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Background: Outpatient monoclonal antibodies are no longer effective and antiviral treatments for coronavirus disease 2019 (COVID-19) disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma (CCP) is promising, clinical trials among outpatients have shown mixed results., Methods: We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching Medline, Embase, medRxiv, World Health Organization COVID-19 Research Database, Cochrane Library, and Web of Science from January 2020 to September 2022., Results: Five included studies from 4 countries enrolled and transfused 2620 adult patients. Comorbidities were present in 1795 (69%). The virus neutralizing antibody dilutional titer levels ranged from 8 to 14 580 in diverse assays. One hundred sixty of 1315 (12.2%) control patients were hospitalized, versus 111 of 1305 (8.5%) CCP-treated patients, yielding a 3.7% (95% confidence interval [CI], 1.3%-6.0%; P = .001) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titer with a 7.6% absolute risk reduction (95% CI, 4.0%-11.1%; P = .0001) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment >5 days after symptom onset or in those receiving CCP with antibody titers below the median titer., Conclusions: Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization and may be most effective when given within 5 days of symptom onset and when antibody titer is higher., Competing Interests: Potential conflicts of interest. R. L. has received fees from Pfizer for serving as subinvestigator of a COVID vaccine trial. F. P. has received fees from Pfizer for serving as a principal investigator for a COVID vaccine trial. D. J. S. is a founder and board member of AliquantumRx with stock options; Hemex Health malaria diagnostics consulting; royalties for malaria diagnostic test control standards from Alere (Binax Inc/D/B/A Inverness Medical); consulting fees for legal malaria case from Mabrey Firm (2019); the following grants or contracts: NIH/NIAID R01AI150763, NIH R21TR001737, NIH R01AI111962, DOD TB210115 (CDMRP Tick-Borne Disease Research Program); the following patents: USP 9642865 (issued 9 May 2017, New angiogenesis inhibitors), USP 7270948 (issued 18 September 2007, Detection of malaria parasites by laser desorption mass spectrometry), Salts and polymorphs of cethromycin for the treatment of disease (pending, application 20210163522), and Macrolide compounds and their use in liver stage malaria and related disease (pending, application PCT/US2015/046665); and participation on 2018 NIAID Safety Monitoring Committee/Independent Safety Monitor Intramural, all outside the submitted work. B. J. A. R. reports advisory board membership for Roche and AstraZeneca on a COVID-19 therapy; membership on a data and safety monitoring board (DSMB) for Exevir; consulting fees from Roche and AstraZeneca; grants or contracts and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Gilead Sciences; and support for attending meetings and/or travel from Pfizer. J. J. Z. reports consulting fees from City of Hope; cell therapy consultant; participation on DSMB for the PACER trial; DSMB for the Tolerant trial; and advisory boards for Sanofi and Sobi. L. J. D. reports the following grants or contracts: 75A50120C00094 (BARDA), Collection, testing, and provision of COVID-19 convalescent plasma for NHLBI/NIH (C3PO) through America's Blood Centers; US Veterans Health Administration, Pittsburgh (contract number 36C24E20D0027, VA CURES-1); and Vanderbilt University (Collection, testing, and provision of COVID-19 convalescent plasma for Association of Convalescent Plasma Treatment with Mortality and Clinical Trajectory in Patients Hospitalized with COVID-19 in the Community Setting). B. P. reports the following grants or contracts: COVID Trials, Incyte, Parexel, Novartis Pharmaceuticals, Partner Therapeutics, Fulcrum Therapeutics (to University Health Science Center), and Pulmonary Hypertension Trials, United Therapeutics, GlaxoSmithKline, Insmed, Merck Sharp & Dohme (to University of Texas Health Center). C. W. C. reports consulting honorarium for participation on NHLBI ACTIV4 CONNECTS Steering Committee. I. E. reports support for attending meetings and/or travel for 50 Congreso Argentino de Medicina Respiratoria 2022, Abstract Scholarship, American Thoracic Society, International Conference in Philadelphia, 2020 Assembly on Pediatrics. G. P. M. reports grants or contracts from Pfizer, Moderna, Medicago, and Merck for clinical research (as principal investigator), and payment for presentations from Moderna. D. O. reports consulting fees paid to author from the Fight Infectious Diseases Foundation and the Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol. B. R. M. reports the following grants or contracts: NIH/NIAID R01AI150763, NIH R21TR001737, NIH R01AI111962, and DOD TB210115 (CDMRP Tick-Borne Disease Research Program). D. W. reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AstraZeneca, and support for attending meetings and/or travel from Laboratorios Raffo. C. R. reports grants or contracts from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, AIDSfonds, and Health∼Holland; participation on a DSMB or advisory board as well as support for attending meetings and/or travel from Gilead Sciences and ViiV Healthcare; and gifts for the #awarehivukraine foundation. M. A. H. reports grants or contracts from Gilead, Insmed, and AN2 Therapeutics, as well as participation on the AIDS Clinical Trials Group Tuberculosis Transformative Science Group Study Monitoring Committee. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Hydroxychloroquine (HCQ) was initially promoted as an oral therapy for early treatment of coronavirus disease 2019 (COVID-19). Conventional meta-analyses cannot fully address the heterogeneity of different designs and outcomes of randomized controlled trials (RCTs) assessing the efficacy of HCQ in outpatients with mild COVID-19. We conducted a pooled analysis of individual participant data from RCTs that evaluated the effect of HCQ on hospitalization and viral load reduction in outpatients with confirmed COVID-19. We evaluated the overall treatment group effect by log-likelihood ratio test (-2LL) from a generalized linear mixed model to accommodate correlated longitudinal binary data. The analysis included data from 11 RCTs. The outcome of virological effect, assessed in 1560 participants (N = 795 HCQ, N = 765 control), did not differ significantly between the two treatment groups (-2LL = 7.66; p = 0.18) when adjusting for cohort, duration of symptoms, and comorbidities. The decline in polymerase chain reaction positive tests from day 1 to 7 was 42.0 and 41.6 percentage points in the HCQ and control groups, respectively. Among the 2037 participants evaluable for hospitalization (N = 1058 HCQ, N = 979 control), we found no significant differences in hospitalization rate between participants receiving HCQ and controls (odds ratio 0.995; 95% confidence interval 0.614-1.610; -2LL = 0.0; p = 0.98) when adjusting for cohort, duration of symptoms, and comorbidities. This individual participant data meta-analysis of 11 HCQ trials that evaluated severe acute respiratory syndrome-coronavirus 2 viral clearance and COVID-19 hospitalization did not show a clinical benefit of HCQ. Our meta-analysis provides evidence to support the interruption in the use of HCQ in mild COVID-19 outpatients to reduce progression to severe disease., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when <20% of recruitment target was achieved. A Bayesian-adaptive individual patient data meta-analysis was implemented. Outpatients aged ≥50 years and symptomatic for ≤7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with ≤5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution., Trial Registration: Clinicaltrials.gov NCT04621123 and NCT04589949., Registration: NCT04621123 and NCT04589949 on https://www., Clinicaltrials: gov., (© 2022. The Author(s).)

Background: Two years into the pandemic, convincing evidence in favour of convalescent plasma (ConvP) as a treatment for coronavirus disease 2019 (COVID-19) is still lacking. This contrasts sharply with the efficacy of potent virus-neutralizing monoclonal antibodies. However, resistance of the Omicron variant against almost all licensed monoclonals turns back the clock, and we can expect that ConvP will regain interest. Indeed, the efficacy of virus-neutralizing monoclonal antibodies supports the premise that ConvP will work when used at the right time, at the right dose, and containing antibodies with the right affinity., Objectives: This study aimed to review available evidence on dosing of ConvP for COVID-19 and provide guidance for future trials or patient care., Sources: Because no dose-finding human trials were ever performed, we reviewed COVID-19 animal model studies and human trials that provide (in)direct data on the pharmacokinetics and pharmacodynamics of ConvP. We also discuss the identification of appropriate ConvP donors in the context of emerging severe acute respiratory syndrome coronavirus 2 variants., Content: Compared with dosing in animal studies, almost all human trials used substantially lower doses. Identifying donors with sufficiently high virus-neutralizing antibody titres is challenging, in particular when new variants escape immunity induced by ancestral variants. Ways to avoid underdosing are (a) use of ConvP from two different donors, (b) use only ConvP known to neutralize the variant with which the patient is infected, (c) use two ConvP units with a neutralizing antibody titre ≥1/1250 (when only one plasma unit is available, neutralizing antibody titre of ≥1/2500 is recommended), (d) use an antibody test that correlates well with virus neutralization (use of international units per ml (IU/ml) for virus neutralization is strongly encouraged), and (e) use of donors shortly after a third mRNA vaccination may simplify the donor selection process., Implications: In future trials on ConvP for COVID-19, more stringent donor selection criteria and/or higher volume transfusions should be used., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Evidence on the determinants of the magnitude of humoral responses and neutralizing titers in individuals with mild COVID-19 is scarce., Methods: In this cohort study of mild COVID-19 patients, we assessed viral load (VL) by RT-qPCR at two/three time points during acute infection, and anti-SARS-CoV-2 antibodies by ELISA and plasma neutralizing responses using a pseudovirus assay at day 60., Results: Seventy-one individuals (65% female, median 42 years old) were recruited and grouped into high viral load (VL) >7.5 Log 10 copies/mL (n=20), low, VL ≤7.5 Log 10 copies/mL (n=22), or as Non-early seroconverters with a positive PCR (n=20), and healthy individuals with a negative PCR (n=9). Individuals with high or low VL showed similar titers of total neutralizing antibodies at day 60, irrespective of maximal VL or viral dynamics. Non-early seroconverters had lower antibody titers on day 60, albeit similar neutralizing activity as the groups with high or low VL. Longer symptom duration and older age were independently associated with increased humoral responses., Conclusions: In mild SARS-CoV-2-infected individuals, the duration of symptoms and age (but not VL) contribute to higher humoral responses., Competing Interests: Outside the submitted work JB and JC are founders and shareholders of AlbaJuna Therapeutics, S.L. BC is founder and shareholder of AlbaJuna Therapeutics, S.L and AELIX Therapeutics, S.L. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pradenas, Ubals, Urrea, Suñer, Trinité, Riveira-Muñoz, Marfil, Ávila-Nieto, Rodríguez de la Concepción, Tarrés-Freixas, Laporte, Ballana, Carrillo, Clotet, Mitjà and Blanco.)

Background: Convalescent plasma has been proposed as an early treatment to interrupt the progression of early COVID-19 to severe disease, but there is little definitive evidence. We aimed to assess whether early treatment with convalescent plasma reduces the risk of hospitalisation and reduces SARS-CoV-2 viral load among outpatients with COVID-19., Methods: We did a multicentre, double-blind, randomised, placebo-controlled trial in four health-care centres in Catalonia, Spain. Adult outpatients aged 50 years or older with the onset of mild COVID-19 symptoms 7 days or less before randomisation were eligible for enrolment. Participants were randomly assigned (1:1) to receive one intravenous infusion of either 250-300 mL of ABO-compatible high anti-SARS-CoV-2 IgG titres (EUROIMMUN ratio ≥6) methylene blue-treated convalescent plasma (experimental group) or 250 mL of sterile 0·9% saline solution (control). Randomisation was done with the use of a central web-based system with concealment of the trial group assignment and no stratification. To preserve masking, we used opaque tubular bags that covered the investigational product and the infusion catheter. The coprimary endpoints were the incidence of hospitalisation within 28 days from baseline and the mean change in viral load (in log 10 copies per mL) in nasopharyngeal swabs from baseline to day 7. The trial was stopped early following a data safety monitoring board recommendation because more than 85% of the target population had received a COVID-19 vaccine. Primary efficacy analyses were done in the intention-to-treat population, safety was assessed in all patients who received the investigational product. This study is registered with ClinicalTrials.gov, NCT04621123., Findings: Between Nov 10, 2020, and July 28, 2021, we assessed 909 patients with confirmed COVID-19 for inclusion in the trial, 376 of whom were eligible and were randomly assigned to treatment (convalescent plasma n=188 [serum antibody-negative n=160]; placebo n=188 [serum antibody-negative n=166]). Median age was 56 years (IQR 52-62) and the mean symptom duration was 4·4 days (SD 1·4) before random assignment. In the intention-to-treat population, hospitalisation within 28 days from baseline occurred in 22 (12%) participants who received convalescent plasma versus 21 (11%) who received placebo (relative risk 1·05 [95% CI 0·78 to 1·41]). The mean change in viral load from baseline to day 7 was -2·41 log 10 copies per mL (SD 1·32) with convalescent plasma and -2·32 log 10 copies per mL (1·43) with placebo (crude difference -0·10 log 10 copies per mL [95% CI -0·35 to 0·15]). One participant with mild COVID-19 developed a thromboembolic event 7 days after convalescent plasma infusion, which was reported as a serious adverse event possibly related to COVID-19 or to the experimental intervention., Interpretation: Methylene blue-treated convalescent plasma did not prevent progression from mild to severe illness and did not reduce viral load in outpatients with COVID-19. Therefore, formal recommendations to support the use of convalescent plasma in outpatients with COVID-19 cannot be concluded., Funding: Grifols, Crowdfunding campaign YoMeCorono., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The relationship between SARS-CoV-2 viral load and infectiousness is poorly known. Using data from a cohort of cases and high-risk contacts, we reconstructed viral load at the time of contact and inferred the probability of infection. The effect of viral load was larger in household contacts than in non-household contacts, with a transmission probability as large as 48% when the viral load was greater than 10 10 copies per mL. The transmission probability peaked at symptom onset, with a mean probability of transmission of 29%, with large individual variations. The model also projects the effects of variants on disease transmission. Based on the current knowledge that viral load is increased by two- to eightfold with variants of concern and assuming no changes in the pattern of contacts across variants, the model predicts that larger viral load levels could lead to a relative increase in the probability of transmission of 24% to 58% in household contacts, and of 15% to 39% in non-household contacts., Competing Interests: AM, MK, FB, JB, OM, MC, MM, JG No competing interests declared, (© 2021, Marc et al.)

Angiotensin converting enzyme 2 (ACE2) is a host ectopeptidase and the receptor for the SARS-CoV-2 virus, albeit virus-ACE2 interaction goes far beyond viral entry into target cells. Controversial data exists linking viral infection to changes in ACE2 expression and function, which might influence the subsequent induction of an inflammatory response. Here, we tested the significance of soluble ACE2 enzymatic activity longitudinally in nasopharyngeal swabs and plasma samples of SARS-CoV-2 infected patients, along with the induction of inflammatory cytokines. Release of soluble functional ACE2 increases upon SARS-CoV-2 infection in swabs and plasma of infected patients, albeit rapidly decreasing during infection course in parallel with ACE2 gene expression. Similarly, SARS-CoV-2 infection also induced the expression of inflammatory cytokines. These changes positively correlated with the viral load. Overall, our results demonstrate the existence of mechanisms by which SARS-CoV-2 modulates ACE2 expression and function, intracellular viral sensing and subsequent inflammatory response, offering new insights into ACE2 dynamics in the human upper respiratory tract and pointing towards soluble ACE2 levels as a putative early biomarker of infection severity.

Background: Mass testing for early identification and isolation of infectious COVID-19 individuals is efficacious for reducing disease spread. Antigen-detecting rapid diagnostic tests (Ag-RDT) may be suitable for testing strategies; however, benchmark comparisons are scarce., Methods: We used 286 nasopharyngeal specimens from unexposed asymptomatic individuals collected between December 2020 and January 2021 to assess five Ag-RDTs marketed by Abbott, Siemens, Roche Diagnostics, Lepu Medical, and Surescreen., Results: For the overall sample, the performance parameters of Ag-RDTs were as follows: Abbott assay, sensitivity 38.6% (95%CI 29.1-48.8) and specificity 99.5% (97-100%); Siemens, sensitivity 51.5% (41.3-61.6) and specificity 98.4% (95.3-99.6); Roche, sensitivity 43.6% (33.7-53.8) and specificity 96.2% (92.4-98.5); Lepu, sensitivity 45.5% (35.6-55.8) and specificity 89.2% (83.8-93.3%); Surescreen, sensitivity 28.8% (20.2-38.6) and specificity 97.8% (94.5-99.4%). For specimens with cycle threshold (Ct) <30 in RT-qPCR, all Ag-RDT achieved a sensitivity ≥70%. The modelled negative- and positive-predictive value for 1% prevalence were >99% and <50%, respectively., Conclusions: When screening unexposed asymptomatic individuals, two Ag-RDTs achieved sensitivity ≥80% for specimens with Ct<30 and specificity ≥96%. The estimated negative predictive value suggests the suitability of Ag-RDTs for mass screenings of SARS-CoV-2 infection in the general population., Competing Interests: Declaration of Competing Interest We declare no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Scarce data are available on what variables affect the risk of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the development of symptomatic COVID-19, and, particularly, the relationship with viral load. We aimed to analyse data from linked index cases of COVID-19 and their contacts to explore factors associated with transmission of SARS-CoV-2., Methods: In this cohort study, patients were recruited as part of a randomised controlled trial done between March 17 and April 28, 2020, that aimed to assess if hydroxychloroquine reduced transmission of SARS-CoV-2. Patients with COVID-19 and their contacts were identified by use of the electronic registry of the Epidemiological Surveillance Emergency Service of Catalonia (Spain). Patients with COVID-19 included in our analysis were aged 18 years or older, not hospitalised, had quantitative PCR results available at baseline, had mild symptom onset within 5 days before enrolment, and had no reported symptoms of SARS-CoV-2 infections in their accommodation or workplace within the 14 days before enrolment. Contacts included were adults with a recent history of exposure and absence of COVID-19-like symptoms within the 7 days preceding enrolment. Viral load of contacts, measured by quantitative PCR from a nasopharyngeal swab, was assessed at enrolment, at day 14, and whenever the participant reported COVID-19-like symptoms. We assessed risk of transmission and developing symptomatic disease and incubation dynamics using regression analysis. We assessed the relationship of viral load and characteristics of cases (age, sex, number of days from reported symptom onset, and presence or absence of fever, cough, dyspnoea, rhinitis, and anosmia) and associations between risk of transmission and characteristics of the index case and contacts., Findings: We identified 314 patients with COVID-19, with 282 (90%) having at least one contact (753 contacts in total), resulting in 282 clusters. 90 (32%) of 282 clusters had at least one transmission event. The secondary attack rate was 17% (125 of 753 contacts), with a variation from 12% when the index case had a viral load lower than 1 × 10 6 copies per mL to 24% when the index case had a viral load of 1 × 10 10 copies per mL or higher (adjusted odds ratio per log 10 increase in viral load 1·3, 95% CI 1·1-1·5). Increased risk of transmission was also associated with household contact (3·0, 1·59-5·65) and age of the contact (per year: 1·02, 1·01-1·04). 449 contacts had a positive PCR result at baseline. 28 (6%) of 449 contacts had symptoms at the first visit. Of 421 contacts who were asymptomatic at the first visit, 181 (43%) developed symptomatic COVID-19, with a variation from approximately 38% in contacts with an initial viral load lower than 1 × 10 7 copies per mL to greater than 66% for those with an initial viral load of 1 × 10 10 copies per mL or higher (hazard ratio per log 10 increase in viral load 1·12, 95% CI 1·05-1·20; p=0·0006). Time to onset of symptomatic disease decreased from a median of 7 days (IQR 5-10) for individuals with an initial viral load lower than 1 × 10 7 copies per mL to 6 days (4-8) for those with an initial viral load between 1 × 10 7 and 1 × 10 9 copies per mL, and 5 days (3-8) for those with an initial viral load higher than 1 × 10 9 copies per mL., Interpretation: In our study, the viral load of index cases was a leading driver of SARS-CoV-2 transmission. The risk of symptomatic COVID-19 was strongly associated with the viral load of contacts at baseline and shortened the incubation time of COVID-19 in a dose-dependent manner., Funding: YoMeCorono, Generalitat de Catalunya., Translations: For the Catalan translation of the abstract see Supplementary Materials section., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking., Methods: We conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)-confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days., Results: The analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported., Conclusions: Postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053.)., (Copyright © 2020 Massachusetts Medical Society.)

Hydroxychloroquine (HCQ) was initially promoted as an oral therapy for early treatment of coronavirus disease 2019 (COVID‐19). Conventional meta‐analyses cannot fully address the heterogeneity of different designs and outcomes of randomized controlled trials (RCTs) assessing the efficacy of HCQ in outpatients with mild COVID‐19. We conducted a pooled analysis of individual participant data from RCTs that evaluated the effect of HCQ on hospitalization and viral load reduction in outpatients with confirmed COVID‐19. We evaluated the overall treatment group effect by log‐likelihood ratio test (−2LL) from a generalized linear mixed model to accommodate correlated longitudinal binary data. The analysis included data from 11 RCTs. The outcome of virological effect, assessed in 1560 participants (N = 795 HCQ, N = 765 control), did not differ significantly between the two treatment groups (−2LL = 7.66; p = 0.18) when adjusting for cohort, duration of symptoms, and comorbidities. The decline in polymerase chain reaction positive tests from day 1 to 7 was 42.0 and 41.6 percentage points in the HCQ and control groups, respectively. Among the 2037 participants evaluable for hospitalization (N = 1058 HCQ, N = 979 control), we found no significant differences in hospitalization rate between participants receiving HCQ and controls (odds ratio 0.995; 95% confidence interval 0.614–1.610; −2LL = 0.0; p = 0.98) when adjusting for cohort, duration of symptoms, and comorbidities. This individual participant data meta‐analysis of 11 HCQ trials that evaluated severe acute respiratory syndrome‐coronavirus 2 viral clearance and COVID‐19 hospitalization did not show a clinical benefit of HCQ. Our meta‐analysis provides evidence to support the interruption in the use of HCQ in mild COVID‐19 outpatients to reduce progression to severe disease. [ABSTRACT FROM AUTHOR]

Background No effective treatments for coronavirus disease 2019 (COVID-19) exist. We aimed to determine whether early treatment with hydroxychloroquine (HCQ) would be efficacious for outpatients with COVID-19. Methods Multicenter open-label, randomized, controlled trial conducted in Catalonia, Spain, between 17 March and 26 May 2020. Patients recently diagnosed with <5-day of symptom onset were assigned to receive HCQ (800 mg on day 1 followed by 400 mg once daily for 6 days) or usual care. Outcomes were reduction of viral load in nasopharyngeal swabs up to 7 days after treatment start, disease progression up to 28 days, and time to complete resolution of symptoms. Adverse events were assessed up to 28 days. Results A total of 293 patients were eligible for intention-to-treat analysis: 157 in the control arm and 136 in the intervention arm. The mean age was 41.6 years (SD, 12.6), mean viral load at baseline was 7.90 log10 copies/mL (SD, 1.82), and median time from symptom onset to randomization was 3 days. No differences were found in the mean reduction of viral load at day 3 (−1.41 vs −1.41 log10 copies/mL in the control and intervention arm, respectively) or at day 7 (−3.37 vs −3.44). Treatment did not reduce risk of hospitalization (7.1% control vs 5.9% intervention) nor shorten the time to complete resolution of symptoms (12 days, control vs 10 days, intervention). No relevant adverse events were reported. Conclusions In patients with mild COVID-19, no benefit was observed with HCQ beyond the usual care. [ABSTRACT FROM AUTHOR]

We would like to express our concern about the limited capacity of actions taken by the Spanish Government to successfully control the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak and end the exponential growth phase of new cases. Novel coronavirus disease 2019 (COVID-19) pandemic: increased transmission in the EU/EEA and the UK-sixth update. Https://www.ecdc.europa.eu/sites/default/files/documents/RRA-sixth-update-Outbreak-of-novel-coronavirus-disease-2019-COVID-19.pdf March 12, 2020, 3 R Li, S Pei, B Chen, Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (COVID-19). medRxiv. [Extracted from the article]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging viral infection causing coronavirus disease 2019 (COVID-19). Hydroxychloroquine and chloroquine have garnered unprecedented attention as potential therapeutic agents against COVID-19 following several small clinical trials, uncontrolled case series, and public figure endorsements. While there is a growing body of scientific data, there is also concern for harm, particularly QTc prolongation and cardiac arrhythmias. Here, we perform a rapid narrative review and discuss the strengths and limitations of existing in vitro and clinical studies. We call for additional randomized controlled trial evidence prior to the widespread incorporation of hydroxychloroquine and chloroquine into national and international treatment guidelines. [ABSTRACT FROM AUTHOR]