INTRODUCTION
Coronavirus disease-2019 (COVID-19) was officially announced by the World Health Organisation (WHO) on December 31, 2019,1 and declared a global pandemic by the WHO on March 11, 2020.2,3 COVID-19 is predominantly self-limited while up to 20% will progress to severe disease. Early treatment to prevent disease progression and complications is pronounced currently as an urgent need.4-8
Antimalarial medications, chloroquine and hydroxychloroquine were among the first drugs introduced for treatment and prophylaxis.9,10 Although countries continued keeping these drugs in their treatment protocols, the WHO cautioned against administering these unproven treatments.11-14
Basically, therapeutics for COVID-19 fall into three categories: Antiviral, immune-based, and adjunctive therapies. Some antiviral medications, antibiotics and immuno-therapeutics have been introduced for COVID-19 based on the experiences of previous coronavirus diseases and in-vitro findings.15-19 The therapeutics investigated in trials include ivermectin,16,17 melatonin,18,20 and monoclonal antibodies.15,19
The National Institutes of Health (NIH) COVID-19 Treatment Guidelines panel has outlined evidence-based statements on primary therapeutics for COVID-19 according to the available research.17,21,22
Antiviral medications including remdesivir and favipiravir; immunomodulators such as interferons, corticosteroids, monoclonal antibodies, and anticoagulation and convalescent plasmas are the subjects of this review as well as research on some therapeutics under investigation with insufficient or no evidence to highlight the multidimensional progress on this issue. There are more than 60 thousand COVID-19 publications available on PubMed. It is important that the choice of therapeutic agents by the medical professionals should rely on the best possible evidence currently available.23
Objective of the study
The aim of this study was to establish the current knowledge and evidence on the therapeutic efficacy of some prominent agents utilized in the treatment of COVID-19 through a review of the existing evidence-based medical literature universally. Since information on this issue is evolving rapidly, the content within this review intends to serve as a reference for the information available at the time of publication.
Methods
Information Sources and Criteria of Eligibility
The literature search was performed as recommended for systematic reviews24 through the databases PubMed, Scopus, Google Scholar and the Cochrane Library, only in English, using the keywords COVID-19 therapy and treatment. Additional studies were identified through other means (such as Medscape, references of articles, and press releases).
Article Search
There was no time limit set regarding the study period and publication dates. Starting on 20 June, 2020, an online search was performed until November 10, 2020. Newly appearing articles and other data were covered by continuing the literature search until January 30, 2021.
Study Selection and Recruitment of Articles
The publications identified were screened by the researchers based on title and abstract in order to find the relevant articles. Cohort studies, randomised controlled trials, meta-analyses, narrative and systematic reviews were recruited into the study list. Pre-print articles, case reports and case series other than those in the review studies were excluded.
Subsequently, 59 full articles were assessed in order to eliminate any articles with study types and content other than those in the inclusion criteria and to select those articles containing a strength of evidence. Some articles were excluded due to the insufficient quality of the research methods, analyses of the data or interpretation of the findings (Figure 1).
Data Collection Process
Data were collected using a data extraction form which covered the following features of the articles: The database, journal name and issue, authors and title; time, setting and the universe of studies; the number of participants, the number of studies (for reviews); and the aim, type, methods, results and outcomes of the studies. The data extraction and assessment were carried out by the two researchers independently. Decisions were made after discussion and by consensus based on the evidence.
Data Items
Data items included the following variables:
Participants: COVID-19 patient groups of differing ages and severity (mild, moderate, severe), hospitalised and non-hospitalised patients, need of oxygen supplementation
Interventions: Therapies applied in COVID-19: Pharmacotherapeutics such as antivirals, chloroquine and hydroxychloquine, anticoagulation, monoclonal antibodies, interferons, convalescent plasma, corticosteroids etc.
Comparisons: Therapies applied to control groups: Usual care, antivirals (lopinavir/ritonavir, oseltamivir, umifenovir), antibiotics and placebos.
Outcomes: 28-day all-cause mortality, in-hospital mortality, death or mechanical ventilation (MV) within 28 days, lethality, improvement of radiologic findings, days to viral clearance, mean or median days to viral clearance, recovery at day 28, time to recovery measured as discharge from hospital, improvement in oxygen support class, organ-support free days, improvement and clinical recovery rate, and median recovery time.
Study design: Cohort studies, randomised controlled trials, meta-analyses, narrative and systematic reviews.
Funding sources: Studies with conflicts of interest
Risk of Bias in Individual Studies
Assessment of the risk of bias included methods of randomisation, treatment allocation and blinding. The novel and urgent nature of COVID-19 therapeutic interventions resulted in weaknesses in preventing bias, as a lack of controls, randomisation or blinding were declared in the method sections of the studies and these were used in assessing the strength of the evidence.
Summary Measures
Principal summary measures included hazard ratios, relative risks, odds ratios, their confidence intervals, risk differences, lethality, other epidemiological measures, statistical tests and their p values.
Limitations
Since COVID-19 has a short history of only one year, the results of the studies selected have limitations due to the infection’s novel nature, time restrictions, low participant sizes, the lack of sufficient previous experience, and the uncertain nature of future advances. Furthermore, the rapid progress in the treatment of COVID-19 limits the comprehensiveness of a review due to the time needed to finalise studies.
The fact that only English publications have been covered in this study may be considered a bias regarding publication language.
Results
In this study, the selection of the research articles was based on the quality of the evidence in the studies. The number of studies screened, assessed and included are displayed in the flow diagram (Figure 1).
Randomised controlled trials, systematic reviews and meta-analyses comprised 15 of the total 25 studies selected. Eleven randomised controlled trials, one controlled trial, five cohort studies, four reviews, two systematic reviews, one systematic review and meta-analysis, and one meta-analysis were included. Some preliminary research other than these was also covered in the main text of the article, although not included in the tables.
The studies reviewed were conducted in the following countries: China, the Netherlands, Italy, France, the United States of America (USA), Columbia, Iran, Mexico, Denmark, the United Kingdom (UK), Korea, Singapore, India, Greece, Germany, Spain, Japan, Hong Kong, Taiwan, Australia, Brazil, Canada, New Zealand, Ireland and Thailand. The details of the publications selected are presented in Tables 1, 2, 3, 4, 5. The contents of the articles are presented under the headings relevant to the therapeutic agents.
Prophylactic Dose/Treatment-Dose Anticoagulation
Increased venous and arterial thromboembolic events have been reported previously. In a cohort study of 2773 patients, the association of treatment dose anticoagulation (AC) and in-hospital survival was investigated. The mortality rate of the intervention group was significantly lower than the control group among patients who required MV (Table 1) (p<0.001).25
On the other hand, the results of an interim analysis released on January 28, 2021, based on three international randomised open-label trials on the use of anticoagulation from 17 countries revealed contrasting findings to this cohort study. Accelerating COVID-19 therapeutic interventions and vaccines (ACTIV-4a) conducted at 60 international sites), Randomised embedded multi-factorial adaptive platform trial at 290 international sites (REMAP-CAP) and Antithrombotic therapy to ameliorate complications of COVID-19 (ATTACC at 58 international sites) compared the effectiveness of therapeutic and prophylactic doses of anticoagulation in reducing the need for organ-support. The intervention was heparin treatment versus usual care pharmacologic venous thromboembolism (VTE) prophylaxis. The enrolment of severe state patients requiring intensive care unit (ICU)-level care were paused after an interim analysis demonstrated that therapeutic heparin did not improve organ-support free days at day 21. However, therapeutic dose anticoagulation treatment was superior to usual care pharmacologic VTE prophylaxis for moderate state patients (hospitalised, not on ICU organ support).26
Currently, the NIH COVID-19 Treatment Guidelines Panel recommends prophylactic dose anticoagulation for hospitalised patients.27
Chloroquine-Hydroxychloroquine
A study on the association of hydroxychloroquine use and intubation or death revealed no significant association between hydroxychloroquine use and intubation or death (Table 1).28
A randomised controlled trial (RCT) of 150 patients investigated virus elimination by high dose hydroxychloroquine, which showed no significant difference from the current standard care (Table 1).29
A systematic review by Hernandez et al.30 disclosed further data on hydroxychloroquine or chloroquine use in COVID-19 (Table 1). Four randomised controlled trials and 10 cohort studies assessed its treatment effects. The evidence on the benefits and harms of hydroxychloroquine or chloroquine were depicted as very weak and conflicting.30
In a later update of the systematic review, five new randomised trials and 4 cohort studies revealed no new evidence regarding its therapeutic efficacy (Table 1).31 In addition, there was now a low strength of evidence that hydroxychloroquine had positive effect on all-cause mortality and the need for MV.31 In the RECOVERY trial, an RCT comparing a range of treatments with usual care in hospitalised patients, the primary outcome was 28-day mortality. The enrolment of patients in the hydroxychloroquine group was closed after an analysis determined a lack of efficacy (Table 1).32 Furthermore, a randomised study from Brazil revealed increased lethality with higher doses of chloroquine (Table 1).33 The large SOLIDARITY-WHO and ORCHID-NIH trials were prematurely discontinued, with press releases announcing a lack of efficacy.31
Convalescent Plasma
The efficacy and safety of convalescent plasma has been appraised as uncertain due to a lack of RCTs.34
The data from several small observational studies demonstrated improvements of symptoms (Table 2).35-38 The strength of evidence is assessed as very low.
Convalescent plasma is under investigation in 11 studies registered in clinical trials (a total of 1106 patients). The ongoing trials are taking place in China, Italy, the USA, Columbia and Iran.36
Monoclonal antibodies-Bamlanivimab and Tocilizumab
Monoclonal antibodies are biotherapeutics for passive immunotherapy against viral infections similar to convalescent plasma. In animal models, there is evidence that antibody therapy may reduce viral load.19,39-43
Bamlanivimab
Bamlanivimab, one of the monoclonal antibodies, was studied in a phase II RCT for treating ambulatory mild or moderate COVID-19 patients. Patients were randomised for treatment by one of three doses, or a placebo. The 2800 mg dose resulted in a significant decrease of viral load in the intervention group.41 In addition, bamlanivimab demonstrated a lower relative risk of hospitalisation (Table 2).41
The NIH Guidelines Panel announced in its February 11, 2021, update that bamlanivimab and the combination of casirivimab and imdevimab are available through the FDA’s emergency use authorisations (EUAs) for the treatment of mild to moderate outpatients at high risk of progressing to severe disease and/or hospitalisation.17,40
Tocilizumab
Non-randomised studies have suggested mortality benefit with tocilizumab, a humanized monoclonal antibody in COVID-19 patients.15
In a randomised clinical trial studying the effect of early tocilizumab administration, hospitalised patients with severe COVID-19 requiring oxygen but not ICU-level care were investigated. The trial was stopped early after initial analyses showed no evidence of improvement in primary outcomes.43
In the STOP-COVID study of the USA, the treatment of critically ill patients with tocilizumab was investigated by time to death and 30-day mortality. Tocilizumab treated patients had a lower risk of death compared to the others (Table 2).42 In contrast to the findings from STOP-COVID and multiple observational studies, none of the tocilizumab RCTs reported mortality benefit at 28 or 30 days, and only two of these trials reported outcomes meeting predefined thresholds for efficacy (Table 2).23
An update of NIH Panel on February 11, 2021 pointed out that there is insufficient evidence to recommend either for or against the use of tocilizumab or sarilumab for patients within 24 hours of ICU, requiring MV or NIV. For patients not requiring ICU-level care, the panel recommended against the use of these agents except in a clinical trial.17
Interferons
Interferons are cytokines with antiviral properties. Hence, they have been suggested as a potential treatment for COVID-19 due to their antiviral activity.44 Interferon studies covered in this review include one cohort study, one RCT and the preliminary results of an ongoing RCT.
Interferon Beta-1b
The first interferon RCT was a phase 2 clinical trial utilising interferon beta-1b for therapy (Table 3).45 In the trial group, hospitalised patients were randomised into triple therapy (interferon beta-1b, lopinavir/ritonavir, and ribavirin) or double therapy (lopinavir/ritonavir and ribavirin). The control group received only lopinavir/ritonavir therapy. The median time to negative nasopharyngeal swab was 7 days in the total combination therapy group and 12 days in the control group (hazard ratio: 4.37, p=0.001). Further analyses revealed that the shortening of the time to viral clearance was due to the effect of the interferon beta1b group.45
Interferon Alfa-2b
A cohort study investigated the efficacy of nebulized interferon alfa 2b among 77 hospitalised patients. Three patient groups received either umifenovir, interferon alfa 2b or both agents. The end point was viral clearance. Interferon accelerated viral clearance by 7 days.46 However, this study had limitations and a low strength of evidence (Table 3).
Interferon Beta-1a
The results of an RCT from the UK evaluating the effects of inhaled interferon beta-1a among hospitalised patients was reported on July 20, 2020 (Table 3).47 Compared to the control group, the intervention group patients were more likely to recover by day 28 [odds ratio (OR): 3.86, p=0.017]. In addition, the intervention group had decreased odds of developing severe disease.47
The interferon studies covered in this review have several limitations including low patient size (total 305) and display a low strength of evidence.
Remdesivir
Remdesivir is an antiviral known to have inhibitory activity against SARS-CoV and MERS-CoV. In vitro studies revealed the efficacy of remdesivir in inhibiting SARS-CoV-2 as well.
The therapeutic effectiveness of remdesivir was investigated in a multicentre randomised, controlled trial covering 10 countries with 1063 hospitalised patients. The primary outcome was the time to recovery (Table 4).48
The final report was published in October, 2020.48,49 Patients in the remdesivir group had a shorter time to recovery (median 10 days, compared with 15 days; rate ratio for recovery 1.29; p<0.001).49 Those patients who received remdesivir were found more likely to have clinical improvement on day 15 (OR: 1.5) (Table 4).49 The strength of evidence was appraised as high for this study.
A double-blind controlled trial of 237 patients from China found no significant differences in favour of the trial group (Table 4).50
In a multinational cohort study of 53 hospitalised severely ill patients, remdesivir therapy improved the oxygen support class in 68% of the patients and 47% were discharged. Of those receiving MV, 57% were extubated. The overall mortality rate and mortality among MV patients were lower than previously reported (Table 4).51
A multi-country RCT of 397 patients with severe disease but without the need for MV were randomised into therapy with remdesivir to receive either 5 or 10-day treatments. There was no significant difference between the two groups on day 14 regarding clinical improvement as assessed on an ordinal scale (Table 4).52
Remdesivir has been approved by the FDA for use among hospitalised COVID-19 patients and endorsed globally.8
The remdesivir studies in this review cover some earlier and later research. Three RCTs and one cohort study included 1749 hospitalised cases covering multiple countries. The results have consistently manifested the efficacy of remdesivir, as shown by the assessments of relevant studies with moderate to high strengths of evidence.
Favipiravir
In the light of in vitro studies, research in China, Japan, and Russia have introduced favipiravir as a promising agent with its advantage of being an oral formulation utilized on an outpatient basis.53 Recently, treatment guidelines from multiple countries have included favipiravir in their treatment protocols.53,54
The studies on favipiravir treatment covered in this review include a controlled trial and a review of observational studies.
An early controlled trial published in March 2020 announced that favipiravir treatment resulted in a shorter viral clearance time compared to lopinavir/ritonavir treatment (p<0.001). Favipiravir treatment was associated with significant improvement rates in chest imaging (91.43% vs. 62.22%, p=0.004). (Table 4).53 The study was non-randomised and open-label. The strength of evidence is accordingly evaluated as low.
A recent review of observational favipiravir interventions has highlighted its therapeutic effectiveness in terms of recovery rates and clinical improvements among mild to moderate patients. The findings demonstrated high recovery rates at days 7 and 14 for both mild and moderate cases in one study. Clinical improvement was reported for 66.7% overall in another study. The Japan observational registry revealed similar results for mild and moderate COVID-19 cases (Table 4).54 However, although the number of patients is high, the quality of evidence is appraised as very low due to study type and the lack of control groups.
A pre-print publication regarding favipiravir efficacy should be mentioned, even though the study is not within the inclusion criteria of our review. In this prospective randomised controlled, open-label multicentre trial involving 240 patients with mostly moderate COVID-19 from China, the therapeutic effectiveness of favipiravir versus umifenovir was studied. The clinical recovery rate on day 7 was significantly higher (p=0.019) for the favipiravir group (71.4%) than the umifenovir group (55.8%). However, there was no difference between the groups regarding ICU admission and all-cause mortality.55
Favipiravir is widely used across many highly populated communities of middle income countries in Asia. However, more RCTs are mandatory for higher evidence-based results.
Corticosteroids
Corticosteroids were not advised for COVID-19 treatment unless needed for other conditions according to WHO, US CDC and IDSA early recommendations.2,39
The approach for treating patients with COVID-19 changed dramatically when the results of the UK-based RECOVERY trial were reported in June, 2020. This was an RCT of 6425 patients receiving dexamethasone or usual care. Treatment with dexamethasone reduced mortality by one-third in those patients receiving MV (rate ratio: 0.64) and by one-fifth in patients receiving oxygen (rate ratio: 0.82) compared with usual care. However, there was no benefit for those patients not receiving respiratory support (Table 5).56
The WHO REACT Working group studied the results of the current data on corticosteroid therapy on COVID-19 in a meta-analysis. A total of 1703 patients were randomised in seven trials for a prospective meta-analysis (Table 5).57
There were 222 deaths in the trial group and 425 deaths in the control group; 28-day all-cause mortality was lower among those patients receiving corticosteroids (OR=0.66, p<0.001). The association was similar for dexamehasone and hydrocortisone suggesting a general benefit for glucocorticoids.57
Following this, a systematic literature search and meta-analysis of RCTs and observational studies on adults was performed from December, 2019 to October, 2020 comprising a total of 20,197 patients in 37 retrospective observational studies and five RCTs. The findings confirmed the previous findings. The primary outcomes were short-term mortality (including 28-day, 30-day) and the secondary outcomes were MV, length of hospital stay, and secondary infections. The findings have confirmed a beneficial effect of corticosteroids on short-term mortality and a reduction in the need for MV. The overall risk estimate was 0.72, suggesting a beneficial effect of steroid use on the mortality of patients hospitalised with moderate or severe respiratory failure. Fewer patients required MV in the corticosteroids group [relative risk (RR): 0.71] (Table 5).58
The relevant research indicated in this review highlighted the efficacy of corticosteroids in reducing mortality among critically ill patients requiring oxygen. The trials on this topic cover more than 28 thousand (28,325) patients and the results indicate high evidence. Corticosteroids are the only therapeutics which are currently shown to be effective in reducing mortality in COVID-19.
The details of the presented articles of this review are illustrated in tables: Table 1,25,28-33 Table 2,23,35-38,41-42 Table 3,45-47,59 Table 4,48-54 and Table 5.56-58
Discussion
New findings from recent research draw attention to the urgent need for new approaches and agents for managing COVID-19, including in mild and moderate cases. A prospective cohort study with patients recovering from COVID-19 displayed evidence of ventricular dysfunction and signs of myocardial inflammation in 78% of the patients.60,61 In addition, post-mortem research has shown inflammation is ongoing in the heart muscle weeks after recovery. These findings may be precursors of a considerable burden of heart failure in the coming years.62
In this review, we aimed to contribute to the collection and dissemination of the new evidence for COVID-19 therapy regarding all forms of the disease. We shall discuss our findings together with expert opinions and global statements about this issue.
A considerable number of studies on the therapeutic efficacy of various treatments for COVID-19 have weaknesses regarding the study sample and research methods utilized. Currently, evidence comes mostly from those studies conducted among hospitalised patients, while more research is essential for the therapy of mild and moderate forms.8,53
The results of studies in this review show evidence for the efficacy of the antiviral remdesivir and also corticosteroids. The efficacy of therapeutic dose anticoagulation has been demonstrated among moderately ill, but not severely ill, patients in preliminary research.26 However, these studies have yet to be finalised before general consideration for use in this group. Weak therapeutic evidence exists for favipiravir, interferons alfa-2b, beta-1b and beta-1a; convalescent plasma and monoclonal antibodies, this needs further research.41,45-47 Bamlanimivab deserves special mention with emerging data of promising efficacy. Bamlanivimab and the combination of casirivimab and imdevimab are currently recommended for mild to moderate COVID-19 at high risk or progressing to severe disease and/or hospitalisation.17
Dexamethasone and other corticosteroids comprised the only drug group demonstrating reductions in mortality among hospitalised patients requiring MV or high-flow oxygen. Dexamethasone was also effective in decreasing the number of people requiring oxygen.56-58 Accordingly, the NIH Treatment Guidelines Panel recommends the use of corticosteroids for patients in need of oxygen supplementation.22
Remdesivir exhibited high evidence of efficacy for the therapy of COVID-19.48-52 Even though the NIH Panel does not recommend for or against the use of remdesivir in hospitalised patients not requiring oxygen, remdesivir remains the only drug approved by the FDA for use among hospitalised patients.22 The use of remdesivir for mild to moderate COVID-19 cases is a subject of medical research currently and remains a challenge for the medical community with the disadvantage of its route of administration. Favipiravir was found to be effective for the treatment of mild to moderate COVID-19 cases in observational studies and one controlled trial covered in this study.
Remdesivir and favipiravir have been currently included in multiple COVID-19 treatment guidelines globally.8 Japan, Russia, Saudi Arabia, Thailand, Kenya and four states from India have recommended the use of favipiravir oral therapy in mild to moderate COVID-19 in their treatment guidelines.53,54 Around 27 favipiravir studies including RCTs are ongoing in China, Japan, Italy, the USA, the UK, Canada, Egypt, Thailand, France and Iran.60 The results of these studies will highlight the efficacy of this antiviral with more evidence, which is convenient for use on an outpatient basis.
Antiviral medications other than remdesivir were not seen to have sufficient evidence for COVID-19 therapy. The Solidarity trial in 30 countries, sponsored by the WHO, assessed hydroxychloroquine, interferon, lopinavir/ritonavir, and remdesivir in hospitalised patients. None of these drugs, nor tocilizumab, showed an effect on mortality.23,39,63
No evidence for the use of chloroquine and hydroxychloroquine has been identified among the current research available. Conversely, weak evidence has been announced by some studies against the use of these agents.31
CONCLUSION
The data based on sound research on all aspects of COVID-19 is mounting rapidly. The findings of the latest research on COVID-19 therapy point to the necessity of considering the results of ongoing larger trials and providing instant knowledge to health professionals. Progress in this area is vital since it may be influential in preventing later consequences, sequellae and deaths from COVID-19 among the growing patient population.
The findings demonstrated in this review may be of assistance for medical practitioners in order to highlight the therapeutics with the best current evidence to assist in their decisions on treatment approaches for COVID-19.
MAIN POINTS
● While there is currently no globally approved treatment for COVID-19, multiple agents are under trial for the treatment COVID-19; yet a discrepancy exists between high income and other countries of the world regarding the drugs preferred.
● This study presents an overview of the mostly evidence-based global research on this issue, with randomised controlled trials, systematic reviews and meta-analyses comprising 15 out of the total 25 studies included.
● The results show sufficient evidence for the efficacy of remdesivir and corticosteroids based on international research, with reduced mortality demonstrated only for corticosteroids.
● Favipiravir, anticoagulation, interferons and monoclonal antibodies were agents with promising but weaker evidence of therapeutic efficacy and so need further investigations.
● The inclusion of favipiravir studies may be a reminder to global researchers to review the evidence about this agent as well, since it has been prescribed widely in a number of countries worldwide.
ETHICS
Peer-review: Externally peer-reviewed.
Authorship Contributions
Concept: Ö.A., Ş.Ç., Design: Ö.A., Ş.Ç., Data Collection and/or Processing: Ö.A., Ş.Ç., Analysis and/or Interpretation: Ö.A., Ş.Ç., Literature Search: Ö.A., Ş.Ç., Writing: Ö.A., Critical Review: Ş.Ç.
DISCLOSURES
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The author declared that this study had received no financial support.