ABSTRACT
Objectives We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-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. Methods We 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. Results The intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-β-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-β-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. Conclusion In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.
Subject(s)
COVID-19ABSTRACT
There are very limited antiviral therapeutic options for coronavirus infections, therefore global drug re-purposing efforts are paramount to identify available compounds that could provide clinical benefits to patients with COVID-19. Ivermectin was first approved for human use as an endectocide in the 1980s. It remains one of the most important global health medicines in history and has recently been shown to exert in vitro activity against SARS-CoV-2. However, the macrocyclic lactone family of compounds has not previously been evaluated for activity against SARS-CoV-2. The present study aims at comparing their anti-viral activity in relevant pulmonary cell lines in vitro. Here, in vitro antiviral activity of the avermectins (ivermectin and selamectin) and milbemycins (moxidectin and milbemycin oxime) were assessed against a clinical isolate from a CHU Montpellier patient infected with SARS-CoV-2 in 2020. Ivermectin demonstrated anti-SARS-CoV-2 activity in vitro in human pulmonary cells in comparison to VeroE6 (with EC50 of 1-3 M). Similarly, the other macrocyclic lactones moxidectin, milbemycin oxime and selamectin reduced SARS-CoV-2 replication in vitro (with EC50 of 2-5 M). Immunofluorescence assays with ivermectin and moxidectin showed a reduction in the number of infected and polynuclear cells suggesting a drug action on viral cell fusion. However, cellular toxicity of the avermectins and milbemycins during infection showed a very low selectivity index <10 for all compounds. In conclusion, none of these agents appears suitable for human use for its anti-SARS-CoV-2 activity per se, due to low selectivity index. This is discussed in regards to recent clinical COVID studies on ivermectin.
Subject(s)
COVID-19 , Coronavirus Infections , Drug-Related Side Effects and Adverse ReactionsABSTRACT
IntroductionSARS-CoV-2 nucleocapsid antigen (N-Ag) can be detected in the blood of patients with Covid-19. In this study, we used a highly sensitive and specific nucleocapsid-Ag assay to explore the presence of N-Ag in urine during the course of Covid-19, and explore its relationship with the severity of the disease. Material and MethodsUrine and blood samples were collected from 82 patients with a SARS-CoV-2 infection proven by PCR and included in the COVIDotheque. We explored the presence of N-Ag in urine and blood using the AAZ N-Ag test, studied the kinetics of the marker according to the time since the onset of symptoms and evaluated the association between N-Ag levels, clinical severity and inflammation. ResultsIn the first and second weeks of Covid-19, hospitalized patients tested positive for urinary N-Ag (81.25% and 71.79%, respectively) and blood N-Ag (93.75% and 94.87%, respectively). N-Ag levels in urine and blood were moderately correlated with the number of days after the onset of symptoms (r=-0.43, p<0.0001; r=-0.55 p<0.0001, respectively). The follow up of seven SARS-CoV-2 infected patients confirmed the waning of N-Ag in urine and blood over the course of the disease. High urinary N-Ag levels were associated with the absence of SARS-CoV-2 nucleocapsid-IgG (N-IgG), admission in intensive care units, high C-reactive protein levels, lymphopenia, eosinopenia, and high lactate dehydrogenase (LDH). ConclusionOur study demonstrate that N-Ag is present in the urine of patients hospitalized in the early phase of Covid-19. As a direct marker of SARS-CoV-2, urinary N-Ag reflects the dissemination of viral compounds in the body. Urine N-Ag is a promising marker to predict adverse evolution of SARS-CoV-2 infections.
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19 , Inflammation , LymphopeniaABSTRACT
Background: Response to the COVID-19 outbreak calls for rapid and accurate diagnostic tests to control the pandemic outbreak. We aimed to evaluate saliva specimen as well as rapid RT-LAMP test for diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Methods: This monocentric study screened outpatients that were either symptomatic or contact-cases of a COVID-19 confirmed case.Nasopharyngeal-swabs (NPS) and saliva were collected simultaneously and tested by RT-qPCR. Saliva samples were also analyzed using an extraction-free rapid RT-LAMP test (EasyCOV®). Infected participants were those with a positive (Ct value <35) NP and/or salivary RT-qPCR (Composite Reference Test, CRTest).Findings: Between the 1st September and the 7th of October 2020, samples of 443 adults were collected and analyzed. The mean age was 32·2 years, 59·4% declared mild symptoms at the time of sampling and 40·6% were asymptomatic. Positivity rate of NP and/or salivary RT-qPCR was 16·0% (71/443) and the concordance between these two methods was 87·3%. Sensitivity and specificity of RT-LAMP compared to CRTest were 85·9% (95% CI 77·8%-94·0%) and 99·5% (98·7%-100%), respectively. RT-LAMP accuracy was 91·0% and 98·2% compared to NP and salivary RT-qPCR, respectively. All 52 participants with a salivary RT-qPCR Ct value <31 were positive by RT-LAMP. Performances of RT-LAMP for symptomatic and asymptomatic participants were similar.Interpretation: We demonstrated that self-collected saliva and a rapid RT-LAMP-based field test are reliable alternatives for SARS-CoV-2 detection. Their use could complement, simplify and accelerate COVID-19 diagnostics.Clinical Trial Registration: NCT04337424Funding Statement: SkillCell, CNRS, Region OccitanieDeclaration of Interests: Dr. J Reynes reports personal fees from Gilead company, personal feesfrom ViiV Healthcare company, personal fees from MSD Company, personalfees from Pfizer Company, personal fees from TheratechnologiesCompany, outside the submitted work.Dr. F Molina reports grants from SkillCell ; personal fees fromSkillCell, outside the submitted work. In addition, Dr. Molina has apatent Patent # EP20166524 pending.Dr. J Espeut, Dr. J Baptiste and Dr. F Santos Schneider reportspersonal fees from SkillCell, outside the submitted workThe other authors declared no competing interest.Ethics Approval Statement: The study was approved by a French ethic committee (CPP-lle de France XI) on April 03, 2020 and a substantial modification was approved on May 11, 2020.
Subject(s)
COVID-19 , Coronavirus Infections , Multiple Sulfatase Deficiency DiseaseABSTRACT
Background: Lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-beta-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking. Objective: To determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-beta-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients. Design: Open-label, randomized, adaptive, controlled trial. Setting: Multi-center trial with patients from France. Participants: 583 COVID-19 inpatients requiring oxygen and/or ventilatory support Intervention: Standard 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 micrograms 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). Measurements: 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 and safety analyses. Results: Adjusted 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. Limitations: Not a placebo-controlled, no anti-inflammatory agents tested. Conclusion: No 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. Registration: NCT04315948. Funding: PHRC 2020, Dim OneHealth, REACTing
Subject(s)
COVID-19ABSTRACT
ObjectivesThe implementation of rapid diagnostic tests (RDTs) may enhance the efficiency of SARS-CoV-2 testing, as RDTs are widely accessible and easy to use. The aim of this study was to evaluate the performance of a diagnosis strategy based on a combination of antigen and IgM/IgG serological RDTs. MethodsPlasma and nasopharyngeal samples were collected between 14 March and 11 April 2020 at hospital admission from 45 patients with RT-PCR confirmed COVID-19 and 20 negative controls. SARS-CoV-2 antigen (Ag) was assessed in nasopharyngeal swabs using the Coris Respi-Strip. For IgM/IgG detection, SureScreen Diagnostics and Szybio Biotech RDTs were used in addition to laboratory assays (Abbott Alinity i SARS-CoV-2 IgG and Theradiag COVID-19 IgM ELISA). ResultsUsing the Ag RDT, 13 out of 45 (29.0%) specimens tested positive, the sensitivity was 87.0% for Cycle Threshold (CT) values [≤] 25 and 0% for CT values > 25. IgG detection was associated with high CT values and the amount of time after the onset of symptoms. The profile of isolated IgM on RDTs was more frequently observed during the first and second week after the onset of symptoms. The combination of Ag and IgM/IgG RDTs enabled the detection of up to 84.0% of COVID-19 confirmed cases at hospital admission. ConclusionAntigen and antibody-based RDTs showed suboptimal performances when used alone. However when used in combination, they are able to identify most COVID-19 patients admitted in an emergency department.
Subject(s)
COVID-19ABSTRACT
Background: Recent studies suggested that olfactory and gustatory disorders were highly correlated with COVID-19, but olfaction was evaluated solely on reported symptoms, after COVID-19 diagnosis, or in combined mild and severe COVID-19. We investigated the diagnostic value of patient-reported and clinically tested chemosensory disorders in patients attending a COVID-19 screening center. Methods: In this prospective diagnostic test study, we consecutively included healthcare workers and outpatients with symptoms or close index case contact. Prior to nasopharyngeal swabbing for SARS-CoV-2 RT-PCR, participants were interviewed for symptoms, then underwent the Clinical Olfactory Dysfunction Assessment (CODA), which is a standardized test developed for a simple and fast olfactory evaluation. Participants identified and rated the intensity of three scents, summing to a score ranging from zero to six. Findings: Among 809 participants, 58 (7·2%) tested positive for SARS-CoV-2. Patient-reported chemosensory disorders prevalence was 34·5% in COVID-19 confirmed cases ( vs 3·9%, p<0·001). Olfactory disorders, either reported or clinically tested (CODA≤3), yielded similar sensitivities of 0·31 (95% CI 0·20–0·45) and 0·34 (0·22–0·48), and specificities of 0·97 (0·96–0·98) and 0·98 (0·96–0·99) respectively for COVID-19 diagnosis. Concordance was high between reported and clinically tested olfactory disorders, AC1=0·95 (95% CI 0·93–0·97). 18 of 19 participants with both reported olfactory disorders and CODA≤3 had COVID-19. Interpretation: Olfactory disorders are highly specific but poorly sensitive for COVID-19. Patients with olfactory disorders are prevalent in and suggestive of COVID-19, particularly if clinical testing confirms anamnesis. However, normal olfaction is common in COVID-19.Trial Registration: registered on ClinicalTrials.gov (NCT04407494)Funding Statement: This research did not receive any funding.Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: This study was a prospective monocentric study, approved by the Institutional Review Board (IRBMPT-2020_03_202000424).
Subject(s)
COVID-19 , Seizures , Mental Retardation, X-Linked , Olfactory Nerve DiseasesABSTRACT
We assessed the expression of the cell adhesion molecule Sialoadhesin (CD169), a type I interferon-inducible receptor, on monocytes (mCD169) in 53 adult patients admitted to the hospital during the COVID-19 outbreak for a suspicion of SARS-CoV-2 infection. mCD169 was strongly overexpressed in 30 out of 32 (93.7%) confirmed COVID-19 cases, compared to three out of 21 (14.3%) patients for whom the diagnosis of COVID-19 was finally ruled out. mCD169 was associated with the plasma interferon alpha level and thrombocytopenia. mCD169 testing may be helpful for the rapid triage of suspected COVID-19 patients during an outbreak.
Subject(s)
COVID-19ABSTRACT
Covid-19 crisis showed us that rapid massive virus detection campaign is a key element in SARS-CoV-2 pandemic response. The classical RT-PCR laboratory platforms must be complemented with rapid and simplified technologies to enhance efficiency of large testing strategies. To this aim, we developed EasyCoV, a direct saliva RT-LAMP based SARS-CoV-2 virus detection assay that do not requires any RNA extraction step. It allows robust and rapid response under safe and easy conditions for healthcare workers and patients. EasyCov test was assessed under double blind clinical conditions (93 asymptomatic healthcare worker volonteers, 10 actively infected patients, 20 former infected patients tested during late control visit). EasyCov results were compared with classical laboratory RT-PCR performed on nasopharyngeal samples. Our results show that compared with nasopharyngeal laboratory RT-PCR, EasyCov SARS-CoV-2 detection test has a sensitivity of 72.7%. Measured on healthcare worker population the specificity was 95.7%. LAMP technology on saliva is clearly able to identify subjects with infectivity profile. Among healthcare worker population Easycov test detected one presymptomatic subject. Because it is simple, rapid and painless for patients, EasyCov saliva SARS-Cov-2 detection test may be useful for large screening of general population.