How the Malian press treated hydroxychloroquine at the beginning of the COVID-19 pandemic

BackgroundThe global debate on the efficacy of hydroxychloroquine (HCQ) on COVID-19 has gone far beyond the scientific framework and has been highly politicized. These issues immediately invested the debate on HCQ and made it an object of particular crystallization. This study analyzes, through the Malian press, the echo of this debate in the national background. MethodsMixed methods design, based on a review of 452 articles about COVID-19 published by six major Malian newspapers, from January 1st to July 31st 2020. Results of a content analysis with WORDSTAT8 software were further explained by a thematic qualitative analysis using and deductive-indictive approach. ResultsThe debate on HCQ has had very little echo in the Malian press despite some interest, because of a lack of anchoring and thus of a "response" at the national level. The national health authorities, who adopted the treatment as part of clinical trials, and the press, stayed away from both the medical and the "ideological" components of the debate, despite these a priori directly involved a country like Mali. ConclusionsThe paper sheds light on the issues at stake in the HCQ debate based on a case study of an atypical country in terms of impacts of Covid-19. The governance of COVID helped crystallize political opposition to the presidential regime leading to a coup in August.

Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial

BackgroundThe antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring. MethodsIn this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-{beta}-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population. FindingsBetween March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420). At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29). InterpretationRemdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15. FundingEuropean Union Commission, French Ministry of Health, DIM One Health Ile-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER "European Regional Development Fund", Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead.

An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19 - Final results from the DisCoVeRy trial

ObjectivesWe evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-{beta}-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring. MethodsWe conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely. ResultsThe intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-{beta}-1a, n=147; hydroxychloroquine, n=150; control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36); lopinavir/ritonavir-IFN-{beta}-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08); hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). 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. ConclusionIn adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-{beta}-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.

Modeling remdesivir antiviral efficacy in COVID-19 hospitalized patients of the randomized, controlled, open-label DisCoVeRy trial

Despite several clinical studies, the antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. We analyzed nasopharyngeal normalized viral loads collected in the 29 days following randomization from 665 hospitalized patients included in the DisCoVeRy trial, allocated to either standard of care (SoC, N=329) or SoC + remdesivir for 10 days (N=336). We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in reducing viral production. To identify factors associated with viral kinetics, additional analyses were conducted stratified either on time of treatment initiation ([≤] or > 7 days since symptom onset) or viral load at randomization (< or [≥] 3.5 log10 copies/104 cells). In our model, remdesivir reduced viral production by 2-fold on average (95%CI: 1.5-3.2). Using the estimated parameter of the model, simulations predict that remdesivir reduces time to viral clearance by 0.7 day compared to SoC, with large inter-individual variabilities (Inter-Quartile Range, IQR: 0.0-1.3 days). Exploratory analyses suggest that remdesivir had a larger impact in patients with a high viral load at randomization, reducing viral production by 5-fold on average (95%CI: 2.8-25), leading to a predicted median reduction in the time to viral clearance of 2.4 days (IQR: 0.9-4.5 days). In summary, our model shows that remdesivir reduces viral production from infected cells by a factor 2, leading to a median reduction of 0.7 days in the time to viral clearance compared to SoC. The efficacy was larger in patients with high level of viral load at treatment initiation. One sentence summaryRemdesivir reduces the time to SARS-CoV-2 clearance by 1 day in hospitalized patients, and up to 3 days in those with high viral load at admission.

Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial

BackgroundLopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-{beta}-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking. ObjectiveTo determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-{beta}-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients. DesignOpen-label, randomized, adaptive, controlled trial. SettingMulti-center trial with patients from France. Participants583 COVID-19 inpatients requiring oxygen and/or ventilatory support InterventionStandard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-{beta}-1a (44 g of subcutaneous IFN-{beta}-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days). MeasurementsThe primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses. ResultsAdjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavir versus control, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-{beta}-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE. LimitationsNot a placebo-controlled, no anti-inflammatory agents tested. ConclusionNo improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings. RegistrationNCT04315948. FundingPHRC 2020, Dim OneHealth, REACTing

How do the general population behave with facemasks to prevent COVID-19 in the community?

IMPORTANCE The appropriate use of facemasks, recommended or mandated by authorities, is critical to protect the community and prevent the spread of COVID-19. OBJECTIVE To evaluate the frequency and quality of facemask use in general populations of different socio-spatial backgrounds. DESIGN A multi-site observational study carried out from 25 June 2020 to 21 July 2020. SETTING The observations were carried out in 43 different locations in a region in the west of France, representing various areas: rural and urban, indoor and outdoor, and in areas where masks were mandated or not. An observer was positioned at a predetermined place, facing a landmark, and collected information about the use of facemasks and socio-demographic data. PARTICIPANTS All individual passing between the observer and the landmark were included. EXPOSURE The observer collected information on whether a mask was worn, the type of mask used, the quality of the positioning, gender, and the age category of each individual. MAIN OUTCOMES AND MEASURES The main outcomes were the use of a facemask and the quality of the positioning. Factors associated with these outcomes were identified. RESULTS A total of 3354 observations were recorded. A facemask was worn by 56.4% (n=1892) of individuals, varying from 49% (n=1359) in non-mandatory areas and 91.7% (n=533) in mandatory areas, including surgical facemasks (56.8%, n=1075) and cloth masks (43.2%, n=817). The facemask was correctly positioned in 75.2% (n=1422) of cases. The factors independently associated with wearing a facemask were being indoors (adjusted odds ratio [aOR], 0.37; 95% confidence interval [CI], 0.31-0.44), being in a mandatory area (aOR, 0.14; 95%CI, 0.10-0.20), female gender (aOR, 0.57; 95%CI, 0.49-0.66), and age >40 years (aOR, 0.54; 95%CI, 0.46-0.63). The factors independently associated with correct mask position were rural location (aOR, 0.76; 95%CI, 0.97-0.98), being in an indoor area (aOR, 0.49; 95%CI, 0.38-0.65), use of a cloth mask (aOR, 0.65; 95%CI, 0.52-0.81), and age >40 years (aOR, 0.61; 95%CI 0.49-0.76). CONCLUSIONS AND RELEVANCE Information campaigns should promote the use of cloth masks. Young people in general and men in particular are the priority targets. Simplifying the rules to require universal mandatory masking seems to be the best approach for health authorities.

Airborne contamination of COVID-19 in hospitals: a scoping review of the current evidence.

IntroductionA controversy remains worldwide regarding the transmission routes of SARS-CoV-2 in hospital settings. We reviewed the current evidence on the air contamination with SARS-CoV-2 in hospital settings, and the factors associated to the contamination including the viral load and the particles size. MethodsThe MEDLINE, Embase, Web of Science databases were systematically interrogated for original English-language articles detailing COVID-19 air contamination in hospital settings between 1 December 2019 and 21 July 2020. This study was conducted in accordance with the PRISMA-ScR guidelines. The positivity rate of SARS-CoV-2 viral RNA and culture were described and compared according to the setting, clinical context, air ventilation system, and distance from patient. The SARS-CoV-2 RNA concentrations in copies per m3 of air were pooled and their distribution were described by hospital areas. Particle sizes and SARS-CoV-2 RNA concentrations in copies or TCID50 per m3 were analysed after categorization of sizes in < 1 {micro}m, 1-4 {micro}m, and > 4 {micro}m. ResultsAmong 2,034 records identified, 17 articles were included in the review. Overall, 27.5% (68/247) of air sampled from close patients environment were positive for SARS-CoV-2 RNA, without difference according to the setting (ICU: 27/97, 27.8%; non-ICU: 41/150, 27.3%; p = 0.93), the distance from patients (< 1 meter: 1/64, 1.5%; 1-5 meters: 4/67, 6%; p = 0.4). In other areas, the positivity rate was 23.8% (5/21) in toilets, 9.5% (20/221) in clinical areas, 12.4% (15/121) in staff areas, and 34.1% (14/41) in public areas. A total of 78 viral cultures were performed in three studies, and 3 (4%) were positive, all from close patients environment. The median SARS-CoV-2 RNA concentrations varied from 1.103 copies per m3 (IQR: 0.4.103-9.103) in clinical areas to 9.7.103 (5.1.103-14.3.103) in the air of toilets or bathrooms. The protective equipment removal and patients rooms had high concentrations/titre of SARS-CoV-2 with aerosol size distributions that showed peaks in the < 1 {micro}m region, and staff offices in the > 4{micro}m region. ConclusionIn hospital, the air near and away from COVID-19 patients is frequently contaminated with SARSCoV-2 RNA, with however, rare proofs of their viability. High viral loads found in toilet/bathrooms, staff and public hallways suggests to carefully consider these areas.

Open Science Saves Lives: Lessons from the COVID-19 Pandemic

In the last decade Open Science principles have been successfully advocated for and are being slowly adopted in different research communities. In response to the COVID-19 pandemic many publishers and researchers have sped up their adoption of Open Science practices, sometimes embracing them fully and sometimes partially or in a sub-optimal manner. In this article, we express concerns about the violation of some of the Open Science principles and its potential impact on the quality of research output. We provide evidence of the misuses of these principles at different stages of the scientific process. We call for a wider adoption of Open Science practices in the hope that this work will encourage a broader endorsement of Open Science principles and serve as a reminder that science should always be a rigorous process, reliable and transparent, especially in the context of a pandemic where research findings are being translated into practice even more rapidly. We provide all data and scripts at https://osf.io/renxy/.

Neurological manifestations associated with COVID-19: a nationwide registry

BackgroundThe clinical description of the neurological manifestations in COVID-19 patients is still underway. This study aims to provide an overview of the spectrum, characteristics and outcomes of neurological manifestations associated with SARS-CoV-2 infection. MethodsWe conducted a nationwide, multicentric, retrospective study during the French COVID-19 epidemic in March-April 2020. All COVID-19 patients with de novo neurological manifestations were eligible. ResultsWe included 222 COVID-19 patients with neurological manifestations from 46 centers throughout the country. Median age was 65 years (IQR 53-72), and 136 patients (61.3%) were male. COVID-19 was severe or critical in almost half of the patients (102, 45.2%). The most common neurological diseases were COVID-19 associated encephalopathy (67/222, 30.2%), acute ischemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%), and Guillain-Barre Syndrome (15/222, 6.8%). Neurological manifestations appeared after first COVID-19 symptoms with a median (IQR) delay of 6 (3-8) days in COVID-19 associated encephalopathy, 7 (5-10) days in encephalitis, 12 (7-18) days in acute ischemic cerebrovascular syndrome and 18 (15-28) days in Guillain-Barre Syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 MRI (70.7%). Brain MRI of encephalitis patients showed heterogeneous acute non vascular lesion in 14/21 patients (66.7%) with associated small ischemic lesion or microhemorrhages in 4 patients. Among patients with acute ischemic cerebrovascular syndrome, 13/57 (22.8%) had multi territory ischemic strokes, with large vessel thrombosis in 16/57 (28.1%). Cerebrospinal fluid was analyzed in 97 patients (43.7%), with pleocytosis in 18 patients (18.6%). A SARS-CoV-2 PCR was performed in 75 patients and was positive only in 2 encephalitis patients. Among patients with encephalitis, ten out of 21 (47.6%) fully recovered, 3 of whom received corticosteroids (CS). Less common neurological manifestations included isolated seizure (8/222, 3.6%), critical illness neuropathy (8/222, 3.6%), transient alteration of consciousness (5/222, 2.3%), intracranial hemorrhage (5/222, 2.3%), acute benign lymphocytic meningitis (3/222, 1.4%), cranial neuropathy (3/222, 1.4%), single acute demyelinating lesion (2/222, 0.9%), Tapia syndrome (2/222, 0.9%), cerebral venous thrombosis (1/222, 0.5%), sudden paraparesis (1/222, 0.5%), generalized myoclonus and cerebellar ataxia (1/222, 0.5%), bilateral fibular palsy (1/222, 0.5%) and isolated neurological symptoms (headache, anosmia, dizziness, sensitive or auditive symptoms, hiccups, 15/222, 6.8%). The median (IQR) follow-up of the 222 patients was 24 (17-34) days with a high short-term mortality rate (28/222, 12.6%). ConclusionNeurological manifestations associated with COVID-19 mainly included CAE, AICS, encephalitis and GBS. Clinical spectrum and outcomes were broad and heterogeneous, suggesting different underlying pathogenic processes.

Repurposed prophylaxis strategies for COVID-19: a systematic review

IntroductionEfficient therapeutic strategies are needed to counter the COVID-19 pandemic, caused by the SARSCoV-2 virus. In a context where specific vaccines are not yet available, the containment of the pandemic would be facilitated with efficient prophylaxis. MethodsWe screened several clinical trials repositories and platforms in search of the prophylactic strategies that are investigated against COVID-19 in late April 2020. ResultsUp to April 27, 2020, we found 68 clinical trials targeting medical workers (n = 43, 63%), patients relatives (n = 16, 24%) or individuals at risk of severe COVID-19 (n = 5, 7%). (Hydroxy)chloroquine was the most frequently evaluated treatment (n = 46, 68%), before BCG vaccine (n = 5, 7%). Sixty-one (90%) clinical trials were randomized with a median of planned inclusions of 600 (IQR 255-1515). ConclusionThe investigated prophylaxis strategies cover both pre- and post-exposure prophylaxis and study numerous immune enhancers and antivirals, although most research efforts are focused on (hydroxy)chloroquine.

Review and methodological analysis of trials currently testing treatment and prevention options for the novel coronavirus disease (COVID-19) globally.

BackgroundAs COVID-19 cases continue to rise globally within an unprecedented short period of time, solid evidence from large randomised controlled trials is still lacking. Currently, numerous trials testing potential treatment and preventative options are undertaken globally. ObjectivesWe summarised all currently registered clinical trials examining treatment and prevention options for COVID-19. Additionally, we evaluated the quality of the retrieved interventional studies. Data sourcesClinicaltrials.gov, the Chinese Clinical Trial Registry and the European Union Clinical Trials Register were systematically searched. Study eligibility criteriaRegistered clinical trials examining treatment and/or prevention options for COVID-19 were included. No language, country or study design restrictions were applied. We excluded withdrawn or cancelled studies and trials not reporting therapeutic or preventative strategies for COVID-19. Participants and interventionsNo restrictions in terms of participants age and medical background or type of intervention were enforced. MethodsThe registries were searched using the term "coronavirus" or "COVID-19" from their inception until 26th March 2020. Additional manual search of the registries was also performed. Eligible studies were summarised and tabulated. Interventional trials were methodologically analysed, excluding expanded access studies and trials testing Traditional Chinese Medicine. ResultsIn total, 309 trials evaluating therapeutic management options, 23 studies assessing preventive strategies and 3 studies examining both were retrieved. Interventional treatment studies were mostly randomised (n=150, 76%) and open-label (n=73, 37%) with a median number of planned inclusions of 90 (IQR 40-200). Major categories of interventions that are currently being investigated are discussed. ConclusionNumerous clinical trials have been registered since the onset of the COVID-19 pandemic. Summarised data on these trials will assist physicians and researchers to promote patient care and guide future research efforts for COVID-19 pandemic containment. However, up to the end of March, 2020, significant information on reported trials was often lacking.

A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19

BackgroundAlthough a number of antiviral agents have been evaluated for coronaviruses there are no approved drugs available. To provide an overview of the landscape of therapeutic research for COVID-19, we conducted a review of registered clinical trials. MethodsA review of currently registered clinical trials was performed on registries, including the Chinese (chictr.org.cn) and US (clinicaltrials.gov) databases to identify relevant studies up to March, 7th 2020. The search was conducted using the search terms "2019-nCoV", "COVID-19", "SARS-CoV-2", "Hcov-19", "new coronavirus", "novel coronavirus". We included interventional clinical trials focusing on patients with COVID-19 and assessing antiviral drugs or agents. FindingsOut of the 353 studies identified, 115 clinical trials were selected for data extraction. Phase IV trials were the most commonly reported study type (n=27, 23%). However, 62 trials (54%) did not describe the phase of the study. Eighty percent (n=92) of the trials were randomized with parallel assignment and the median number of planned inclusions was 63 (IQR, 36-120). Open-label studies were the most frequent (46%) followed by double-blind (13%) and single blind studies (10%). The most frequently assessed therapies were: stem cells therapy (n=23 trials), lopinavir/ritonavir (n=15), chloroquine (n=11), umifenovir (n=9), hydroxychloroquine (n=7), plasma treatment (n=7), favipiravir (n=7), methylprednisolone (n=5), and remdesivir (n=5). Remdesivir was tested in 5 trials with a median of 400 (IQR, 394-453) planned inclusions per trial, while stem cells therapy was tested in 23 trials, but had a median of 40 (IQR, 23-60) planned inclusions per trial. Lopinavir/ritonavir was associated with the highest total number of planned inclusions (2606) followed by remdesivir (2155). Only 52% of the clinical trials reported the treatment dose (n=60) and only 34% (n=39) the duration. The primary outcome was clinical in 76 studies (66%), virological in 27 (23%); radiological in 9 (8%) or immunological in three studies (3%). InterpretationNumerous clinical trials have been registered since the beginning of the COVID-19 outbreak, however, a number of information regarding drugs or trial design were lacking. FundingNone