Hydroxychloroquine Alone or in Combination with Cobicistat-Boosted Darunavir for Treatment of Mild COVID-19: A Cluster-Randomized Clinical Trial

Mitjà, Oriol; Corbacho, Marc; G-Beiras, Camila; Tebé, Cristian; Tobías, Aurelio; Ballana, Ester; Mitjà, Jordi; Clua, Mireia; Bertran, Laia; Sarquella, Maria; Gavilán, Sergi; Ubals, María; Alemany, Andrea; Riera-Martí, Núria; Suñer, Clara; Alvarez, C. S.; Laporte, Pep; Admella, Pol; Ara, Jordi; Argimón, Josep M.; Casabona, Jordi; Cuatrecasas, Gabriel; Cañadas, Paz; Elizalde-Torrent, Aleix; Fabregat, Robert; Farré, Magı́; Forcada, Anna; Flores-Mateo, Gemma; Muntada, Esteve; Nadal, Núria; Narejos, Silvia; Nieto, Aroa; Peñafiel, Judith; Prat, Núria; Quiñones, Carles; Reyes-Urueña, Juliana; Ramírez-Vilaplana, Ferrán; Ruiz, Lı́dia; Riveira-Muñoz, Eva; Sierra, Alba; Velasco, César; Vivanco-Hidalgo, Rosa María; Sentís, Alexis; Clotet, Bonaventura; Vall-Mayans, Martí

doi:10.2139/ssrn.3615997

Cited by 6 publications

(6 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several randomised controlled trials were not included in the analysis: two trials that evaluated different durations of the same drug, because both arms would have been classified within the same treatment node3240; one trial that compared lincomycin with azithromycin,55 because neither arm was connected to the network; 10 trials that compared technetium 99m-methyl diphosphonate ( 99 mTC-MDP),62 azvudine,63 colchicine,64 febuxostat,65 hydroxychloroquine,6667686970 and hydroxychloroquine with darunavir-cobicistat6869 because they were identified, or the data were available, after the analysis was completed. Table 2 describes the randomised controlled trials that were identified after the data analysis and that will be included in the next update.…”

Section: Resultsmentioning

confidence: 99%

Drug treatments for covid-19: living systematic review and network meta-analysis

Siemieniuk

Bartoszko

Zeraatkar

et al. 2020

BMJ

677

659

View full text Add to dashboard Cite

ObjectiveTo compare the effects of treatments for coronavirus disease 2019 (covid-19).DesignLiving systematic review and network meta-analysis.Data sourcesUS Centers for Disease Control and Prevention COVID-19 Research Articles Downloadable Database, which includes 25 electronic databases and six additional Chinese databases to 20 July 2020.Study selectionRandomised 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.MethodsAfter duplicate data abstraction, a bayesian random effects 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.Results23 randomised controlled trials were included in the analysis performed on 26 June 2020. The certainty of the evidence for most comparisons was very low because of risk of bias (lack of blinding) and serious imprecision. Glucocorticoids were the only intervention with evidence for a reduction in death compared with standard care (risk difference 37 fewer per 1000 patients, 95% credible interval 63 fewer to 11 fewer, moderate certainty) and mechanical ventilation (31 fewer per 1000 patients, 47 fewer to 9 fewer, moderate certainty). These estimates are based on direct evidence; network estimates for glucocorticoids compared with standard care were less precise because of network heterogeneity. Three drugs might reduce symptom duration compared with standard care: hydroxychloroquine (mean difference −4.5 days, low certainty), remdesivir (−2.6 days, moderate certainty), and lopinavir-ritonavir (−1.2 days, low certainty). Hydroxychloroquine might increase the risk of adverse events compared with the other interventions, and remdesivir probably does not substantially increase the risk of adverse effects leading to drug discontinuation. No other interventions included enough patients to meaningfully interpret adverse effects leading to drug discontinuation.ConclusionGlucocorticoids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care. The effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.Systematic review registrationThis review was not registered. The protocol is included as a supplement.Readers’ noteThis 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.

show abstract

Section: Resultsmentioning

confidence: 99%

Drug treatments for covid-19: living systematic review and network meta-analysis

Siemieniuk

Bartoszko

Zeraatkar

et al. 2020

BMJ

677

659

View full text Add to dashboard Cite

show abstract

“…The severity of two studies 12,13 included in update 2 of the WHO -COVID-19 Living Network Meta-Analysis group site were not present on the website so these were extracted from the original manuscript. Where severity was captured as not reported (NR) by the WHO -COVID-19 Living Network Meta-Analysis group we considered that patients with this severity may have been present in the trial and therefore considered this as part of the possible severity range of patients.…”

Section: Methodsmentioning

confidence: 99%

Definitions matter: heterogeneity of COVID-19 disease severity criteria and incomplete reporting compromise meta-analysis

Guérin

McLean

Rashan

et al. 2021

Preprint

View full text Add to dashboard Cite

Therapeutic efficacy in COVID-19 is dependent upon disease stage and severity (treatment effect heterogeneity). Unfortunately, definitions of severity vary widely. This compromises the meta-analysis of randomised controlled trials (RCTs) and the therapeutic guidelines derived from them. The World Health Organisation "living" guidelines for the treatment of COVID-19 are based on a network meta-analysis (NMA) of published RCTs. We reviewed the 81 studies included in the WHO COVID-19 living NMA and compared their severity classifications with the severity classifications employed by the international COVID-NMA initiative. The two were concordant in only 35% (24/68) of trials. Of the RCTs evaluated 69% (55/77) were considered by the WHO group to include patients with a range of severities (12 mild-moderate; 3 mild-severe; 18 mild-critical; 5 moderate-severe; 8 moderate-critical; 10 severe-critical), but the distribution of disease severities within these groups usually could not be determined, and data on the duration of illness and/or oxygen saturation values were often missing. Where severity classifications were clear there was substantial overlap in mortality across trials in different severity strata. This imprecision in severity assessment compromises the validity of some therapeutic recommendations; notably extrapolation of "lack of therapeutic benefit" shown in hospitalised severely ill patients on respiratory support to ambulant mildly ill patients is not warranted. Both harmonised unambiguous definitions of severity and individual patient data meta-analyses are needed to guide and improve therapeutic recommendations in COVID-19.

show abstract

“…Overall, 48 studies reported the number of patients required for MV during the study period. 2, 5, 15-17, 36-39, 41-44, 47-50, 56, 57, 60-63, 65, 69, 72, 76, 78, 82, 83, 87, 92, 95-97, 100, 103-105, 108-110, 112-114, 116, 117, 120 with 41405 patients and 4455 events. We included azithromycin, hydroxychloroquine, hydroxychloroquine plus azithromycin, remdesivir, lopinavir/ritonavir, convalescent plasma, methylprednisolone, dexamethasone, hydrocortisone, immunoglobulin, interferon beta, recombinant human GCSF, tocilizumab, vitamin D 3 , baricitinib plus remdesivir, sulodexide and SOC as treatment nodes in the NMA.…”

Section: Resultsmentioning

confidence: 99%

A Systematic Review and Network Meta-Analysis for COVID-19 Treatments

Zhang

Jin

Wen

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundNumerous interventions for coronavirus disease 2019 (COVID-19) have been investigated by randomized controlled trials (RCTs). This systematic review and Bayesian network meta-analysis (NMA) aim to provide a comprehensive evaluation of efficacy of available treatments for COVID-19.MethodsWe searched for candidate COVID-19 studies in WHO COVID-19 Global Research Database, PubMed, PubMed Central, LitCovid, Proquest Central and Ovid up to December 19, 2020. RCTs for suspected or confirmed COVID-19 patients were included, regardless of publication status or demographic characteristics. Bayesian NMA with fixed effects was conducted to estimate the effect sizes using posterior means and 95% equal-tailed credible intervals (CrIs), while that with random effects was carried out as well for sensitivity analysis. Bayesian hierarchical models were used to estimate effect sizes of treatments grouped by their drug classifications.ResultsWe identified 96 eligible RCTs with a total of 51187 patients. Compared with the standard of care (SOC), this NMA showed that dexamethasone led to lower risk of mortality with an odds ratio (OR) of 0.85 (95% CrI [0.76, 0.95]; moderate certainty) and lower risk of mechanical ventilation (MV) with an OR of 0.68 (95% CrI [0.56, 0.83]; low certainty). For hospital discharge, remdesivir (OR 1.37, 95% CrI [1.15, 1.64]; moderate certainty), dexamethasone (OR 1.20, 95% CrI [1.08, 1.34]; low certainty), interferon beta (OR 2.15, 95% CrI [1.26, 3.74]; moderate certainty), tocilizumab (OR 1.40, 95% CrI [1.05, 1.89]; moderate certainty) and baricitinib plus remdesivir (OR 1.75, 95% CrI [1.28, 2.39]; moderate certainty) could all increase the discharge rate respectively. Recombinant human granulocyte colony-stimulating factor indicated lower risk of MV (OR 0.20, 95% CrI [0.10, 0.40]; moderate certainty); and patients receiving convalescent plasma resulted in better viral clearance (OR 2.28, 95% CrI [1.57, 3.34]; low certainty). About two-thirds of the studies included in this NMA were rated as high risk of bias, and the certainty of evidence was either low or very low for most of the comparisons.ConclusionThe Bayesian NMA identified superiority of several COVID-19 treatments over SOC in terms of mortality, requirement of MV, hospital discharge and viral clearance. These results provide a comprehensive comparison of current COVID-19 treatments and shed new light on further research and discovery of potential COVID-19 treatments.

show abstract

Hydroxychloroquine Alone or in Combination with Cobicistat-Boosted Darunavir for Treatment of Mild COVID-19: A Cluster-Randomized Clinical Trial

Cited by 6 publications

References 9 publications

Drug treatments for covid-19: living systematic review and network meta-analysis

Drug treatments for covid-19: living systematic review and network meta-analysis

Definitions matter: heterogeneity of COVID-19 disease severity criteria and incomplete reporting compromise meta-analysis

A Systematic Review and Network Meta-Analysis for COVID-19 Treatments

Contact Info

Product

Resources

About