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1.
Journal of Internal Medicine ; : 1, 2022.
Article in English | Academic Search Complete | ID: covidwho-1769735

ABSTRACT

Background Objective Methods Results Conclusion Persistent symptoms of SARS‐CoV‐2 are prevalent weeks to months following the infection. To date, it is difficult to disentangle the direct from the indirect effects of SARS‐CoV‐2, including lockdown, social, and economic factors.The study aims to characterize the prevalence of symptoms, functional capacity, and quality of life at 12 months in outpatient symptomatic individuals tested positive for SARS‐CoV‐2 compared to individuals tested negative.From 23 April to 27 July 2021, outpatient symptomatic individuals tested for SARS‐CoV‐2 at the Geneva University Hospitals were followed up 12 months after their test date.At 12 months, out of the 1447 participants (mean age 45.2 years, 61.2% women), 33.4% reported residual mild to moderate symptoms following SARS‐CoV‐2 infection compared to 6.5% in the control group. Symptoms included fatigue (16% vs. 3.1%), dyspnea (8.9% vs. 1.1%), headache (9.8% vs. 1.7%), insomnia (8.9% vs. 2.7%), and difficulty concentrating (7.4% vs. 2.5%). When compared to the control group, 30.5% of SARS‐CoV‐2 positive individuals reported functional impairment at 12 months versus 6.6%. SARS‐CoV‐2 infection was associated with the persistence of symptoms (adjusted odds ratio [aOR] 4.1;2.60–6.83) and functional impairment (aOR 3.54;2.16–5.80) overall, and in subgroups of women, men, individuals younger than 40 years, those between 40–59 years, and in individuals with no past medical or psychiatric history.SARS‐CoV‐2 infection leads to persistent symptoms over several months, including in young healthy individuals, in addition to the pandemic effects, and potentially more than other common respiratory infections. Symptoms impact functional capacity up to 12 months post infection. [ FROM AUTHOR] Copyright of Journal of Internal Medicine is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

2.
BMJ Open ; 12(3): e048502, 2022 03 02.
Article in English | MEDLINE | ID: covidwho-1723715

ABSTRACT

BACKGROUND: To summarise specific adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir in patients with COVID-19. METHODS: We searched 32 databases through 27 October 2020. We included randomised trials comparing any of the drugs of interest to placebo or standard care, or against each other. We conducted fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the grading of recommendations assessment, development and evaluation approach. RESULTS: We included 16 randomised trials which enrolled 8152 patients. For most interventions and outcomes the certainty of the evidence was very low to low except for gastrointestinal adverse effects from hydroxychloroquine, which was moderate certainty. Compared with standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury (risk difference (RD) 8 fewer per 1000, 95% CI 27 fewer to 21 more) or cognitive dysfunction/delirium (RD 3 more per 1000, 95% CI 12 fewer to 19 more). Low certainty evidence suggests that hydroxychloroquine may increase the risk of cardiac toxicity (RD 10 more per 1000, 95% CI 0 more to 30 more) and cognitive dysfunction/delirium (RD 33 more per 1000, 95% CI 18 fewer to 84 more), whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI 23 more to 110 more) compared with standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea (RD 168 more per 1000, 95% CI 58 more to 330 more) and nausea and/or vomiting (RD 160 more per 1000, 95% CI 100 more to 210 more) compared with standard care or placebo. DISCUSSION: Hydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. Remdesivir may have no important effect on risk of acute kidney injury or cognitive dysfunction/delirium. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.


Subject(s)
Adenosine Monophosphate/adverse effects , Alanine/adverse effects , COVID-19 , Hydroxychloroquine , Lopinavir/adverse effects , Ritonavir/adverse effects , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19/drug therapy , Drug Combinations , Humans , Hydroxychloroquine/adverse effects , Randomized Controlled Trials as Topic , SARS-CoV-2
3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-314781

ABSTRACT

Background: Since the beginning of the COVID-19 pandemic, no direct antiviral treatment is effective as post-exposure prophylaxis (PEP). Lopinavir/ritonavir (LPV/r) was repurposed as a potential PEP agent against COVID-19.Methods: We conducted a pragmatic open-label, parallel, cluster-randomized superiority trial in four sites in Switzerland and Brazil. Clusters were randomized to receive LPV/r PEP (400/100 mg) twice daily for 5 days or no PEP (surveillance). The primary outcome is the occurrence of COVID-19 within 21 days post-enrollment.Findings: Of 318 participants, 157 (49.4%) were women, median age was 39 (interquartile range, 28-50) years. A total of 209 (179 clusters) participants were randomized to LPV/r PEP and 109 (95 clusters) to surveillance. Baseline characteristics were similar, with the exception of baseline SARS-CoV-2 PCR positivity, which was 3-fold more frequent in the LPV/r arm (34/209 [16.3%] vs 6/109 [5.5%], respectively). During 21-day follow-up, 48/318 (15.1%) participants developed COVID-19: 35/209 (16.7%) in the LPV/r group and 13/109 (11.9%) in the surveillance group (unadjusted hazard ratio 1.44;95% CI, 0.76 to 2.73). In the primary endpoint analysis adjusted for propensity score to receive LPV/r, the hazard ratio for developing COVID-19 in the LPV/r group vs surveillance was 0.53 (95% CI, 0.23 to 1.23, respectively;P =.14).Interpretation: LPV/r role as PEP for COVID-19 remains unanswered. In this trial, LPV/r over 5 days did not significantly reduce incidence of COVID-19 in exposed individuals. We observed a change in directionality of the effect in favor of LPV/r after adjusting for baseline SARS-CoV-2 PCR results, indicating a potential role of antivirals in COVID-19 prevention.Clinical Trial Registration Details: ClinicalTrials.gov (Identifier: NCT04364022);Swiss National Clinical Trial Portal: SNCTP 000003732.Funding Information: Fondation privée des HUG and Swiss National Fund (project number: 33IC30_166819).Declaration of Interests: None reported.Ethics Approval Statement: The protocol and amendments were approved by Swissmedic and local ethics committees in Switzerland and Brazil. Participants provided written informed consent before study entry.

5.
J Clin Med ; 10(8)2021 Apr 10.
Article in English | MEDLINE | ID: covidwho-1526830

ABSTRACT

PURPOSE: To assess the diagnostic performances of five automated anti-SARS-CoV-2 immunoassays, Epitope (N), Diasorin (S1/S2), Euroimmun (S1), Roche N (N), and Roche S (S-RBD), and to provide a testing strategy based on pre-test probability. METHODS: We assessed the receiver operating characteristic (ROC) areas under the curve (AUC) values, along with the sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs), of each assay using a validation sample set of 172 COVID-19 sera and 185 negative controls against a validated S1-immunofluorescence as a reference method. The three assays displaying the highest AUCs were selected for further serodetection of 2033 sera of a large population-based cohort. RESULTS: In the validation analysis (pre-test probability: 48.1%), Roche N, Roche S and Euroimmun showed the highest discriminant accuracy (AUCs: 0.99, 0.98, and 0.98) with PPVs and NPVs above 96% and 94%, respectively. In the population-based cohort (pre-test probability: 6.2%) these three assays displayed AUCs above 0.97 and PPVs and NPVs above 90.5% and 99.4%, respectively. A sequential strategy using an anti-S assay as screening test and an anti-N as confirmatory assays resulted in a 96.7% PPV and 99.5% NPV, respectively. CONCLUSIONS: Euroimmun and both Roche assays performed equally well in high pre-test probability settings. At a lower prevalence, sequentially combining anti-S and anti-N assays resulted in the optimal trade-off between diagnostic performances and operational considerations.

6.
EClinicalMedicine ; 42: 101188, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1499828

ABSTRACT

BACKGROUND: Since the beginning of the COVID-19 pandemic, no direct antiviral treatment is effective as post-exposure prophylaxis (PEP). Lopinavir/ritonavir (LPV/r) was repurposed as a potential PEP agent against COVID-19. METHODS: We conducted a pragmatic open-label, parallel, cluster-randomised superiority trial in four sites in Switzerland and Brazil between March 2020 to March 2021. Clusters were randomised to receive LPV/r PEP (400/100 mg) twice daily for 5 days or no PEP (surveillance). Exposure to SARS-CoV-2 was defined as a close contact of >15 minutes in <2 metres distance or having shared a closed space for ≥2 hours with a person with confirmed SARS-CoV-2 infection. The primary outcome is the occurrence of COVID-19 defined by a SARS-CoV-2 infection (positive oropharyngeal SARS-CoV-2 PCR and/or a seroconversion) and ≥1 compatible symptom within 21 days post-enrolment. ClinicalTrials.gov (Identifier: NCT04364022); Swiss National Clinical Trial Portal: SNCTP 000003732. FINDINGS: Of 318 participants, 157 (49.4%) were women; median age was 39 (interquartile range, 28-50) years. A total of 209 (179 clusters) participants were randomised to LPV/r PEP and 109 (95 clusters) to surveillance. Baseline characteristics were similar, with the exception of baseline SARS-CoV-2 PCR positivity, which was 3-fold more frequent in the LPV/r arm (34/209 [16.3%] vs 6/109 [5.5%], respectively). During 21-day follow-up, 48/318 (15.1%) participants developed COVID-19: 35/209 (16.7%) in the LPV/r group and 13/109 (11.9%) in the surveillance group (unadjusted hazard ratio 1.44; 95% CI, 0.76-2.73). In the primary endpoint analysis, which was adjuted for baseline imbalance, the hazard ratio for developing COVID-19 in the LPV/r group vs surveillance was 0.60 (95% CI, 0.29-1.26; p =0.18). INTERPRETATION: The role of LPV/r as PEP for COVID-19 remains unanswered. Although LPV/r over 5 days did not significantly reduce the incidence of COVID-19 in exposed individuals, we observed a change in the directionality of the effect in favour of LPV/r after adjusting for baseline imbalance. LPV/r for this indication merits further testing against SARS-CoV-2 in clinical trials. FUNDING: Swiss National Science Foundation (project no.: 33IC30_166819) and the Private Foundation of Geneva University Hospitals (Edmond Rothschild (Suisse) SA, Union Bancaire Privée and the Fondation pour la recherche et le traitement médical).

7.
J Clin Epidemiol ; 139: 68-79, 2021 11.
Article in English | MEDLINE | ID: covidwho-1466592

ABSTRACT

OBJECTIVE: To describe the characteristics of Covid-19 randomized clinical trials (RCTs) and examine the association between trial characteristics and the likelihood of finding a significant effect. STUDY DESIGN: We conducted a systematic review to identify RCTs (up to October 21, 2020) evaluating drugs or blood products to treat or prevent Covid-19. We extracted trial characteristics (number of centers, funding sources, and sample size) and assessed risk of bias (RoB) using the Cochrane RoB 2.0 tool. We performed logistic regressions to evaluate the association between RoB due to randomization, single vs. multicentre, funding source, and sample size, and finding a statistically significant effect. RESULTS: We included 91 RCTs (n = 46,802); 40 (44%) were single-center, 23 (25.3%) enrolled <50 patients, 28 (30.8%) received industry funding, and 75 (82.4%) had high or probably high RoB. Thirty-eight trials (41.8%) reported a statistically significant effect. RoB due to randomization and being a single-center trial were associated with increased odds of finding a statistically significant effect. CONCLUSIONS: There is high variability in RoB among Covid-19 trials. Researchers, funders, and knowledge-users should be cognizant of the impact of RoB due to randomization and single-center trial status in designing, evaluating, and interpreting the results of RCTs. REGISTRATION: CRD42020192095.


Subject(s)
COVID-19/prevention & control , Randomized Controlled Trials as Topic/methods , Research Design/standards , COVID-19/epidemiology , Epidemiologic Studies , Humans
8.
BMJ ; 374: n2231, 2021 09 23.
Article in English | MEDLINE | ID: covidwho-1438073

ABSTRACT

OBJECTIVE: To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021). STUDY SELECTION: Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate. METHODS: After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm. RESULTS: As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) -4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD -4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD -3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD -4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative. CONCLUSION: In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a data supplement. FUNDING: This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321). READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website (www.covid19lnma.com).


Subject(s)
Antibodies, Viral/therapeutic use , COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , SARS-CoV-2/immunology , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , Bayes Theorem , COVID-19/immunology , Clinical Trials as Topic , Humans , Immunization, Passive , Network Meta-Analysis , Treatment Outcome
9.
Nature ; 595(7866): 172, 2021 07.
Article in English | MEDLINE | ID: covidwho-1303752

Subject(s)
COVID-19 , Humans , SARS-CoV-2
10.
Lancet ; 398(10295): 117-118, 2021 07 10.
Article in English | MEDLINE | ID: covidwho-1301082
11.
J Psychiatr Res ; 140: 53-59, 2021 08.
Article in English | MEDLINE | ID: covidwho-1253250

ABSTRACT

OBJECTIVE: Psychiatric impact of COVID-19 is still explored and previous data suggest potential risks of anxiety, depression and PTSD related to COVID-19. We aimed to explore the predictive value of risk factors during hospitalization (T0) for COVID-19 for anxiety, depression and PTSD and at three months (T1) because they could differ over these two time points. METHODS: We performed a screening of mental suffering in hospitalized patients for COVID-19, as well as specialized care and three months longitudinal follow-up. We evaluated at T0 and at T1 the prevalence of anxiety, depression and PTSD in survivors who benefited from early detection and treatment, and assessed possible risk factors in adults surviving COVID-19 between the 30th March and the 1st of July 2020. RESULTS: 109 patients were screened at T0 and 61 of these were reassessed at T1. At T0, we found 44.9% pathological score on peritraumatic dissociation experiences questionnaire (PDEQ), 85.4% of post-traumatic stress disorder symptoms (PTSS), 14.6% of pathological rate of post-traumatic stress disorder scale 5 (PCL5) and at T1, 86.9% of PTSS, 10.6% of pathological rate of PCL5. Finally, PDEQ score at T0 during hospitalization was positively correlated to PCL-5 score at T1 (ß = 0.26, p = 0.01) and that was confirmed in multivariate analysis (ß = 0.04, p = 0.02 for the log of PCL-5 per point on the PDEQ). CONCLUSION: Screening of psychiatric symptoms during hospitalization for COVID-19 should be systematic, especially peritraumatic dissociation to offer an early treatment and prevent PTSD, which seemed frequent for hospitalized patients for COVID-19 at three months.


Subject(s)
COVID-19 , Stress Disorders, Post-Traumatic , Adult , Dissociative Disorders/epidemiology , Humans , Longitudinal Studies , SARS-CoV-2 , Stress Disorders, Post-Traumatic/epidemiology
12.
Respiration ; 100(8): 786-793, 2021.
Article in English | MEDLINE | ID: covidwho-1238620

ABSTRACT

BACKGROUND: The COVID-19 pandemic has led to shortage of intensive care unit (ICU) capacity. We developed a triage strategy including noninvasive respiratory support and admission to the intermediate care unit (IMCU). ICU admission was restricted to patients requiring invasive ventilation. OBJECTIVES: The aim of this study is to describe the characteristics and outcomes of patients admitted to the IMCU. METHOD: Retrospective cohort including consecutive patients admitted between March 28 and April 27, 2020. The primary outcome was the proportion of patients with severe hypoxemic respiratory failure avoiding ICU admission. Secondary outcomes included the rate of emergency intubation, 28-day mortality, and predictors of ICU admission. RESULTS: One hundred fifty-seven patients with COVID-19-associated pneumonia were admitted to the IMCU. Among the 85 patients admitted for worsening respiratory failure, 52/85 (61%) avoided ICU admission. In multivariate analysis, PaO2/FiO2 (OR 0.98; 95% CI: 0.96-0.99) and BMI (OR 0.88; 95% CI: 0.78-0.98) were significantly associated with ICU admission. No death or emergency intubation occurred in the IMCU. CONCLUSIONS: IMCU admission including standardized triage criteria, self-proning, and noninvasive respiratory support prevents ICU admission for a large proportion of patients with COVID-19 hypoxemic respiratory failure. In the context of the COVID-19 pandemic, IMCUs may play an important role in preserving ICU capacity by avoiding ICU admission for patients with worsening respiratory failure and allowing early discharge of ICU patients.


Subject(s)
COVID-19/therapy , Noninvasive Ventilation , Respiratory Care Units/statistics & numerical data , Respiratory Insufficiency/therapy , Aged , COVID-19/complications , COVID-19/mortality , Female , Health Personnel/statistics & numerical data , Humans , Male , Middle Aged , Respiratory Insufficiency/virology , Retrospective Studies , Sick Leave/statistics & numerical data , Switzerland/epidemiology
13.
BMJ ; 373: n949, 2021 04 26.
Article in English | MEDLINE | ID: covidwho-1203960

ABSTRACT

OBJECTIVE: To determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19. DESIGN: Living systematic review and network meta-analysis. DATA SOURCES: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 25 March 2021, and six additional Chinese databases to 20 February 2021. STUDY SELECTION: Randomised trials of people at risk of covid-19 who were assigned to receive prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. METHODS: Random effects bayesian network meta-analysis was performed after duplicate data abstraction. Included studies were assessed for risk of bias using a modification of the Cochrane risk of bias 2.0 tool, and certainty of evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. RESULTS: The first iteration of this living network meta-analysis includes nine randomised trials-six of hydroxychloroquine (n=6059 participants), one of ivermectin combined with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo. Two trials (one of ramipril and one of bromhexine hydrochloride) did not meet the sample size requirements for network meta-analysis. Hydroxychloroquine has trivial to no effect on admission to hospital (risk difference 1 fewer per 1000 participants, 95% credible interval 3 fewer to 4 more; high certainty evidence) or mortality (1 fewer per 1000, 2 fewer to 3 more; high certainty). Hydroxychloroquine probably does not reduce the risk of laboratory confirmed SARS-CoV-2 infection (2 more per 1000, 18 fewer to 28 more; moderate certainty), probably increases adverse effects leading to drug discontinuation (19 more per 1000, 1 fewer to 70 more; moderate certainty), and may have trivial to no effect on suspected, probable, or laboratory confirmed SARS-CoV-2 infection (15 fewer per 1000, 64 fewer to 41 more; low certainty). Owing to serious risk of bias and very serious imprecision, and thus very low certainty of evidence, the effects of ivermectin combined with iota-carrageenan on laboratory confirmed covid-19 (52 fewer per 1000, 58 fewer to 37 fewer), ivermectin alone on laboratory confirmed infection (50 fewer per 1000, 59 fewer to 16 fewer) and suspected, probable, or laboratory confirmed infection (159 fewer per 1000, 165 fewer to 144 fewer) remain very uncertain. CONCLUSIONS: Hydroxychloroquine prophylaxis has trivial to no effect on hospital admission and mortality, probably increases adverse effects, and probably does not reduce the risk of SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, it is highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a supplement. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.


Subject(s)
COVID-19 , Carrageenan/pharmacology , Global Health/statistics & numerical data , Hydroxychloroquine/pharmacology , Ivermectin/pharmacology , Anti-Infective Agents/pharmacology , COVID-19/prevention & control , Chemoprevention/methods , Chemoprevention/statistics & numerical data , Humans , SARS-CoV-2 , Treatment Outcome , Uncertainty
14.
BMJ ; 372: n526, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1112324

ABSTRACT

CLINICAL QUESTION: What is the role of drugs in preventing covid-19? WHY DOES THIS MATTER?: There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19. RECOMMENDATION: The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty). HOW THIS GUIDELINE WAS CREATED: This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. UNDERSTANDING THE NEW RECOMMENDATION: The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19. UPDATES: This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. READERS NOTE: This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity.


Subject(s)
COVID-19/prevention & control , Chemoprevention , Hydroxychloroquine/pharmacology , Risk Assessment , COVID-19/epidemiology , Chemoprevention/methods , Chemoprevention/standards , Clinical Decision-Making/methods , Humans , Immunologic Factors/pharmacology , SARS-CoV-2/drug effects , Uncertainty , World Health Organization
15.
Clin Microbiol Infect ; 27(4): 532-537, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1032461

ABSTRACT

BACKGROUND: While the landscape of vaccine and treatment candidates against the novel coronavirus disease 2019 (COVID-19) has been reviewed systematically, prophylactic candidates remain unexplored. OBJECTIVES: To map pre- and postexposure prophylactic (PrEP and PEP) candidate for COVID-19. DATA SOURCES: PubMed/Medline, Embase, International Committee of Medical Journal Editors and International Clinical Trials Registry Platform clinical trial registries and medRxiv. STUDY ELIGIBILITY CRITERIA AND PARTICIPANTS: All studies in humans or animals and randomized controlled trials (RCTs) in humans reporting primary data on prophylactic candidates against COVID-19, excluding studies focused on key populations. INTERVENTIONS: PrEP and PEP candidate for COVID-19. METHODS: Systematic review and qualitative synthesis of COVID-19 PrEP and PEP studies and RCTs complemented by search of medRxiv and PubMed and Embase for studies reporting RCT outcomes since systematic review search completion. RESULTS: We identified 13 studies (from 2119 database records) and 117 RCTs (from 5565 RCTs listed in the registries) that met the inclusion criteria. Non-RCT studies reported on cross-sectional studies using hydroxychloroquine (HCQ) in humans (n = 2) or reported on animal studies (n = 7), most of which used antibodies. All five completed RCTs focused on the use of HCQ as either PrEP or PEP, and these and the cross-sectional studies reported no prophylactic effect. The majority of ongoing RCTs evaluated HCQ or other existing candidates including non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, anti(retro)virals or use of vitamins and supplements. CONCLUSIONS: The key message from completed studies and RCTs seems to be that HCQ does not work. There is little evidence regarding other compounds, with all RCTs using candidates other than HCQ still ongoing. It remains to be seen if the portfolio of existing molecules being evaluated in RCTs will identify successful prophylaxis against COVID-19 or if there is a need for the development of new candidates.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/prevention & control , Post-Exposure Prophylaxis , Pre-Exposure Prophylaxis , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Antimalarials/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Randomized Controlled Trials as Topic , SARS-CoV-2/immunology , Vaccines
16.
Swiss Med Wkly ; 150: w20446, 2020 12 14.
Article in English | MEDLINE | ID: covidwho-1004915

ABSTRACT

AIMS OF THE STUDY: Hydroxychloroquine and lopinavir/ritonavir have been used as experimental therapies to treat COVID-19 during the first wave of the pandemic. Randomised controlled trials have recently shown that there are no meaningful benefits of these two therapies in hospitalised patients. Uncertainty remains regarding the potential harmful impact of these therapies as very early treatments and their burden to the health care system. The present study investigated the length of hospital stay (LOS), mortality, and costs of hydroxychloroquine, lopinavir/ritonavir or their combination in comparison with standard of care among patients hospitalised for coronavirus disease 2019 (COVID-19). METHODS: This retrospective observational cohort study took place in the Geneva University Hospitals, Geneva, Switzerland (n = 840) between 26 February and 31 May 2020. Demographics, treatment regimens, comorbidities, the modified National Early Warning Score (mNEWS) on admission, and contraindications to COVID-19 treatment options were assessed. Outcomes included LOS, in-hospital mortality, and drug and LOS costs. RESULTS: After successful propensity score matching, patients treated with (1) hydroxychloroquine, (2) lopinavir/ritonavir or (3) their combination had on average 3.75 additional hospitalisation days (95% confidence interval [CI] 1.37–6.12, p = 0.002), 1.23 additional hospitalisation days (95% CI −1.24 – 3.51, p = 0.319), and 4.19 additional hospitalisation days (95% CI 1.52–5.31, p <0.001), respectively, compared with patients treated with the standard of care. Neither experimental therapy was significantly associated with mortality. These additional hospital days amounted to 1010.77 additional days for hydroxychloroquine and hydroxychloroquine combined with lopinavir/ritonavir, resulting in an additional cost of US$ 2,492,214 (95%CI US$ 916,839–3,450,619). CONCLUSIONS: Prescribing experimental therapies for COVID-19 was not associated with a reduced LOS and might have increased the pressure put on healthcare systems.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/epidemiology , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Ritonavir/therapeutic use , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , COVID-19/mortality , Child , Child, Preschool , Comorbidity , Drug Combinations , Drug Therapy, Combination , Health Expenditures , Hospital Mortality/trends , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Infant , Length of Stay/statistics & numerical data , Lopinavir/administration & dosage , Lopinavir/adverse effects , Middle Aged , Pandemics , Retrospective Studies , Ritonavir/administration & dosage , Ritonavir/adverse effects , SARS-CoV-2 , Severity of Illness Index , Sex Factors , Socioeconomic Factors , Therapies, Investigational/methods , Young Adult
17.
BMJ Open ; 10(11): e040110, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-922574

ABSTRACT

INTRODUCTION: Lopinavir/ritonavir (LPV/r) has been proposed as repurposed drugs for pre-exposure and postexposure prophylaxis as well as therapy of COVID-19. Coronavirus postexposure prophylaxis (COPEP) trial aims at assessing their efficacy as postexposure ring-prophylaxis among adults exposed to SARS-CoV-2. METHODS AND ANALYSIS: COPEP is a two-arm open-label cluster-randomised trial conducted in three cantons of Switzerland. Asymptomatic contacts (≥16 years) of individuals diagnosed with COVID-19 will be randomised (2:1) to either LPV/r (400 mg/100 mg two times per day) for 5 days, or a standard of care arm (no treatment). Asymptomatic individuals may be either SARS-CoV-2 positive or negative. Contacts living in the single household will form a cluster and will be randomised into the same arm. All participants will be followed-up for 21 days and undergo daily monitoring for COVID-19 symptoms. The primary endpoint is 21-day incidence of laboratory-confirmed COVID-19 with ≥1 compatible symptom, analysed in an intention-to-treat (ITT) analysis. The secondary endpoints include the 21-day incidence of COVID-19 as well as SARS-CoV-2 infection in a modified ITT analysis, excluding participants who had a positive SARS-CoV-2 RT-PCR from oropharyngeal swab and/or a positive SARS-CoV-2 IgG serology at baseline. Assuming a 21-day incidence for COVID-19 of 20% among contacts without postexposure chemoprophylaxis, to detect a relative risk reduction of 60% (ie, translating in an absolute reduction from 20% to 8%), with a power of 80%, an alpha of 5%. Accounting for design effect of cluster design of circa 1.1, we plan to enrol 200 participants to the LPV/r arm and 100 to the standard of care arm, 300 participants in total. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Commission Cantonale d'Ethique de la Recherche, Ethikkommission Nordwest- und Zentralschweiz and Comitato Etico Cantonale (ref 2020-00864) and Swissmedic (2020DR3056). Results from this trial will be disseminated via journal articles and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov Registry (NCT04364022); Swiss National Clinical Trial Portal Registry (SNCTP 000003732). REGISTERED REPORT IDENTIFIER: CCER 2020-0864.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/prevention & control , Lopinavir/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Post-Exposure Prophylaxis/methods , Ritonavir/therapeutic use , Betacoronavirus , COVID-19 , Drug Combinations , Humans , Randomized Controlled Trials as Topic , SARS-CoV-2 , Switzerland
18.
BMJ ; 370: m3379, 2020 09 04.
Article in English | MEDLINE | ID: covidwho-744846

ABSTRACT

UPDATES: This is the tenth version (ninth update) of the living guideline, replacing earlier versions, available as data supplements. New recommendations will be published as updates to this guideline. CLINICAL QUESTION: What is the role of drugs in the treatment of patients with covid-19? CONTEXT: The evidence base for therapeutics for covid-19 is evolving with numerous recently completed randomised controlled trials (RCTs). In this update the Guideline Development Group (GDG) developed new recommendations for patients with non-severe covid-19, concerning the use of nirmatrelvir/ritonavir (2 RCTs, 3100 participants) and remdesivir (5 RCTs, 2710 participants). We have also revised the structure of the guideline to accommodate for an increasing number of effective treatment options to choose between. NEW RECOMMENDATION: • Nirmatrelvir/ritonavir: a strong recommendation for its use in patients at highest risk of hospitalisation; and a conditional recommendation against its use in patients at low risk of hospitalisation. In the absence of trial data, no recommendation on nirmatrelvir/ritonavir was made in patients with severe or critical illness. • Remdesivir: a conditional recommendation for its use in patients at highest risk of hospitalisation. UNDERSTANDING THE NEW RECOMMENDATIONS: In patients with non-severe illness at highest risk of hospitalisation, the recommendations for treatment with nirmatrelvir/ritonavir and remdesivir reflect what the GDG considered to be important reductions in admission to hospital (moderate certainty) with little or no impact on mortality, mechanical ventilation, time to symptom resolution (low to very low certainty), and adverse effects leading to drug discontinuation (high certainty for nirmatrelvir/ritonavir, moderate certainty for remdesivir), though diarrhoea and altered taste were noted more often with nirmatrelvir/ritonavir. Several treatment alternatives are now available for patients with non-severe covid-19 at highest risk of hospitalisation. In the absence of direct comparisons in trials, indirect comparisons from the living network meta-analysis have been used to inform the use of one drug over another with a related mechanism of action. Choices will depend on availability of the drugs, routes of administration (only intravenous for remdesivir), duration of treatment, and time from onset of symptoms to starting treatment in the trials. The strong recommendation for nirmatrelvir/ritonavir reflects what the GDG considered to represent a superior choice over other treatment options for those with non-severe illness at highest risk; it may prevent more hospitalisations than the alternatives, has fewer harms than molnupiravir, and is easier to administer than intravenous options such as remdesivir and the monoclonal antibodies. For monoclonal antibodies, efficacy may depend on the given SARS-CoV-2 variant, with a less certain benefit seen with the omicron BA1-2 variant which is dominating in many regions. There are no clinical data on combination treatment, and currently the GDG advises against combining antivirals in the absence of supporting evidence. UPDATES TO PRIOR RECOMMENDATIONS: The conditional (weak) recommendation for remdesivir in patients with non-severe illness at highest risk of hospitalisation replaces a previous conditional recommendation against treatment with remdesivir in all patients with covid-19 regardless of disease severity. The recommendation for patients with severe or critical illness is being updated using new evidence. PRIOR RECOMMENDATIONS: • Recommended for patients with severe or critical covid-19­a strong recommendation for systemic corticosteroids; a strong recommendation for IL-6 receptor blockers (tocilizumab or sarilumab), in combination with corticosteroids; a strong recommendation for baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids; and a conditional recommendation for casirivimab-imdevimab, for those with seronegative status, (where rapid viral genotyping is available to confirm infection with a susceptible SARS-CoV-2 variant). • Recommended for patients with non-severe covid-19­conditional recommendations for those at highest risk of hospitalisation for molnupiravir; sotrovimab; and for casirivimab-imdevimab (where rapid viral genotyping is available to confirm infection with a susceptible SARS-CoV-2 variant). • Not recommended for patients with non-severe covid-19­a conditional recommendation against systemic corticosteroids; and a strong recommendation against convalescent plasma. • Not recommended for patients with severe or critical covid-19­a recommendation against convalescent plasma, except in the context of a clinical trial; and a conditional recommendation against ruxolitinib and tofacitinib. • Not recommended, regardless of covid-19 disease severity­a strong recommendation against hydroxychloroquine; a strong recommendation against lopinavir/ritonavir; and a recommendation against ivermectin, except in the context of a clinical trial. ABOUT THIS GUIDELINE: This living guideline from the World Health Organization (WHO) incorporates new recommendations on two drugs for covid-19 and updates existing recommendations. The GDG typically evaluates a therapy when WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF, with a summary version here in The BMJ.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , COVID-19 , Humans , Pandemics , SARS-CoV-2 , World Health Organization
19.
JMIR Mhealth Uhealth ; 8(8): e20025, 2020 08 19.
Article in English | MEDLINE | ID: covidwho-694813

ABSTRACT

BACKGROUND: The ongoing coronavirus disease (COVID-19) pandemic forced health jurisdictions worldwide to significantly restructure and reorganize their medical activities. In response to the rapidly evolving body of evidence, a solid communication strategy is needed to increase the reach of and adherence to locally drafted and validated guidance to aide medical staff with COVID-19-related clinical decisions. OBJECTIVE: We present a usage analysis of a dedicated mobile health (mHealth) platform as part of an institutional knowledge dissemination strategy of COVID-19-related guidance to all health care workers (HCWs) in a large academic hospital. METHODS: A multidisciplinary team of experts drafted local guidance related to COVID-19. In total, 60 documents and 17 external links were made available through the platform. Documents were disseminated using a recently deployed mHealth platform for HCWs. Targeted dissemination of COVID-19-related content began on March 22, 2020. Using a third-party statistics tool, data concerning user activity and content use was anonymously collected. A quantitative analysis of user activity was performed over a 4-month period, separated into 3 periods: 2 months before (Period A), 2 weeks after (Period B), and 6 weeks following (Period C) targeted dissemination. Regional epidemiological data (daily new COVID-19 cases and total COVID-19-related hospitalizations) was extracted from an official registry. RESULTS: During the study period, the platform was downloaded by 1233 new users. Consequently, the total number of users increased from 1766 users before Period A to a total of 2999 users at the end of Period C. We observed 27,046 document views, of which 12,728 (47.1%) were COVID-19-related. The highest increase in activity occurred in Period B, rapidly following targeted dissemination, with 7740 COVID-19-related content views, representing 71.2% of total content views within the abovementioned period and 550 daily views of COVID-19-related documents. Total documents consulted per day increased from 117 (IQR 74-160) to 657 (IQR 481-1051), P<.001. This increase in activity followed the epidemiological curbing of newly diagnosed COVID-19 cases, which peaked during Period B. Total active devices doubled from 684 to 1400, daily user activity increased fourfold, and the number of active devices rose from 53 (IQR 40-70) to 210 (IQR 167-297), P<.001. In addition, the number of sessions per day rose from 166 (IQR 110-246) to 704 (IQR 517-1028), P<.001. A persistent but reduced increase in total documents consulted per day (172 [IQR 131-251] versus 117 [IQR 74-160], P<.001) and active devices (71 [IQR 64-89] versus 53 [IQR 40-70]) was observed in Period C compared to Period A, while only 29.8% of the content accessed was COVID-19-related. After targeted dissemination, an immediate increase in activity was observed after push notifications were sent to users. CONCLUSIONS: The use of an mHealth solution to disseminate time-sensitive medical knowledge seemed to be an effective solution to increase the reach of validated content to a targeted audience.


Subject(s)
Coronavirus Infections/prevention & control , Disease Outbreaks/prevention & control , Health Personnel , Information Dissemination/methods , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Telemedicine , COVID-19 , Coronavirus Infections/epidemiology , Humans , Pneumonia, Viral/epidemiology
20.
BMJ ; 370: m2980, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-691120

ABSTRACT

OBJECTIVE: To compare the effects of treatments for coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis. STUDY SELECTION: Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. METHODS: After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. RESULTS: 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low. CONCLUSION: Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol is publicly available in the supplementary material. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fourth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/isolation & purification , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Respiration, Artificial/statistics & numerical data , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Betacoronavirus/pathogenicity , COVID-19 , Centers for Disease Control and Prevention, U.S./statistics & numerical data , China/epidemiology , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/mortality , Coronavirus Infections/virology , Databases, Factual/statistics & numerical data , Drug Combinations , Evidence-Based Medicine/methods , Evidence-Based Medicine/statistics & numerical data , Glucocorticoids/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Network Meta-Analysis , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , Ritonavir/therapeutic use , SARS-CoV-2 , Severity of Illness Index , Standard of Care , Treatment Outcome , United States/epidemiology
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