statistically significant (p = 0.0290) in the glenzocimab arm vs placebo. No Serious Adverse Event (SAE) was deemed related to study drug; bleeding related events were reported in 6 patients (7 events) and 4 patients (4 events) in glenzocimab and placebo arms, respectively.ConclusionsTherapeutic GPVI inhibition assessment during COVID-19 was conducted in response to a Public Health emergency. Glenzocimab in coagulopathic patients under therapeutic heparin was neither associated with increased bleeding, nor SAE. Clinical impact of glenzocimab on COVID-19 ARDS was not demonstrated. A potential role for GPVI inhibition in other types of ARDS deserves further experimentation. Glenzocimab is currently studied in stroke (ACTISAVE: NCT05070260) and cardiovascular indications.

BackgroundComparison of changes in body composition, adipokines and inflammatory markers after initial therapy with a nucleos(t)ide reverse transcriptase inhibitor (N(t)RTI)- sparing or containing regimen are scarce.DesignRandomised Clinical Trial.MethodsThis is the body composition substudy of NEAT 001/ANRS 143, a randomised trial comparing darunavir/ritonavir (DRV/r) plus either raltegravir (RAL) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in 805 ART naïve HIV-infected adults. The primary endpoint was percentage change in limb fat at week 96. Secondary endpoints were associations among these changes and metabolic markers (IL-6, insulin, leptin, adiponectin, FGF-23).Results126 subjects (61 DRV/r + RAL and 65 DRV/r + TDF/FTC) were included. The rate of change in BMI between groups for RAL versus TDF/FTC at week 96 was 1.5% per 48-week period (p = 0.015). The rate of change in limb fat mass, trunk fat mass, total body fat and total lean mass was for RAL versus TDF/FTC at week 96 was 2.5% (p = 0.38), 7.3% ((p = 0.021), 4.9% (p = 0.061) and 1.3% (p = 0.12) respectively. Baseline insulin and leptin levels were correlated with baseline limb fat and trunk fat mass [r = 0.31 (p = 0.0043)/r = 0.28 (p = 0.0011) for limb fat, and r = 0.63 (pConclusionsAfter week 96 a N(t)RTI sparing regimen of DRV/r + RAL produced a numerically greater percentage increase in body composition variables with only change in trunk fat mass and BMI being significant.

The integrase (IN) strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), comprise the newest drug class approved for the treatment of HIV-1 infection, which joins the existing classes of reverse transcriptase, protease and binding/entry inhibitors. The efficacy of first-line regimens has attained remarkably high levels, reaching undetectable viral loads in 90% of patients by Week 48; however, there remain patients who require a change in regimen due to adverse events, virologic failure with emergent resistance or other issues of patient management. Large, randomized clinical trials conducted in antiretroviral treatment-naive individuals are required for drug approval in this population in the US, EU and other countries, with the primary endpoint for virologic success at Week 48. However, there are differences in the definition of virologic failure and the evaluation of drug resistance among the trials. This review focuses on the methodology and tabulation of resistance to INSTIs in phase 3 clinical trials of first-line regimens and discusses case studies of resistance.

BackgroundMost adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load.Methods and findingsUsing data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements 500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30-0.40) for counts ConclusionsDespite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count

Background & Aims: In France, bulevirtide (BLV) became available in September 2019 through an early access program to treat patients with HDV. The aim of this analysis was to evaluate the efficacy and safety of BLV in patients with HIV and HDV coinfection. Methods: Patients received BLV 2 mg ± pegylated interferon-α (pegIFNα) according to the physician’s decision. The primary endpoint (per-protocol analysis) was the virological response rate at Week 48, defined as the proportion of patients with undetectable serum HDV RNA or a HDV RNA decline >2 log10 IU/ml from baseline. Results: The characteristics of the 38 patients were as follows: 28 male, mean age 47.7 years, and mean baseline HDV RNA viral load 5.7 ± 1.2 log10 IU/ml. Median HIV viral load and mean CD4 count were 32 (30–65) copies/ml and 566 ± 307/mm3, respectively. Eight patients stopped treatment before Week 48. At Week 48, 10 of 19 patients (52.6%) in the 2 mg BLV group and five of seven patients (71.4%) in the 2 mg BLV + pegIFNɑ group had reached virological response (no HDV RNA available in four patients). At Week 48, seven of 19 patients in the 2 mg BLV group and three of six patients in the 2 mg BLV + pegIFNɑ group had a combined response (virological response and normal alanine aminotransferase level). Conclusions: Adults living with HIV coinfected with HDV can be treated by BLV with a virological response in more than 50% of patients. The combination of BLV and pegIFNɑ showed a strong virological response. Impact and implications: Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug–drug interaction is reported. Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug–drug interaction is reported. Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug–drug interaction is reported.

Abstract The increase in worldwide travel is making imported malaria a growing health concern in non-endemic countries. Most data on the pathophysiology of malaria come from endemic areas. Little is known about cytokine profiles during imported malaria. This study aimed at deciphering the relationship between cytokine host response and malaria severity among imported cases in France. This study reports cytokine profiles in adults with Plasmodium falciparum malaria included in the PALUREA prospective study conducted between 2006 and 2010. The patients were classified as having uncomplicated malaria (UM) or severe malaria (SM), with this last further categorized as very severe malaria (VSM) or less severe malaria (LSM). At hospital admission, eight blood cytokines were assayed in duplicate using Luminex® technology: interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-10, tumor necrosis factor (TNF)α, interferon (IFN)γ, and macrophage migration inhibitory factor (MIF). These assays were repeated on days 1 and 2 in the SM group. Of the 278 patients, 134 had UM and 144 SM. At hospital admission, over half the patients had undetectable levels of IL-1α, IL-1β, IL-2, IL-4, IFNγ, and TNFα, while IL-10 and MIF were significantly higher in the SM vs. the UM group. Higher IL-10 was significantly associated with higher parasitemia (R = 0.32 [0.16–0.46]; P = 0.0001). In the SM group, IL-10 elevation persisting from admission to day 2 was significantly associated with subsequent nosocomial infection. Of eight tested cytokines, only MIF and IL-10 were associated with disease severity in adults with imported P. falciparum malaria. At admission, many patients had undetectable cytokine levels, suggesting that circulating cytokine assays may not be helpful as part of the routine evaluation of adults with imported malaria. Persisting high IL-10 concentration was associated with subsequent nosocomial infection, suggesting its possible interest in immune monitoring of most severe patients.

ABSTRACTBackground The economic consequences of the recent COVID-19 pandemic were substantial. However, direct medical costs in France have not been determined.Objective To describe patient characteristics, intensity of care, mortality, and direct medical costs in patients hospitalised for COVID-19 infections in France.Study design A retrospective study of the French national hospital claims database for 2020.Setting Hospital care.Patients or other participants All patients hospitalised for COVID-19 in 2020 were included and classified by hospitalisation duration into acute phase and prolonged COVID-19.Intervention Stratification by intensity of care (Level 1: no or low-flow oxygen support; Level 2: non-invasive ventilation; Level 3: mechanical ventilation).Main outcome measure Cost of hospital care in 2020 Euros from a payer perspective.Results 199,455 patients were hospitalised for COVID-19 in France in 2020. 17,824 patients (8.9%) received mechanical ventilation and 32,602 patients (16.3%) died. Mean per patient cost was €5,510 ± 7,142. This cost was highest in patients receiving Level 3 care, patients aged >80 years and in those with prolonged COVID.Conclusion The economic burden of hospitalisations for COVID-19 infections in France during 2020 was substantial. The study provides robust baseline data to benchmark advances in the standard of care and to nurture epidemiological models.

Abstract Appropriately selected neutralising monoclonal antibodies (nmAbs) are an effective treatment for patients with mild or moderate coronavirus disease 2019 (COVID-19) who are at high risk of progression to severe disease. In contrast, the efficacy of nmAbs in patients hospitalised with COVID-19 has been mixed, and clinical benefit has largely been restricted to seronegative patients [i.e. those lacking endogenous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies] in the trials with positive outcomes. This review summarises the major clinical trial data investigating nmAb treatment for hospitalised patients with COVID-19, and explores current definitions of seropositivity, what they mean in a late-pandemic context and discusses the current late-pandemic challenges associated with defining ‘seroprotection’ in a clinically meaningful way. We conclude that following widespread vaccination, increasing numbers of prior infections and emerging viral variants, seropositivity now reflects a range of immune coverage rather than a binary tool with which to aid decision-making on a clinically actionable timescale. Treatment decisions with nmAbs in a late-pandemic context would therefore likely best rely on information regarding clinical status, time since symptom onset, underlying patient condition(s) and the dominant circulating variant, should they be approved for future use in hospitalised patients with COVID-19.

Noncholera vibriosis is a rare, opportunistic bacterial infection caused by Vibrio spp. other than V. cholerae O1/O139 and diagnosed mainly during the hot summer months in patients after seaside activities. Detailed knowledge of circulating pathogenic strains and heterogeneities in infection outcomes and disease dynamics may help in patient management. We conducted a multicenter case-series study documenting Vibrio infections in 67 patients from 8 hospitals in the Bay of Biscay, France, over a 19-year period. Infections were mainly caused by V. alginolyticus (34%), V. parahaemolyticus (30%), non-O1/O139 V. cholerae (15%), and V. vulnificus (10%). Drug-susceptibility testing revealed intermediate and resistant strains to penicillins and first-generation cephalosporins. The acute infections (e.g., those involving digestive disorder, cellulitis, osteitis, pneumonia, and endocarditis) led to a life-threatening event (septic shock), amputation, or death in 36% of patients. Physicians may need to add vibriosis to their list of infections to assess in patients with associated risk factors.

Summary: Background: Lack of specific definitions of clinical characteristics, disease severity, and risk and preventive factors of post-COVID-19 syndrome (PCS) severely impacts research and discovery of new preventive and therapeutics drugs. Methods: This prospective multicenter cohort study was conducted from February 2020 to June 2022 in 5 countries, enrolling SARS-CoV-2 out- and in-patients followed at 3-, 6-, and 12-month from diagnosis, with assessment of clinical and biochemical features, antibody (Ab) response, Variant of Concern (VoC), and physical and mental quality of life (QoL). Outcome of interest was identification of risk and protective factors of PCS by clinical phenotype, setting, severity of disease, treatment, and vaccination status. We used SF-36 questionnaire to assess evolution in QoL index during follow-up and unsupervised machine learning algorithms (principal component analysis, PCA) to explore symptom clusters. Severity of PCS was defined by clinical phenotype and QoL. We also used generalized linear models to analyse the impact of PCS on QoL and associated risk and preventive factors. CT registration number: NCT05097677. Findings: Among 1796 patients enrolled, 1030 (57%) suffered from at least one symptom at 12-month. PCA identified 4 clinical phenotypes: chronic fatigue-like syndrome (CFs: fatigue, headache and memory loss, 757 patients, 42%), respiratory syndrome (REs: cough and dyspnoea, 502, 23%); chronic pain syndrome (CPs: arthralgia and myalgia, 399, 22%); and neurosensorial syndrome (NSs: alteration in taste and smell, 197, 11%). Determinants of clinical phenotypes were different (all comparisons p

Abstract Background Raltegravir (RAL) has favorable tolerability and safety profile, with few and manageable drug interactions. The use of RAL 1200 mg once daily (qd) for first-line therapy is well established. We assessed efficacy and safety of RAL 1200 mg qd, as part of triple combined antiretroviral therapy (cART), for maintenance strategy. Methods The QDISS trial (NCT03195452) was a 48-week multicenter, single-arm, open-label study designed to evaluate the ability of 2 NRTIs + RAL 1200 mg qd to maintain virological suppression in HIV-1 infected subjects on a stable cART with 2 NRTIs and a third agent for at least 6 months. The primary endpoint was the proportion of participants with HIV-1 RNA

Abstract Background In HCV-infected patients with advanced liver disease, the direct antiviral agents-associated clinical benefits remain debated. We compared the clinical outcome of patients with a previous history of decompensated cirrhosis following treatment or not with direct antiviral agents from the French ANRS CO22 HEPATHER cohort. Methods We identified HCV patients who had experienced an episode of decompensated cirrhosis. Study outcomes were all-cause mortality, liver-related or non-liver-related deaths, hepatocellular carcinoma, liver transplantation. Secondary study outcomes were sustained virological response and its clinical benefits. Results 559 patients met the identification criteria, of which 483 received direct antiviral agents and 76 remained untreated after inclusion in the cohort. The median follow-up time was 39.7 (IQR: 22.7–51) months. After adjustment for multivariate analysis, exposure to direct antiviral agents was associated with a decrease in all-cause mortality (HR 0.45, 95% CI 0.24–0.84, p = 0.01) and non-liver-related death (HR 0.26, 95% CI 0.08–0.82, p = 0.02), and was not associated with liver-related death, decrease in hepatocellular carcinoma and need for liver transplantation. The sustained virological response was 88%. According to adjusted multivariable analysis, sustained virological response achievement was associated with a decrease in all-cause mortality (HR 0.29, 95% CI 0.15–0.54, p

Summary: Background: Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the HIV-induced epigenetic modifications. Methods: 184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples [96 weeks of follow-up]) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and DNA methylation-based estimates of leucocyte composition. Findings: We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio. Interpretation: Control of HIV viraemia after 96 weeks of ART initiation partly restores the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection. Funding: NEAT-ID Foundation and Instituto de Salud Carlos III, co-funded by European Union.

Background Quantification of COVID-19 burden may be useful to support the future allocation of resources.Objective To evaluate the public health impact of COVID-19 in French ambulatory patients with at least one risk factor for severe disease.Study design A Markov model was used to estimate life years, costs, number of hospitalisations, number of deaths and long/prolonged COVID forms over a time horizon of 2 years. The hospitalisation probabilities were derived from an early access cohort, and the hospitalisation stay characteristics were derived from the French national hospital discharge database. Several scenario analyses were conducted.Results The number of hospitalisations reached 256 per 1,000 patients over the acute phase (first month of simulation), and 382 per 1,000 patients over 2 years. The number of deaths was 37 per 1,000 patients, and the number of long/prolonged COVID forms reached 407 per 1,000 patients. These translated into a reduction of 0.7 days of life per patient in the first month, with an associated cost of €1,578, and a reduction of 27 days of life over the time horizon, with an associated cost of €4,280. The highest burden was observed for patients over 80 years old, and those not vaccinated. The scenarios with a less severe situation or new treatments available showed a non-negligible burden reduction.Conclusion This study allowed us to quantify the considerable burden related to COVID-19 in infected patients, with at least one risk factor for severe form. Strategies with the ability to substantially reduce this burden in France are urgently required.

Abstract Background Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunting an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions. By providing immediate immunity and inhibiting entry into cells, neutralizing antibody treatment is of interest for patient with COVID-19-induced moderate pneumonia. Convalescent plasma to treat infected patients is therefore a relevant therapeutic option currently under assessment (CORIMUNO-PLASM NCT04324047). However, the difficulties of collecting plasma on the long term are not adapted to a broad use across all populations. New polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) developed by Xenothera and administered intravenous. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, blocking infection of ACE-2-positive human cells with SARS-CoV-2. Methods Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates. A first human study with another fully representative GH-pAb from Xenothera is ongoing in recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans. The objectives of this 2-step phase 2 randomized double-blinded, placebo-controlled study are to define the safety and the optimal XAV-19 dose to administrate to patients with SARS-CoV-2 induced moderate pneumonia, and to assess the clinical benefits of a selected dose of XAV-19 in this population. Discussion This study will determine the clinical benefits of XAV-19 when administered to patients with SARS-CoV-2-induced moderate pneumonia. As a prerequisite, a first step of the study will define the safety and the dose of XAV-19 to be used. Such treatment might become a new therapeutic option to provide an effective treatment for COVID-19 patients (possibly in combination with anti-viral and immunotherapies). Further studies could later evaluate such passive immunotherapy as a potential post-exposure prophylaxis. Trial registration ClinicalTrials.gov NCT04453384 , registered on 1 July 2020, and EUDRACT 2020-002574-27, registered 6 June 2020.

Summary: Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial. Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979. Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42–1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively. Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn. Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19–20–0151, PHRC COVID-19–20–0029], Fondation de l'Assistance Publique – Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale” (FRM). Tocilizumab was provided by Roche.

Amino acid substitutions and deletions in the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. XAV-19 is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2. XAV-19 target epitopes were found distributed all over the RBD and particularly cover the receptor binding motives (RBMs), in direct contact sites with the angiotensin converting enzyme-2 (ACE-2). Therefore, in Spike/ACE-2 interaction assays, XAV-19 showed potent neutralization capacities of the original Wuhan Spike and of the United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 and live virus variants including the Brazil (Gamma/P.1) and the Indian (Delta/B.1.617.2) variants. In a selective pressure study on Vero E6 cells conducted over 1 month, no mutation was associated with the addition of increasing doses of XAV-19. The potential to reduce viral load in lungs was confirmed in a human ACE-2 transduced mouse model. XAV-19 is currently evaluated in patients hospitalized for COVID-19-induced moderate pneumonia in phase 2a-2b (NCT04453384) where safety was already demonstrated and in an ongoing 2/3 trial (NCT04928430) to evaluate the efficacy and safety of XAV-19 in patients with moderate-to-severe COVID-19. Owing to its polyclonal nature and its glyco-humanization, XAV-19 may provide a novel safe and effective therapeutic tool to mitigate the severity of coronavirus disease 2019 (COVID-19) including the different variants of concern identified so far.

While most viral infections cause mild symptoms and a spontaneous favorable resolution, some can lead to severe or protracted manifestations, specifically in immunocompromised hosts. Kidney injuries related to viral infections may have multiple causes related to the infection severity, drug toxicity or direct or indirect viral-associated nephropathy. We review here the described virus-associated nephropathies in order to guide diagnosis strategies and treatments in cases of acute kidney injury (AKI) occurring concomitantly with a viral infection. The occurrence of virus-associated nephropathy depends on multiple factors: the local epidemiology of the virus, its ability to infect renal cells and the patient’s underlying immune response, which varies with the state of immunosuppression. Clear comprehension of pathophysiological mechanisms associated with a summary of described direct and indirect injuries should help physicians to diagnose and treat viral associated nephropathies.

Ludwig’s angina has been known for two centuries as a rapidly and frequently fatal progressive gangrenous cellulitis or necrotizing fasciitis of the neck and the floor of the mouth. The management of the usually young patients affected requires a trained team combining medical skills in surgery, antibiotic therapy, and resuscitation. The prognosis is directly related to early surgical debridement and the experience of the team managing these patients. We present four cases of severe necrotizing cervical cellulitis notably associated with concomitant self-medication with non-steroidal anti-inflammatory drugs. Through these cases, we conclude that several surgical steps could be required, combined with broad-spectrum antibiotic therapy. An optimal surgery, draining all collections and excising all necrotic tissues, seems to be a condition needed for antibiotic efficacy and finally healing. Keywords: Ludwig Angina, Necrotizing fasciitis, NSAIDs, Medico-surgical cooperation

Abstract Background Pneumocystis jirovecii pneumonia (PJP) remains a severe disease associated with high rates of invasive mechanical ventilation (MV) and mortality. The objectives of this study were to assess early risk factors for severe PJP and 90-day mortality, including the broncho-alveolar lavage fluid cytology profiles at diagnosis. Methods We prospectively enrolled all patients meeting pre-defined diagnostic criteria for PJP admitted at Nantes university hospital, France, from January 2012 to January 2017. Diagnostic criteria for PJP were typical clinical features with microbiological confirmation of P. jirovecii cysts by direct examination or a positive specific quantitative real-time polymerase chain reaction (PCR) assay. Severe PJP was defined as hypoxemic acute respiratory failure requiring high-flow nasal oxygen with at least 50% FiO2, non-invasive ventilation, or MV. Results Of 2446 respiratory samples investigated during the study period, 514 from 430 patients were positive for P. jirovecii. Of these 430 patients, 107 met criteria for PJP and were included in the study, 53 (49.5%) patients had severe PJP, including 30 who required MV. All patients were immunocompromised with haematological malignancy ranking first (n = 37, 35%), followed by solid organ transplantation (n = 27, 25%), HIV-infection (n = 21, 20%), systemic diseases (n = 13, 12%), solid tumors (n = 12, 11%) and primary immunodeficiency (n = 6, 8%). By multivariate analysis, factors independently associated with severity were older age (OR, 3.36; 95% CI 1.4–8.5; p

In 31 participants who started first-line antiretroviral therapy in the NEAT 001/ANRS 143 clinical trial, we found after 96 weeks a statistically significant increase in blood telomere length (TL) of 0.04 (T/S Ratio) (p = 0.03). This increase was positively correlated with both the change in the percentage of CD4+ T-cells and with the decrease of CD38+ molecules on Central Memory CD8+ and negatively correlated with the change in the percentage of CD4+ Effector Memory cells. Increase in TL could be an expression of immune reconstitution and the associated decrease in immune activation. We acknowledge for the low statistical power due to the small sample size and the potential for false positive results due to multiple testing. Hence, further studies are needed to confirm these observations.

BackgroundThe pathogenic and oncogenic roles of papillomavirus (HPV) infections have been documented and shown to occur in women as well as in men. While other countries have already extended their vaccination guidelines to include boys, in 2019 the French National Authority for Health validated implementation of HPV vaccination in the 2020 vaccination schedule. There is, however, a climate of distrust in regard to vaccination in France, and there have been few studies to date regarding the acceptability of HPV vaccination in boys in France. The aim of this study was, therefore, to evaluate the acceptability of extending the recommendations for HPV vaccination in men, among middle and high school students and their parents.MethodsOur study (HPVac) was a prospective, multicenter, departmental, and descriptive survey applied to a sample of male middle and high school students attending schools in the Loire-Atlantique department and their parents. It took place from January 2017 to January 2018.ResultsWe analyzed the information obtained from 127 parent questionnaires and 145 children questionnaires. In terms of acceptability, 36.6% (n = 53) of the children and 37.8% (n = 48) of the parents were in favour of being vaccinated or of having their children vaccinated against HPV (51.7% (n = 75) and 50.4% (n = 64), respectively, were undecided). The perception of a risk stemming from HPV infection was positively associated with acceptability of the HPV vaccine. Being against vaccines in general, being discouraged by their parents, parents thinking that their child is not at risk, and the belief that the vaccine is not mandatory were arguments cited and significantly associated with a willingness to be vaccinated.ConclusionThis study revealed a lack of information among boys and their parents about HPV and its vaccination. It also clearly showed that taking time to discuss the consequences of an infection and the merits of being vaccinated can help parents overcome their reluctance. The children then generally go along with their parent's choice.

BACKGROUND:The association between liver stiffness measurements (LSM) and mortality has not been fully described. In particular the effect of LSM on all-cause mortality taking sustained virological response (SVR) into account needs further study. METHODS:HIV/HCV participants in the French nation-wide, prospective, multicenter ANRS CO13 HEPAVIH cohort, with ≥1 LSM by FibroScan (FS) and a detectable HCV RNA when the first valid FS was performed were included. Cox proportional hazards models with delayed entry were performed to determine factors associated with all-cause mortality. LSM and SVR were considered as time dependent covariates. RESULTS:1,062 patients were included from 2005 to 2015 (69.8% men, median age 45.7 years (IQR 42.4-49.1)). 21.7% had baseline LSM >12.5 kPa. Median follow-up was 4.9 years (IQR 3.2-6.1). 727 (68.5%) were ever treated for HCV: 189 of them (26.0%) achieved SVR. 76 deaths were observed (26 liver-related, 10 HIV-related, 29 non-liver-non-HIV-related, 11 of unknown cause). At the age of 50, the mortality rate was 4.5% for patients with LSM ≤12.5 kPa and 10.8% for patients with LSM >12.5 kPa. LSM >12.5 kPa (adjusted Hazard Ratio [aHR] = 3.35 [2.06; 5.45], p12.5 kPa was strongly associated with all-cause mortality independently of SVR and other important covariates. Our results suggest that close follow-up of these patients should remain a priority even after achieving SVR.

Compared to the general population, HIV-infected patients are at higher risk of developing non-AIDS-defining cancers. Chronic HCV infection has also been associated with a higher risk than that of the general population of developing cancers other than hepatocarcinoma. Evaluation of the impact of HCV-related factors on non-AIDS-defining and non HCV-liver (NANL) related cancers among HIV/HCV co-infected patients are scarce. The aim of this study was to identify the impact of HIV/HCV clinical characteristics on NANL related cancers in a large cohort of HIV/HCV-coinfected patients followed from 2005 to 2017. Cox proportional hazards models with delayed entry were used to estimate factors associated with NANL related cancer. Among 1391 patients followed for a median of 5 years, 60 patients developed NANL related cancers, yielding an incidence rate of 8.9 per 1000 person-years (95% CI, [6.6-11.1]). By final multivariable analysis, after adjustment for sex, tobacco or alcohol consumption, baseline CD4 cell count and HCV sustained viral response (SVR), age and a longer duration since HIV diagnosis were independently associated with a higher risk of NANL related cancer (aHR for each additional year 1.10, 95% CI 1.06-1.14, p

As HIV-infected adults on successful antiretroviral therapy (ART) are expected to have close to normal lifespans, they will increasingly develop age-related comorbidities. The objective of this cross-sectional study was to compare in the French Dat'AIDS cohort, the HIV geriatric population, aged 75 years and over, to the elderly one, aged from 50 to 74 years. As of Dec 2015, 16,436 subjects (43.8% of the French Dat'AIDS cohort) were aged from 50 to 74 (elderly group) and 572 subjects (1.5%) were aged 75 and over (geriatric group). Durations of HIV infection and of ART were slightly but significantly different, median at 19 and 18 years, and 15 and 16 years in the elderly and geriatric group, respectively. The geriatric group was more frequently at CDC stage C and had a lower nadir CD4. This group had been more exposed to first generation protease inhibitors and thymidine analogues. Despite similar virologic suppression, type of ART at the last visit significantly differed between the 2 groups: triple ART in 74% versus 68.2%, ART ≥ 4 drugs in 4.7% versus 2.7%; dual therapy in 11.6% versus 16.4% in the elderly group and the geriatric group, respectively. In the geriatric group all co-morbidities were significantly more frequent, except dyslipidemia, 4.3% of the elderly group had ≥4 co-morbidities versus18.4% in the geriatric group. Despite more co-morbidities and more advanced HIV infection the geriatric population achieve similar high rate of virologic suppression than the elderly population. A multidisciplinary approach should be developed to face the incoming challenge of aging HIV population.

The objective was to develop a method of HCV genome sequencing that allowed simultaneous genotyping and NS5A inhibitor resistance profiling. In order to validate the use of a unique RT-PCR for genotypes 1-5, 142 plasma samples from patients infected with HCV were analysed. The NS4B-NS5A partial region was successfully amplified and sequenced in all samples. In parallel, partial NS3 sequences were analyzed obtained for genotyping. Phylogenetic analysis showed concordance of genotypes and subtypes with a bootstrap >95% for each type cluster. NS5A resistance mutations were analyzed using the Geno2pheno [hcv] v0.92 tool and compared to the list of known Resistant Associated Substitutions recently published. In conclusion, this tool allows determination of HCV genotypes, subtypes and identification of NS5A resistance mutations. This single method can be used to detect pre-existing resistance mutations in NS5A before treatment and to check the emergence of resistant viruses while undergoing treatment in major HCV genotypes (G1-5) in the EU and the US.

Despite huge advances in the fight against HIV concerning diagnosis, clinical efficacy of antiretroviral treatments (ART), patient survival and quality of life, there is still no cure. Recent developments in HIV cure research have opened the way for clinical trials which could lead to a temporary or definitive end to ART. However, ethical questions exist about related trial-participation risks. The main goal of the ANRS-APSEC survey was, using Q-methodology, to investigate the viewpoints of people living with HIV (PLWH) and HIV healthcare providers (HHP) regarding motivations for and barriers to participation in HIV Cure-related clinical trials (HCRCT).Thirty-three statements were defined encompassing seven dimensions: treatment and follow-up; risks; benefits; patient-physician relationship; beliefs and attitudes; information; target population. Forty-one PLWH and 41 HHP from five French HIV services were asked to rank-order the statements.Five main viewpoints were elicited from "the most motivated" to "the most reluctant" vis-à-vis HCRCT participation. All placed importance on the wish to participate in HIV research. This result is in line with the HIV-specific culture of joint mobilization. For some viewpoints, the motivation to participate in/propose HCRCT was primarily conditioned by side-effects and/or by constraints, which overall were more accepted by PLWH than HHP. Some viewpoints placed particular importance on HCRCT recruitment strategies. Finally, some expressed a high acceptance of risks and constraints but emphasized the need for information.HIV cure research clinical trials (HCRCT) constitute a risky yet unavoidable step towards the goal of finding a cure. To improve future HCRCT and informed consent designs, based on PLWH and HHP preferences and expectations, we need greater knowledge about how these populations perceive the risks and the benefits of HCRCT. Our results confirmed the importance of careful, studied HCRCT design, management and communication, to ensure PLWH and HHP acceptability and convergence of their expectations.

OBJECTIVES:To study the association between CD4/CD8 ratio and morbidity in HIV-infected patients on antiretroviral therapy (ART). METHODS:The APROCO/COPILOTE cohort enrolled patients initiating a protease inhibitor-containing ART in 1997-1999. The association between occurrence of first non AIDS-defining severe events (NADE) and time-dependent measures of immune restoration was assessed by 4 Cox models with different definitions of restoration, CD4+ cell counts (CD4), CD4/CD8 ratio, both CD4 and CD4/CD8 ratio, or a composite variable (CD4< 500/mm3, CD4 > 500/mm3 and CD4/CD8 ratio < 1, CD4 > 500/mm3 and CD4/CD8 ratio > 1). Models adjusted on baseline characteristics and time-dependent viral load were compared using Akaike Information Criterion. RESULTS:We included 1227 patients. Median duration of follow-up was 9.2 years (IQR: 4.2-11.4). Median CD4 was 530/mm3 at 9 years. Median CD4/CD8 ratio was 0.3 (IQR: 0.2-0.5) at baseline and 0.6 (IQR: 0.4-0.9) after 9 years. Incidence of first NADE was 7.4/100 person-years, the most common being bacterial infections (21%), cardiovascular events (14%) and cancers (10%). For both bacterial infections and cardiovascular events, the CD4/CD8 ratio did not add predictive information to the CD4 cell count. However, low CD4/CD8 ratio was the best predictor of non-AIDS cancers (adjusted HR = 2.13 for CD4/CD8 < 0.5; 95% CI = 1.32-3.44). CONCLUSIONS:CD4/CD8 ratio remains < 1 in most HIV-infected patients despite long-term CD4+ cell counts restoration on ART. A CD4/CD8 ratio < 0.5 could identify patients who require a more intensive strategy of cancer prevention or screening.

[This corrects the article DOI: 10.1371/journal.pone.0155406.].

OBJECTIVES:The objective of this analysis is to perform an indirect comparison of elvitegravir, cobicistat, emtricitabine and tenofovir DF (E/C/F/TDF) to abacavir/lamivudine and dolutegravir (ABC/3TC + DTG) by using 2 trials evaluating each of these regimens in comparison to efavirenz, emtricitabine and tenofovir DF (EFV/FTC/TDF). METHODS:An indirect comparison was performed by using a generalization of Bucher's methodology to calculate risk differences. Two phase III clinical trials (GS-US-236-0102 and SINGLE-described above) were used. RESULTS:Results of the indirect comparison showed no statistically significant risk difference of the efficacy endpoint of achieving HIV RNA < 50 copies/mL between E/C/F/TDF and ABC/3TC + DTG for the ITT population at weeks 48, 96 and 144: respectively -3.7% (CI95% = [-10.8%; 3.4%]), -5.2% (CI95% = [-13.2%; 2.8%]) and -3.1% (CI95% = [-12.0%; 5.7%]). There was no statistically significant differences in the risk difference for serious adverse events (5.7% (CI95% = [-2.2%; 12.3%])), drug related adverse event (2.7% (CI95% = [-7.0%;12.4%])), drug related serious adverse event (0.8% (CI95% = [-1.6%;3.2%])) and death (0.5% (CI95% = [-0.8%;1.8%])), respectively, between E/C/F/TDF and ABC/3TC + DTG. A significant difference was found for discontinuation due to adverse events with a higher rate for E/C/F/TDF (difference = 8.6% (CI95% = [3.3%; 13.9%])). There was also no statistically significant risk difference of the viral resistance of 1.2% (CI95% = [-1.2; 3.7]) between E/C/F/TDF and ABC/3TC + DTG at week 48, 1.7% at week 96 (CI95% = [-1.1; 4.5]) and 2.2% (CI95% = [-1.0; 5.4]) at week 144.

We identified 2 cases of European bat lyssavirus subtype 1 transmission to domestic carnivores (cats) in France. Bat-to-cat transmission is suspected. Low amounts of virus antigen in cat brain made diagnosis difficult.

Virological failure on a boosted-protease inhibitor (PI/r) first-line triple combination is usually not associated with the detection of resistance mutations in the protease gene. Thus, other resistance pathways are being investigated. First-line PI/r monotherapy is the best model to investigate in vivo if the presence of mutations in the cleavage sites (CS) of gag gene prior to any antiretroviral treatment might influence PI/r efficacy. 83 patients were assigned to initiate antiretroviral treatment with first-line lopinavir/r monotherapy in the randomised Monark trial. We compared baseline sequence of gag CS between patients harbouring B or non-B HIV-1 subtype, and between those who achieved viral suppression and those who experienced virological failure while on LPV/r monotherapy up to Week 96. Baseline sequence of gag CS was available for 82/83 isolates; 81/82 carried at least one substitution in gag CS compared to HXB2 sequence. At baseline, non-B subtype isolates were significantly more likely to harbour mutations in gag CS than B subtype isolates (p

BACKGROUND: Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV). METHODS AND FINDINGS: Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (n = 417), or EFV (n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV (33.7%; p = 0.036), while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073), resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (-4.1%) and an increase for patients receiving EFV (+5.9%; p < 0.001). The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV (33.6%; p = 0.007), as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001) and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378). These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs. CONCLUSION: NVP-containing ART shows larger increases in HDL-c and decreases in TC:HDL-c ratio than an EFV-containing regimen. Based on these findings, protease-inhibitor-sparing regimens based on non-nucleoside reverse transcriptase inhibitor, particularly those containing NVP, may be expected to result in a reduced risk of coronary heart disease.