Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients with Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial

Liu, Yueping; Xie, Zhiwei; Lin, Wan-Ying; Cai, Weiping; Wen, Chunyan; Guan, Yubao; Mo, Xiaoneng; Wang, Jian; Wang, Yaping; Peng, Ping; Chen, Xudan; Hong, Wei; Xiao, Guangming; Liu, Jinxin; Zhang, Lieguang; Hu, Fengyu; Li, Feng; Zhang, Fuchun; Deng, Xilong; Li, Linghua

doi:10.1016/j.medj.2020.04.001

Cited by 260 publications

(339 citation statements)

References 15 publications

(16 reference statements)

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“…Two trials compared remdesivir versus placebo [ 32 , 44 ]. Two trials compared lopinavir–ritonavir added to standard care versus standard care alone [ 33 , 41 ]. Eight trials compared hydroxychloroquine added to standard care versus standard care alone [ 35 , 36 , 43 , 49 , 55 , 56 , 59 , 60 ].…”

Section: Resultsmentioning

confidence: 99%

Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

et al. 2020

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Background Coronavirus disease 2019 (COVID-19) is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. Methods and findings This is the first edition of a living systematic review of randomized clinical trials comparing the effects of all treatment interventions for participants in all age groups with COVID-19. We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review is based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Cochrane guidelines, and our 8-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and nonserious adverse events. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until August 7, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 33 randomized clinical trials enrolling a total of 13,312 participants. All trials were at overall high risk of bias. We identified one trial randomizing 6,425 participants to dexamethasone versus standard care. This trial showed evidence of a beneficial effect of dexamethasone on all-cause mortality (rate ratio 0.83; 95% confidence interval [CI] 0.75–0.93; p < 0.001; low certainty) and on mechanical ventilation (risk ratio [RR] 0.77; 95% CI 0.62–0.95; p = 0.021; low certainty). It was possible to perform meta-analysis of 10 comparisons. Meta-analysis showed no evidence of a difference between remdesivir versus placebo on all-cause mortality (RR 0.74; 95% CI 0.40–1.37; p = 0.34, I 2 = 58%; 2 trials; very low certainty) or nonserious adverse events (RR 0.94; 95% CI 0.80–1.11; p = 0.48, I 2 = 29%; 2 trials; low certainty). Meta-analysis showed evidence of a beneficial effect of remdesivir versus placebo on serious adverse events (RR 0.77; 95% CI 0.63–0.94; p = 0.009, I 2 = 0%; 2 trials; very low certainty) mainly driven by respiratory failure in one trial. Meta-analyses and trial sequential analyses showed that we could exclude the possibility that hydroxychloroquine versus standard care reduced the risk of all-cause mortality (RR 1.07; 95% CI 0.97–1.19; p = 0.17; I 2 = 0%; 7 trials; low certainty) and ...

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Section: Resultsmentioning

confidence: 99%

Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

et al. 2020

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“…We included 12 RCTs, 3 non-RCTs and 20 observational (including retrospective/prospective cohort, case-control) studies. Eighteen studies were from China, 10,11,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] six from USA, [47][48][49][50][51][52] five from Italy, [53][54][55][56][57] two from France 6,58 and one each from Brazil, 59 Hong Kong, 60 Spain 61 and Greece. 62 There was no significant difference in the mean age and sex distribution between any of the treatment and comparator groups included in our meta-analysis.…”

Section: Results From Clinical Studiesmentioning

confidence: 99%

“…Four studies [35][36][37][38] consisting of 397 nCOV-2019 cases were included in the meta-analysis and were divided into two groups: 227 subjects to lopinavir-ritonavir group and 170 subjects control group. There was no significant association between the two groups in terms of total adverse events (RR 1.73; 95%CI 0.57 to 5.26) and overall clinical recovery (RR 1.08; 95%CI 0.94 to 1.24).…”

Section: Lopinavir-ritonavir Vs Control Groupsmentioning

confidence: 99%

Efficacy of various treatment modalities for nCOV‐2019: A systematic review and meta‐analysis

Misra

Nath

Hadda

et al. 2020

Eur J Clin Investigation

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Background: Several therapeutic agents have been investigated for treatment of novel coronavirus 2019 (nCOV-2019). We conducted a systematic review and metaanalysis to assess the efficacy of various treatment modalities in nCOV-2019 patients. Methods: A literature search was conducted before 29 June 2020 in PubMed, Google Scholar and Cochrane library databases. A fixed-effect model was applied if I 2 < 50%, else results were combined using random-effect model. Risk ratio (RR) or standardized mean difference (SMD) along with 95% confidence interval (95% CI) was used to pool the results. Between-study heterogeneity was explored using influence and sensitivity analyses, and publication bias was assessed using funnel plots. Entire statistical analysis was conducted in R version 3.6.2. Results: Fifty studies involving 15 in vitro and 35 clinical studies including 9170 nCOV-2019 patients were included. Lopinavir-ritonavir was significantly associated with shorter mean time to clinical recovery (SMD −0.32; 95% CI −0.57 to −0.06), remdesivir was significantly associated with better overall clinical recovery (RR 1.17; 95% CI 1.07 to 1.29), and tocilizumab was associated with less all-cause mortality (RR 0.38; 95% CI 0.16 to 0.93). Hydroxychloroquine was associated with longer time to clinical recovery and less overall clinical recovery. It additionally had higher all-cause mortality and more total adverse events. Conclusion: Our meta-analysis suggests that except in vitro studies, no treatment has shown overall favourable outcomes in nCOV-2019 patients. Lopinavir-ritonavir, remdesivir and tocilizumab may have some benefits, while hydroxychloroquine administration may cause harm in nCOV-2019 patients. Results from upcoming large clinical trials may further clarify role of these drugs. K E Y W O R D S humans, interventions, nCOV-2019, novel coronavirus 2019, treatments 2 of 21 | MISRA et Al. 2 | METHODS 2.1 | Electronic search Electronic databases including, PubMed, EMBASE, Medline, Google Scholar, Cochrane library and clinicaltrials.gov were searched till 29 June 2020. The following MeSH terms or free text terms were used: '2019 novel coronavirus', '2019 nCOV', 'COVID19', 'SARS-CoV-2', 'drug therapy', 'antiviral therapy', 'symptomatic treatment', 'immunotherapy'. The detailed search criteria are given in the Appendix S1. Furthermore, the reference list of all the relevant identified articles was thoroughly searched. Only those articles were included whose full texts were available in English language. Studies published on human subjects after 31 December 2019 since the nCOV-2019 outbreak initiated, were only searched. The protocol for this systematic review and meta-analysis was registered in PROSPERO (ID: CRD42020175792), and there were no major deviations from the published protocol in PROSPERO. 2.2 | Population Subjects diagnosed with pneumonia caused by new coronavirus 2019 infection (nCOV-2019) confirmed positive on highthroughput sequencing or real-time reverse-transcription polymerase chain reaction analysis of thro...

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“…The screening process was shown in figure 1 and 3860 studies were identified according to the research strategy initially. In total, 22 studies containing 12795 patients were adopted in our study and all of them were published in English 10,12,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] . Among trails included, half of them were RCTs, and the other were Non-RCTs.…”

Section: Literature Researchmentioning

confidence: 99%

The therapeutic effect and safety of the drugs for COVID-19: a systematic review and meta-analysis

Qiu

Xiao

et al. 2020

Preprint

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Background: Coronavirus disease 2019 (COVID-19) has spread almost all regions of the world and caused great loss to the whole body of mankind. Thus, numerous clinical trials were conducted to find specific medicine for COVID-19 recently. However, it remains unanswered whether they are beneficial. Objective: This study aimed to evaluate the efficiency and safety of the COVID-19 medicine. Methods: Studies were determined through searching PubMed, Embase, Cochrane Library and Medline. The clinical trials of COVID-19 medicine were involved with eligible end points containing mortality, discharge rate, rate of clinical improvement and rate of serious adverse events. The risk ratio (RR) was adopted for variables as effect magnitude with 95% confidence intervals (CI), and the random‐effects model was adopted for analysis. Results: A total of eleven RCTs and eleven Non-RCTs involving 12,796 patients were included in our study, whose intervening measures contained three major types of COVID-19 medicine, ACEI/ARB, antiviral medicine and chloroquine/hydroxychloroquine. Compared to control group, COVID-19 medicine has the obvious advantage in reducing discharge rate (RR, 1.18; 95% CI, 1.07-1.29, p<0. 05) and clinical improvement rate (RR, 1.15; 95% CI, 1.05-1.26, p<0. 05), no distinct effect on mortality (RR, 0.79; 95% CI, 0.53-1.17, p=0. 24). In addition, the serious adverse events rate (RR, 0.74; 95% CI, 0.62-0.88, p<0. 05) of COVID-19 medicine is lower than control group. Among different types of medicine, significant benefits in lowering the mortality seem to only occur in antiviral medicine. Conclusion: The results indicated antiviral medicine was potential drug of first choice recommended for COVID-19 treatment. Chloroquine/hydroxychloroquine therapy was not recommended for COVID-19 patients. Additionally, the ACEI/ARB could be adopted for COVID-19 treatment when combined with standard treatment.

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Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients with Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial

Cited by 260 publications

References 15 publications

Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

Efficacy of various treatment modalities for nCOV‐2019: A systematic review and meta‐analysis

The therapeutic effect and safety of the drugs for COVID-19: a systematic review and meta-analysis

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