A randomised controlled trial to study the transmission of SARS-CoV-2 and other respiratory viruses during indoor clubbing events (ANRS0066s ITOC study).

BACKGROUND: In the context of the circulation of the SARS-CoV-2 B.1.617.2 (Delta) variant, vaccination re-authorised mass indoor gatherings. The "Indoor Transmission of COVID-19" (ITOC) trial (ClinicalTrials.gov, NCT05311865) aimed to assess the risk of transmission of SARS-CoV-2 and other respiratory viruses during an indoor clubbing event among participants fully-vaccinated against COVID-19. METHODS: ITOC, a randomised, controlled trial in the Paris region (France), enrolled healthy volunteers aged 18-49 years, fully-vaccinated against COVID-19, with no co-morbidities or symptoms, randomised 1:1 to be interventional group "attendees" or control "non-attendees". The intervention, a 7-hour indoor event in a nightclub at full capacity, with no masking, prior SARS-CoV-2 test result or social distancing required. The primary-outcome measure was the numbers of RT-PCR-determined SARS-CoV-2-positive subjects on self-collected saliva 7 days post-gathering in the per-protocol population. Secondary endpoints focused on 20 other respiratory viruses. RESULTS: Healthy participants (n = 1,216) randomised 2:1 by blocks up to 10, 815 attendees and 401 non-attendees, yielding 529 and 287 subjects, respectively, with day-7 saliva samples. One day-7 sample from each group was positive. Looking at all respiratory viruses together, the clubbing event was associated with an increased risk of infection of 1.59 [95% CI 1.04-2.61]. CONCLUSIONS: In the context of low Delta-VOC circulation, no evidence of SARS-CoV-2 transmission among asymptomatic and vaccinated participants was found, but the risk of other respiratory virus transmission was higher.

Efficacy and safety of an early oral switch in low-risk Staphylococcus aureus bloodstream infection (SABATO): an international, open-label, parallel-group, randomised, controlled, non-inferiority trial.

BACKGROUND: Staphylococcus aureus bloodstream infection is treated with at least 14 days of intravenous antimicrobials. We assessed the efficacy and safety of an early switch to oral therapy in patients at low risk for complications related to S aureus bloodstream infection. METHODS: In this international, open-label, randomised, controlled, non-inferiority trial done in 31 tertiary care hospitals in Germany, France, the Netherlands, and Spain, adult patients with low-risk S aureus bloodstream infection were randomly assigned after 5-7 days of intravenous antimicrobial therapy to oral antimicrobial therapy or to continue intravenous standard therapy. Randomisation was done via a central web-based system, using permuted blocks of varying length, and stratified by study centre. The main exclusion criteria were signs and symptoms of complicated S aureus bloodstream infection, non-removable foreign devices, and severe comorbidity. The composite primary endpoint was the occurrence of any complication related to S aureus bloodstream infection (relapsing S aureus bloodstream infection, deep-seated infection, and mortality attributable to infection) within 90 days, assessed in the intention-to-treat population by clinical assessors who were masked to treatment assignment. Adverse events were assessed in all participants who received at least one dose of study medication (safety population). Due to slow recruitment, the scientific advisory committee decided on Jan 15, 2018, to stop the trial after 215 participants were randomly assigned (planned sample size was 430 participants) and to convert the planned interim analysis into the final analysis. The decision was taken without knowledge of outcome data, at a time when 126 participants were enrolled. The new sample size accommodated a non-inferiority margin of 10%; to claim non-inferiority, the upper bound of the 95% CI for the treatment difference (stratified by centre) had to be below 10 percentage points. The trial is closed to recruitment and is registered with ClinicalTrials.gov (NCT01792804), the German Clinical trials register (DRKS00004741), and EudraCT (2013-000577-77). FINDINGS: Of 5063 patients with S aureus bloodstream infection assessed for eligibility, 213 were randomly assigned to switch to oral therapy (n=108) or to continue intravenous therapy (n=105). Mean age was 63·5 (SD 17·2) years and 148 (69%) participants were male and 65 (31%) were female. In the oral switch group, 14 (13%) participants met the primary endpoint versus 13 (12%) in the intravenous group, with a treatment difference of 0·7 percentage points (95% CI -7·8 to 9·1; p=0·013). In the oral switch group, 36 (34%) of 107 participants in the safety population had at least one serious adverse event compared with 27 (26%) of 103 participants in the intravenous group (p=0·29). INTERPRETATION: Oral switch antimicrobial therapy was non-inferior to intravenous standard therapy in participants with low-risk S aureus bloodstream infection. However, it is necessary to carefully assess patients for signs and symptoms of complicated S aureus bloodstream infection at the time of presentation and thereafter before considering early oral switch therapy. FUNDING: Deutsche Forschungsgemeinschaft. TRANSLATIONS: For the German, Spanish, French and Dutch translations of the abstract see Supplementary Materials section.

Ensuring quality control in a COVID-19 clinical trial during the pandemic: The experience of the Inserm C20-15 DisCoVeRy study.

SETTING: Health measures taken during the pandemic deeply modified the clinical research practices. At the same time, the demand for the results of the COVID-19 trials was urgent. Thus, the objective of this article is to share Inserm's experience in ensuring quality control in clinical trials in this challenging context. OBJECTIVES: DisCoVeRy is a phase III randomized study that aimed at evaluating the safety and efficacy of 4 therapeutic strategies in hospitalized COVID-19 adult patients. Between March, 22nd 2020 and January, 20th 2021, 1309 patients were included. In order to guarantee the best quality of data, the Sponsor had to adapt to the current sanitary measures and to their impact on clinical research activity, notably by adapting Monitoring Plan objectives, involving the research departments of the participating hospitals and a network of clinical research assistants (CRAs). RESULTS: Overall, 97 CRAs were involved and performed 909 monitoring visits. The monitoring of 100% of critical data for all patients included in the analysis was achieved, and despite of the pandemic context, a conform consent was recovered for more than 99% of patients. Results of the study were published in May and September 2021. DISCUSSION/CONCLUSION: The main monitoring objective was met thanks to the mobilization of considerable personnel resources, within a very tight time frame and external hurdles. There is a need for further reflection to adapt the lessons learned from this experience to the context of routine practice and to improve the response of French academic research during a future epidemic.

Transmission of SARS-CoV-2 during indoor clubbing events: A clustered randomized, controlled, multicentre trial protocol.

Introduction: The SARS-CoV-2 pandemic led to the implementation of several non-pharmaceutical interventions (NPIs), from closings of bars and restaurants to curfews and lockdowns. Vaccination campaigns started hoping it could efficiently alleviate NPI. The primary objective of the "Indoor Transmission of COVID-19" (ITOC) study is to determine among a fully vaccinated population the relative risk of SARS-CoV-2 transmission during one indoor clubbing event. Secondary objectives are to assess the transmission of other respiratory viruses, risk exposure, and attitudes toward COVID-19 vaccination, health pass, and psychological impact of indoor club closing. Methods and analysis: Four thousand four hundred healthy volunteers aged 18-49 years and fully vaccinated will be included in Paris region. The intervention is an 8-hour indoor clubbing event with no masks, no social distance, maximum room capacity, and ventilation. A reservation group of up to 10 people will recruit participants, who will be randomized 1:1 to either the experimental group (2,200 volunteers in two venues with capacities of 1,000 people each) or the control group (2,200 volunteers asked not to go to the club). All participants will provide a salivary sample on the day of the experiment and 7 days later. They also will answer several questionnaires. Virological analyses include polymerase chain reaction (PCR) of salivary samples and air of the venue, investigating SARS-CoV-2 and 18 respiratory viruses. Ethics and dissemination: Ethical clearance was first obtained in France from the institutional review board (Comité de Protection des Personnes Ile de France VII - CPP), and the trial received clearance from the French National Agency for Medicines and Health Products (Agence National de Sécurité du Médicament - ANSM). The trial is supported and approved by The Agence Nationale Recherche sur le SIDA, les hépatites et maladies émergences (ANRS-MIE). Positive, negative, and inconclusive results will be published in peer-reviewed scientific journals. Trial registration number: IDR-CB 2021-A01473-38. Clinicaltrial.gov, identifier: NCT05311865.

[Chikungunya physiopathology: Infection data from acute to chronic phase]. / Physiopathologie du chikungunya: les marqueurs de l'infection de la phase aiguë à l'atteinte chronique.

During the 2005-2006 austral summer, an outbreak of fever associated with joint pain hit the Reunion Island inhabitants. Chikungunya virus (CHIKV), the agent involved in this epidemic, was known since 50 years and was thus brought to general attention together with the risk of emergence or re-emergence of arboviral infections. This arbovirus rapidly spread worldwide, specifically in India with millions of cases, but also in Europe through imported cases (>2,000) and fewautochthonous cases in Italy and in France. Human pathology is characterized by arthralgia and myalgia, which persist for months or years. Development of macaque model of CHIKV disease evidenced the key role of monocytesmacrophages in viral persistence.We are reporting herein the present knowledge about physiopathology of the virus and the CHIKV disease. Comparison of animal model data in chronic phase of infection and data acquired in follow-up of patients allows us to propose explanation of mechanisms of inflammation associated with viral infection. This review is aimed at opening discussion about the relationship between the CHIKV, the immune response and the development of virus-induced chronic arthralgia and myalgia.

Effect of Professional and Extra-Professional Exposure on Seroprevalence of SARS-CoV-2 Infection among Healthcare Workers of the French Alps: A Multicentric Cross-Sectional Study.

We aimed to report SARS-CoV-2 seroprevalence after the first wave of the pandemic among healthcare workers, and to explore factors associated with an increased infection rate. We conducted a multicentric cross-sectional survey from 27 June to 31 September 2020. For this survey, we enrolled 3454 voluntary healthcare workers across four participating hospitals, of which 83.4% were female, with a median age of 40.6 years old (31.8-50.3). We serologically screened the employees for SARS-CoV-2, estimated the prevalence of infection, and conducted binomial logistic regression with random effect on participating hospitals to investigate associations. We estimated the prevalence of SARS-CoV-2 infection at 5.0% (95 CI, 4.3%-5.8%). We found the lowest prevalence in health professional management support (4.3%) staff. Infections were more frequent in young professionals below 30 years old (aOR = 1.59, (95 CI, 1.06-2.37)), including paramedical students and residents (aOR = 3.38, (95 CI, 1.62-7.05)). In this group, SARS-CoV-2 prevalence was up 16.9%. The location of work and patient-facing role were not associated with increased infections. Employees reporting contacts with COVID-19 patients without adequate protective equipment had a higher rate of infection (aOR = 1.66, (95 CI, 1.12-2.44)). Aerosol-generating tasks were associated with a ~1.7-fold rate of infection, regardless of the uptake of FFP2. Those exposed to clusters of infected colleagues (aOR = 1.77, (95 CI, 1.24-2.53)) or intra-familial COVID-19 relatives (aOR = 2.09, (95 CI, 1.15-3.80)) also had a higher likelihood of infection. This report highlights that a sustained availability of personal protective equipment limits the SARS-CoV-2 infection rate to what is measured in the general population. It also pinpoints the need for dedicated hygiene training among young professionals, justifies the systematic eviction of infected personnel, and stresses the need for interventions to increase vaccination coverage among any healthcare workers.

An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-ß-1a and hydroxychloroquine in hospitalized patients with COVID-19.

OBJECTIVES: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-ß-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support. METHODS: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely. RESULTS: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-ß-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-ß-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. CONCLUSION: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.

Daily or on-demand oral tenofovir disoproxil fumarate/emtricitabine for HIV pre-exposure prophylaxis: experience from a hospital-based clinic in France.

BACKGROUND: On-demand oral tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) has been approved for pre-exposure prophylaxis (PrEP) in MSM in France following the results of clinical studies, but data are limited on real-world experience. DESIGN: A single-center, open-label, prospective cohort study that recruited people at high risk of HIV infection in Paris. METHODS: Participants were enrolled in a single hospital-based outpatient clinic and were proposed to start PrEP with daily or on demand TDF/FTC. At baseline and every 3 months thereafter, patients were tested for HIV and creatinine plasma levels, and data on sexual behavior, other sexually transmitted infections (STIs), and tolerability were collected. RESULTS: From 10 November 2015 to 30 April 2017, 1069 patients were screened and 1049 (98.1%) started PrEP. Median age was 36 years, 99.4% were MSM with a median number of partners of 10, and 793 (75.6%) opted for on demand PrEP. Over 486 person-years of follow-up, four HIV-infections were diagnosed in poorly or nonadherent patients (incidence 0.82/100 person-years). Rate of condomless sex at last intercourse increased from 53.3% at baseline to 79% at month 12 (P < 10), but increase in bacterial STI rates was modest (14.6% at baseline vs. 19.2% at month 12; P < 10). Most adverse events were gastrointestinal and did not lead to PrEP discontinuation. CONCLUSIONS: Most PrEP users were high-risk MSM and opted for on-demand PrEP. PrEP use was associated with a low HIV incidence and a high rate of condomless sex with a modest increase in bacterial STIs.

Chikungunya disease: infection-associated markers from the acute to the chronic phase of arbovirus-induced arthralgia.

At the end of 2005, an outbreak of fever associated with joint pain occurred in La Réunion. The causal agent, chikungunya virus (CHIKV), has been known for 50 years and could thus be readily identified. This arbovirus is present worldwide, particularly in India, but also in Europe, with new variants returning to Africa. In humans, it causes a disease characterized by a typical acute infection, sometimes followed by persistent arthralgia and myalgia lasting months or years. Investigations in the La Réunion cohort and studies in a macaque model of chikungunya implicated monocytes-macrophages in viral persistence. In this Review, we consider the relationship between CHIKV and the immune response and discuss predictive factors for chronic arthralgia and myalgia by providing an overview of current knowledge on chikungunya pathogenesis. Comparisons of data from animal models of the acute and chronic phases of infection, and data from clinical series, provide information about the mechanisms of CHIKV infection-associated inflammation, viral persistence in monocytes-macrophages, and their link to chronic signs.