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. 2021 Mar 17;30(159):200384.
doi: 10.1183/16000617.0384-2020. Print 2021 Mar 31.

Current evidence for COVID-19 therapies: a systematic literature review

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Current evidence for COVID-19 therapies: a systematic literature review

Tobias Welte et al. Eur Respir Rev. .

Abstract

Effective therapeutic interventions for the treatment and prevention of coronavirus disease 2019 (COVID-19) are urgently needed. A systematic review was conducted to identify clinical trials of pharmacological interventions for COVID-19 published between 1 December 2019 and 14 October 2020. Data regarding efficacy of interventions, in terms of mortality, hospitalisation and need for ventilation, were extracted from identified studies and synthesised qualitatively. In total, 42 clinical trials were included. Interventions assessed included antiviral, mucolytic, antimalarial, anti-inflammatory and immunomodulatory therapies. Some reductions in mortality, hospitalisation and need for ventilation were seen with interferons and remdesivir, particularly when administered early, and with the mucolytic drug, bromhexine. Most studies of lopinavir/ritonavir and hydroxychloroquine did not show significant efficacy over standard care/placebo. Dexamethasone significantly reduced mortality, hospitalisation and need for ventilation versus standard care, particularly in patients with severe disease. Evidence for other classes of interventions was limited. Many trials had a moderate-to-high risk of bias, particularly in terms of blinding; most were short-term and some included low patient numbers.This review highlights the need for well-designed clinical trials of therapeutic interventions for COVID-19 to increase the quality of available evidence. It also emphasises the importance of tailoring interventions to disease stage and severity for maximum efficacy.

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Conflict of interest statement

Conflict of interest: T. Welte reports personal fees, fees for lectures and consultancy fees from AstraZeneca, Basilea, Biotest, Bayer, Boehringer, GlaxoSmithKline, Janssens, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Sanofi Aventis, outside the submitted work. Conflict of interest: L.J. Ambrose reports other funding from AstraZeneca, during the conduct of the study. Conflict of interest: G.C. Sibbring reports other funding from AstraZeneca, during the conduct of the study. Conflict of interest: S. Sheikh was an employee and shareholder of AstraZeneca at the time of manuscript preparation. Conflict of interest: H. Müllerová is an employee and shareholder of AstraZeneca. Conflict of interest: I. Sabir is an employee and shareholder of AstraZeneca.

Figures

FIGURE 1
FIGURE 1
a) Current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved interventions for coronavirus disease 2019 (COVID-19). b) Effective therapies in the included trials showing interventions that showed statistically significant differences in outcomes versus the comparator. SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; ECMO: extracorporeal membrane oxygenation; IFN: interferon; SC: standard care; TFF2: trefoil factor 2; SOF: sofosbuvir; DCV: daclatasvir; FAV: favipiravir; LPV/r: lopinavir/ritonavir; RBV: ribavirin; FNC: azvudine; RDV: remdesivir; CHQ: chloroquine diphosphate; BHC: bromhexine; DEX: dexamethasone; MP: methylprednisolone; COL: colchicine; ENOX: enoxaparin; LMW: low molecular weight; rhG-CSF: recombinant human granulocyte colony-stimulating factor. #: includes enoxaparin (anticoagulant), rhG-CSF and auxora (calcium release-activated calcium channel inhibitor).
FIGURE 2
FIGURE 2
Summary of mortality outcomes in trials of a) antivirals, b) antimalarial and mucolytic drugs and c) other therapies included in the qualitative synthesis. Other therapies include anti-inflammatory drugs, anticoagulants, kinase inhibitors, calcium release-activated calcium channel inhibitors, anticoagulants, immunomodulatory therapies and repair therapies. Results from one study are not presented graphically. Deftereos et al. [36] reported event-free survival as a primary outcome, which was defined as survival without meeting the primary clinical end-point (deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death). IFN: interferon; SC: standard care; TFF2: trefoil factor 2; SOF: sofosbuvir; DCV: daclatasvir; RBV: ribavirin; HCQ: hydroxychloroquine; LPV/r: lopinavir/ritonavir; FAV: favipiravir; TZV: triazavirin; PBO: placebo; DRV: darunavir; COBI: cobicistat; ARB: arbidol; RDV: remdesivir; F/U: follow-up; FNC: azvudine; LEF: leflunomide; CHQ: chloroquine diphosphate; AZ: azithromycin; BHC: bromhexine; HC: hydrocortisone; DEX: dexamethasone; IMV: invasive mechanical ventilation; MP: methylprednisolone; RUX: ruxolitinib; ENOX: enoxaparin; LMW: low molecular weight; CP: convalescent plasma; rhG-CSF: recombinant human granulocyte colony-stimulating factor; NAC: N-acetylcysteine. #: treatment administered in addition to SC, as defined by the investigators in each trial; : no between-group comparison; +: treatment on day 1 of study participation; §: treatment on day 6 of study participation; ƒ: outcome was disease progression or death; ##: p-value for comparison of 7-level ordinal outcome (including death) at 14 days; ¶¶: treatment ≤10 days of symptom onset; ++: treatment >10 days of symptom onset; §§: re-analysis of data from Wang et al. [44] using different criteria; ƒƒ: outcome was incidence of hospitalisation or death; ###: p-value for comparisons of the 7-level ordinal outcome (including death) at 15 days; ¶¶¶: participants could be randomly assigned to other interventions within other therapeutic domains; +++: median (95% CI) adjusted odds ratios versus the no-hydrocortisone group were 1.03 (0.53–1.95) and 1.10 (0.58–2.11) for the fixed-dose and shock-dependent dosing hydrocortisone groups, respectively. These yielded 54% and 62% Bayesian posterior probabilities of superiority. *: statistically significant p-value.
FIGURE 3
FIGURE 3
Duration of hospitalisation in trials of a) antivirals, antimalarial and mucolytic drugs and b) other therapies included in the qualitative synthesis. Data are presented as median (IQR) unless indicated otherwise. Other therapies include anti-inflammatory drugs, anticoagulants, immunomodulatory therapies and repair therapies. IFN: interferon; SC: standard care; TFF2: trefoil factor 2; SOF: sofosbuvir; DCV: daclatasvir; RBV: ribavirin; HCQ: hydroxychloroquine; LPV/r: lopinavir/ritonavir; FAV: favipiravir; RDV: remdesivir; PBO: placebo; FNC: azvudine; LEF: leflunomide; AZ: azithromycin; DEX: dexamethasone; MP: methylprednisolone; COL: colchicine; ENOX: enoxaparin; LMW: low molecular weight; CP: convalescent plasma; rhG-CSF: recombinant human granulocyte colony-stimulating factor; NAC: N-acetylcysteine. #: mean±sd; : treatment administered in addition to SC, as defined by the investigators in each trial; +: mean (95% CI); §: post-hoc analysis; ƒ: treatment on day 1 of study participation; ##: treatment on day 6 of study participation; ¶¶: treatment <7 days from symptom onset; ++: treatment ≥7 days from symptom onset; §§: no between-group comparison; ƒƒ: outcome only assessed in survivors; ###: no IQR reported; ¶¶¶: per hospital protocol, all patients meeting acute respiratory distress syndrome criteria were given pre-emptively intravenous ceftriaxone (1 g twice for 7 days) plus azithromycin (500 mg once for 5 days) or clarithromycin (500 mg twice for 7 days), starting on day 1; +++: upper IQR limit could not be determined; §§§: median value could not be determined, HR 1.90 (95% CI 0.45–8.04); p=0.38. *: statistically significant p-value.
FIGURE 4
FIGURE 4
Need for ventilation in trials of a) antivirals and b) other therapies included in the qualitative synthesis. Other therapies include antimalarial drugs, mucolytic drugs, anti-inflammatory drugs, anticoagulants, immunomodulatory therapies and repair therapies. Results from two studies are not presented graphically. Li et al. [39] reported need for intensive mechanical ventilation in two (15.4%) out of 13 severe patients; Deftereos et al. [36] reported need for ventilation among seven patients who met the primary clinical end-point: in the control group, one (14.3%) out of seven patients needed noninvasive mechanical ventilation and five (71.4%) were intubated and ventilated mechanically. The patient in the colchicine group who met the end-point needed invasive mechanical ventilation (MV). NIV: noninvasive ventilation; IFN: interferon; SC: standard care; SOF: sofosbuvir; DCV: daclatasvir; RBV: ribavirin; HCQ: hydroxychloroquine; LPV/r: lopinavir/ritonavir; TZV: triazavirin; PBO: placebo; DRV: darunavir; COBI: cobicistat; RDV: remdesivir; AZ: azithromycin; BHC: bromhexine; DEX: dexamethasone; HC: hydrocortisone; MP: methylprednisolone; RUX: ruxolitinib; rhG-CSF: recombinant human granulocyte colony-stimulating factor; NAC: N-acetylcysteine. #: treatment administered in addition to SC, as defined by the investigators in each trial; : no comparison between groups; +: p-value for clinical status at day 14 (composite of death and ventilation requirement outcomes); §: difference in clinical status distribution versus standard care, OR 1.65 (95% CI 1.09–2.48); ƒ: outcomes reported in patients not receiving ventilation at baseline; between-group differences (95% CI): oxygen −8 (−24– –8); NIV/high-flow oxygen −7 (−14– −1); MV/ECMO, −10 (−15– −4); ##: re-analysis of data from Wang et al. [44] using different criteria; ¶¶: effect estimates versus SC: need for NIV 1.10 (95% CI 0.60–2.03); need for MV 1.77 (95% CI 0.81–3.87); ++: effect estimates versus SC: need for NIV 1.19 (95% CI 0.65–2.21); need for MV 1.15 (95% CI 0.49–2.70); §§: risk ratio: 0.77 (95% CI 0.62–0.95); ƒƒ: HR 2.6 (95% CI −8.6–13.6); ###: values are in comparison to baseline after 3 days after treatment. After discharge/death, the proportion of patients requiring supplementary oxygen was significantly decreased compared to baseline in both groups; ¶¶¶: absolute risk reduction: 32% (95% CI −0.07–0.71). +++: OR (95% CI) 1.21 (0.53–2.72). *: significant p-value or other comparison.

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