Evaluation of the current therapeutic approaches for COVID-19: a meta-analysis

Background and rationale: Limited data on the efficacy and safety of currently applied COVID-19 therapeutics and their impact on COVID-19 outcomes have raised additional concern. Aim and Methods: We estimated the impact of the current treatments on the efficacy and safety of COVID-19 by a meta-analysis. The comprehensive search included studies reporting clinical features and treatment strategies published from January 21, 2020, to May 15, 2020. Results: We included 52 studies that involved 13,966 COVID-19 patients. We found that the most prevalent treatments were antivirals (proportion: 0.74, 95% CI : [0.65, 0.83]) and antibiotics (proportion: 0.73, 95% CI: [0.62, 0.83]). The COVID-19 severity increased among patients taking glucocorticoids (risk ratio (RR) = 1.71, 95% CI: [1.06, 2.76]) or immunoglobulins (RR = 3.83, 95% CI: [1.27, 11.53]), and renal replacement therapy (RRT) and glucocorticoids increased the length of ICU stay (RRT : RR= 11.89, 95% CI: [3.26, 43.39]; glucocorticoids: RR = 3.10, 95% CI: [1.52, 6.29]). The COVID-19 severity and mortality increased among patients taking tocilizumab (severity: F = 25.53, P = 0.02; mortality: F = 19.37, P = 0.02). The most effective treatment was the combination of arbidol with lopinavir/ritonavir compared with placebo (mean difference = 0.5, 95% CI [-0.60, 1.66]), and the safest combination was remdesivir and lopinavir/ritonavir (RR= 0.78, 95% CI [0.32, 1.91]). Conclusion: glucocorticoids, immunoglobulins, RRT, and tocilizumab might worsen COVID-19 outcomes, and the most effective and safest treatment strategy for COVID-19 is the combination of different antivirals.

To estimate the association between treatment and disease severity, we performed COVID-19 risk or not. The severity terms included "severe" versus "non-severe," 2 0 5 "death" versus "survival," "deterioration," versus "discharge," and "ICU" versus 2 0 6 "non-ICU." We performed a subgroup meta-analysis on 42 studies. We also conducted 2 0 7 meta-regression for chloroquine or hydroxychloroquine and tocilizumab for which we 2 0 8 had no sufficient data to perform subgroup meta-analysis. We used the general term 2 0 9 "relative risk (RR)" to uniformly refer to the different severity terms. analysis showed that the COVID-19 severity and mortality increased among patients there were no significant differences among patients taking chloroquine or 2 1 8 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 1 hydroxychloroquine. The pooled RR of eight treatments indicated that the use of 2 1 9 glucocorticoids, immunoglobulin, tocilizumab, and RRT were likely to increase 2 2 0 COVID-19 progression and severity (Table 1 and Supplemental Content 7 and 8). To determine if there are outliers that could influence our analysis results, we 2 2 2 performed leave-one-out (LOO) analyses. In brief, each study was removed once, and 2 2 3 the summary proportion was re-estimated based on the remaining studies. Studies with a statistically significant impact on the fitted model were removed as outliers, To compare the effect of different anti-COVID-19 treatment approaches, we performed network meta-analysis. We included only 13 studies [38, 32, 26, 24, 22, 23, 28, 60, 30, 2 3 9 27, 21, 29, 25] in the analysis because of network inconsistency (Supplemental Content 5).

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. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The best improvement in the effect was the combination of arbidol with lopinavir or were inferred by direct or indirect evidence. We produced a matrix for the effect sizes To determine which COVID-19 treatment is the most effective, we ranked the 2 5 8 treatments based on the P score in the frequentist model (Supplemental Content 12).

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We observed that arbidol plus lopinavir/ritonavir had the highest P score of 0.9995, and lopinavir/ritonavir plus interferon had the second-highest P score of 0.851, 2 6 1 followed by chloroquine (P score = 0.579). These results indicate that the antiviral 2 6 2 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted August 25, 2020. and immune responses changed during the disease progression in COVID-19 3 6 8 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted August 25, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted August 25, 2020. . Rationale and hypothesis for the use of multiple immunosuppressive agents: Anti-antibodies, immunoglobulins, and corticosteroids. Int Immunopharmacol. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted August 25, 2020. . https://doi.org/10.1101/2020.08.24.20180638 doi: medRxiv preprint 1 Total, the total number of patients enrolled in the study. the edge connects. These results were obtained by the random-effect model. a The moderator used in the meta-regression is the number of patients in ICU.

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b The moderator used in the meta-regression is the number of patients died. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted August 25, 2020August 25, . . https://doi.org/10.1101August 25, /2020 doi: medRxiv preprint 4 6 0 5 6 0 6 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted August 25, 2020.  . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.