. 2021 Feb 1;93(5):2705–2721. doi: 10.1002/jmv.26811

Table 1.

An overview of the systematic reviews provided for COVID‐19 treatment

Study authors (year)	Country	Type	Title	Aim	Sample Size (no. of studies)	Method	Drug	Treatment Complication	Conclusion
AminJafari and Ghasemi (2020) ³²	Iran	Systematic review	The possibility of immunotherapy for COVID‐19: A systematic review	To evaluate the existing evidence about immunotherapy for COVID‐19.	7	Not reported	Immunotherapy: Polyclonal antibody by plasma therapy, polypeptide hormone for maturation of T cells, immunoglubolins, ACE2 immunoadhesin and monoclonal antibody against the interleukin‐6 (IL‐6)	Not reported	No serious research has been done on this subject, but similar studies on the related viruses showed remarkable effects. It was suggested that immunotherapy (immunoglobulin and plasma therapy) can be used to improve the clinical outcomes in patients with COVID‐19.
Andrade et al. (2020) ⁴	Brazil	Systematic review	Pharmacological therapies for patients with human coronavirus infections: a rapid systematic review	To evaluate the effects of drug therapies for human coronavirus infections.	36	6 RCTs, 2 clinical trials, 16 retrospective cohorts, 2 prospective cohorts, 1 case‐reports, 6 case series, 3 systematic review	Antimalarial drugs, antivirals, and antiretroviral drugs, immunomodulators, anticoagulant, corticoid, combined therapies	Not reported	The available scientific evidence is preliminary and of low methodological quality.
Piechotta et al. (2020) ³³	Europe	Systematic review	Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a living systematic review	To evaluate the safety and effectiveness of convalescent plasma or hyperimmune immunoglobulin transfusion in the treatment of patients with COVID‐19.	19	2 RCTs, 17 clinical trials	Convalescent plasma or hyperimmune immunoglobulin transfusion	Allergic or respiratory, thrombotic or thromboembolic, and cardiac events	It was not clear whether convalescent plasma decreases all‐cause mortality at hospital discharge. It may lead to little to no difference in the improvement of clinical symptoms at 7 days. It may increase improvement of clinical symptoms at up to 15 days, and at up to 30 days
Chowdhury et al. (2020) ²⁷	USA	Systematic review	A rapid systematic review of clinical trials utilizing CQ and HCQ as a treatment for COVID‐19	To review the literature regarding the clinical use of CQ and HCQ as treatment of COVID‐19.	7	7 clinical trials	HCQ and CQ	Potential risk of QTc prolongation in combination of HCQ plus azithromycin	HCQ or CQ is efficacious compared to supportive care and to LPV/r in the treatment of COVID‐19.
Cortegiani et al. (2020) ³⁴	Italy	Systematic review	A systematic review on the efficacy and safety of chloroquine for the treatment of COVID‐19	To summarize the evidence regarding CQ for the treatment of COVID‐19	6	1 narrative letter, 1 in vitro, 1 editorial, 1 expert consensus paper, 2 national guidelines, ongoing clinical trial	CQ	Anemia, thrombocytopenia or leukopenia, hepatic, renal dysfunction, development of QT interval prolongation or bradycardia, visual and/or mental disturbance/deterioration	CQ seems to be effective in limiting the replication of SARS‐CoV‐2 in vitro. There is sufficient preclinical rationale and evidence regarding the effectiveness of CQ for treatment of COVID‐19 and safety from long‐time use in clinical practice for other indications. Although the use of CQ may be supported by expert opinion, clinical use of this drug should be approved.
Ford et al. (2020) ¹⁶	Switzerland	Systematic review	Systematic review of the efficacy and safety of antiretroviral drugs against SARS, MERS, or COVID‐19: Initial assessment	To evaluate the clinical outcomes of using antiretroviral drugs for the prevention and treatment of coronaviruses and planned clinical trials.	26	23 antiviral drugs for treatment (2 RCTs, 21 observational studies), 3 antiviral drugs for prevention	LPV/r, emtricitabine, tenofovir, atazanavir, ritonavir, darunavir, nelfinavir, indinavir, saquinavir, lamivudine, and zidovudine	LPV/r: Mortality, gastrointestinal complaints (nausea, vomiting, and diarrhea) in	It is ambiguous whether LPV/r and other antiretrovirals improve clinical outcomes or prevent infection among patients at high risk of COVID‐19.
Hernandez, et al. (2020) ²⁶	Peru, USA	Systematic review	HCQ or CQ for Treatment or Prophylaxis of COVID‐19	To evaluate the benefits and harms of HCQ or CQ for the treatment or prophylaxis of COVID‐19.	23	4 RCTs, 10 cohort studies, 9 case‐series	HCQ or CQ	QTc interval ≥ 500 ms	Evidence on the benefits and harms is very weak and conflicting. There were no assessments of these drugs for prophylaxis against COVID‐19.
Li et al. (2020) ¹⁹	China	Systematic review and meta‐analysis	Impact of corticosteroid therapy on outcomes of persons with SARS‐CoV‐2, SARS‐CoV, or MERS‐CoV infection: a systematic review and meta‐analysis	To determine the safety and efficacy of corticosteroids in SARS‐CoV‐2, SARS‐CoV, and MERS‐CoV infections	11	1 RCT, 10 cohort studies	Corticosteroids	Not reported	Corticosteroid was associated with delayed virus clearing, but no significant reduction in death and ICU admission were observed. Hospital length of stay was prolonged, and use of mechanical ventilation increased.
Lima et al. (2020) ³¹	Brazil, Canada	Systematic review	The potential of drug repositioning as a short‑term strategy for the control and treatment of COVID‑19 (SARS‑CoV‑2): a systematic review	To evaluate the drug repositioning strategy against SARS‐CoV‐2.	12	1 RCT, 2 retrospective studies, 2 case reports, 2 in vitro, 5 in silico	Antivirals, antiretroviral, antibiotics, antitumoral, antipsychotic, antifungal, antiemetic, antiplatelet agent, sedative‐hypnotic, hipolipemiant,	Not reported	LPV/r had low effectiveness on COVID‐19, but arbidol, remdesivir, and CQ/HCQ showed promising effects.
Liu et al. (2020) ³⁵	China	Systematic review and meta‐analysis	Efficacy and safety of antiviral treatment for COVID‐19 from evidence in studies of SAR‐SCoV‐2 and other acute viral infections: a systematic review and meta‐analysis	To evaluate the benefits and harms of 7 antiviral treatments for COVID‐19.	19	7 RCTs, 11 cohorts, 1 case‐control	7 antivirals: Ribavirin, CQ, HCQ, umifenovir (arbidol), favipiravir, interferon, LPV/r	Ribavirin: Anemia and bradycardia HCQ: Diarrhea, vomiting, headache, rash, and blurred vision Arbidol: Diarrhea and decreased appetite Favipiravir: diarrhea Interferon‐a: Need for granulocyte colony‐stimulating factor in patients with leukopenia LPV/r: Diarrhea, nausea and vomiting, and stomach ache	Very low‐quality evidence with little or no suggestion of benefit for most treatments and outcomes in both non‐severe and severe COVID‐19 were found. LPV/r with low‐quality evidence was shown to be effective in decreasing in length of stay in ICU and hospital stay. With moderate‐quality evidence, it may increase diarrhea, nausea, and vomiting
Musa et al. (2020) ²⁸	USA	Systematic review	Remdesivir for the treatment of COVID‐19: a systematic review of the literature	To determine the outcomes and adverse events associated with this investigational, antiviral medication	8	8 clinical trials	Remdesivir: 5 trials: 200‐mg intravenous loading dose following by maintenance dose of 100 mg for 9 days. 2 trials: A single, 100‐mg IV infusion	The side‐effects profile of remdesivir remains not well defined	The clinical effectiveness of IV remdesivir for treatment of COVID‐19 and potential side effects remain incompletely defined in the human population.
Nasir et al. (2020) ²⁹	Bangladesh	Systematic review	Systematic review on repurposing use of favipiravir against SARS‐CoV‐2	To evaluate evidence regarding the safety of the repurposing clinical use of favipiravir for the treatment of COVID‐19.	19	2 RCTs, 17 ongoing trials	Favipiravir in combination with other treatments	Increased serum uric acid level	Favipiravir has significantly better treatment effects on disease progression, viral clearance, improved the latency to relief for pyrexia and cough in patients with COVID‐19.
Nasir et al. (2020) ³⁰	Bangladesh	Systematic review	Use of remdesivir in the management of COVID‐19: a systematic review on current evidence	To evaluate the efficacy and safety to identify any promising role for compassionate use of remdesivir in patient who suffered from severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2).	7	2 RCTs, 1 clinical trial, 4 case reports	Remdesivir	Hypotension, skin rashes, abnormal liver function, and diarrhea	Although remdesivir did not have a significant effect on the time to clinical improvement, its benefit may significantly depend on the time of administration (2 h after infection).
Patel et al. (2020) ²⁴	India, USA	Systematic review and meta‐analysis	Does adding of HCQ to the standard care provide any benefit in reducing the mortality among COVID‐19 patients?: a systematic review	To evaluate the early trends of mortality in patients with COVID‐19 treated with HCQ.	6	1 nonrandomized controlled trial, 5 retrospective observational studies	HCQ and supportive Care HCQ plus azithromycin HCQ plus azithromycin and supportive care	QTc interval prolongation	HCQ had no additional benefit for reducing mortality in patients with COVID‐19 when it was added to the standard treatment.
Shah et al. (2020) ²¹	India	Systematic review	A systematic review of the prophylactic role of chloroquine and hydroxychloroquine in coronavirus disease‐19 (COVID‐19)	The evaluate the role of CQ or hydroxychloroquine (HCQ) in preventing the spread of COVID‐19	5	3 in vitro, 2 clinical opinion	CQ or HCQ	Not reported	Clinical opinions advocated the prophylactic use of CQ and HCQ against COVID‐19. The prophylactic use of CQ or HCQ against COVID‐19 needs to be further reviewed as more data pour in.
Siemieniuk et al. (2020) ²⁰	Canada	Systematic review and meta‐analysis	Drug treatments for covid‐19: living systematic review and network meta‐analysis	To compare the effects of treatments for COVID‐19	27	27 RCTs	Glucocorticoids, remdesivir, HCQ, favipiravir, HCQ plus azithromycin, LPVr, umifenovir	Not reported	Glucocorticoids probably reduce mortality and mechanical ventilation in severe COVID ‐19. Remdesivir probably reduces time to symptom resolution, but whether it has an impact on other patient‐important outcomes such as mortality remains uncertain. HCQ may not reduce mortality or mechanical ventilation, and it seems unlikely to have any other benefits. The certainty effects of other drugs are low.
Singh et al. (2020) ²³	India	Systematic review and meta‐analysis	HCQ in patients with COVID‐19: A systematic review and meta‐analysis	To evaluate the effect of HCQ on viral clearance by RT‐PCR negativity and death due to all causes in patients with COVID‐19, as well as the efficacy and safety of HCQ.	7	3 RCTs, 2 clinical trials, 5 retrospective, and prospective cohorts	HCQ	QTc prolongation, nausea, vomiting, and blurred vision	The rate of PCR negativity found no benefit with HCQ. The death due to all causes showed a two‐times increase in HCQ treatment.
Singh et al. (2020) ²⁵	India	Systematic search and narrative review	CQ and HCQ in the treatment of COVID‐19 with or without diabetes: a systematic search and a narrative review with a special reference to India and other developing countries.	To evaluate the efficacy of CQ and HCQ in the treatment of patients with COVID‐19 with or without diabetes.	11	9 in vitro, 2 human trial	CQ and HCQ	Azithromycin plus HCQ may increase the risk of QTc prolongation.	Although evidence of CQ and HCQ is limited considering the potentially favorable benefit‐risk balance of any other valid treatment option, this treatment could be useful in the current context of pandemic COVID‐19 outbreak.
Subramanian et al. (2020) ¹⁴	India	Systematic review	Perspectives on the early quality of evidence guiding the therapeutic management of Sars‐CoV‐2: a systematic literature review	To evaluate the quality of early clinical evidence currently guiding the treatment strategies for COVID‐19 and the therapeutic recommendations of different treatment guidelines	22	5 RCTs, 9 prospective cohorts, 3 retrospective cohorts, 2 case‐series, 3 case reports	CQ and HCQ, remdesivir, corticosteroids, immunotherapy with convalescent plasma/sera, tocilizumab, other antivirals	Not reported	The current evidence provides ambiguous results because of the study designs and the endpoints assessed and different national treatment guidelines.
Verdugo‐Paiva et al. (2020) ²²	Chile, Argentina	Systematic review and meta‐analysis	LPV/r for COVID‐19: A living systematic review	To provide a summary of the evidence on the role of LPV/r in the treatment of patients with COVID‐19.	2	2 RCTs	LPV/r	Not reported	LPV/r could reduce the mortality and the risk of requiring invasive mechanical ventilation, developing respiratory failure, or acute respiratory distress syndrome. But, it did not have an effect on the duration of hospitalization and may lead to an increase in the number of total adverse effects.
Yang et al. (2020) ¹⁸	China	Systematic review and meta‐analysis	The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta‐analysis	To evaluate the influence of corticosteroids on patients with coronavirus infection.	15	Retrospective studies	Corticosteroid	Bacterial infection, hyperglycemia, hypocalcaemia	Patients with severe conditions are more likely to require corticosteroids. Using corticosteroid is associated with increased mortality in patients with coronavirus pneumonia.
Zhao et al. (2020) ¹⁵	China	Systematic review and meta‐analysis	Efficacy of tocilizumab treatment in severely ill COVID‐19 patients	To evaluate the effects of tocilizumab treatment in severely ill COVID‐19 patients.	10	1 RCT, 9 retrospective cohort studies	Tocilizumab	Not reported	Tocilizumab could be useful in the treatment of severely ill COVID‐19 patients.

Abbreviations: CQ, chloroquine; HCQ, hydroxychloroquine; ICU, intensive care unit; RCT, randomized controlled trial.