Antiviral treatment in COVID-19: which is the most promising?—a narrative review

Introduction

Although coronavirus was uncovered for the first time in the 1960s, it hits the humankind with potential lethal afflictions from time to time (1). After severe acute respiratory syndrome (SARS) in 2003 (2) and Middle East Respiratory Syndrome (MERS) in 2012 (3), coronavirus disease 2019 (COVID-19) is the most recent coronavirus that afflicted mankind. Newly uncovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as a single stranded, enveloped, and positive sense RNA virus and added as the seventh representative of coronaviruses that attack humans (4). Among all seven known human coronavirus, SARS-CoV and MERS-CoV were previously recognized for their severe fatal infection, and SARS-CoV-2 is the recently recognized member leaving patients with very severe and fatal infections.

Its high transmissibility and infectivity made this disease a global health emergency which greatly threatened human health and the world economy (5). Due to its rapid spread in almost all continents of the world, it was declared as a pandemic by WHO on March 11^th 2020 (6,7). According to the database of WHO, at the beginning of November 2020, a total of 46 million patients have been diagnosed with COVID-19 and have spread to more than 200 countries along with 1.2 million deaths. The overall case fatality rate is about 2.57%. The COVID-19 fatality rate varies significantly depending on the geographic region, lowest in Southeast Asia with 1.55% and highest in America with 3.10%. Moreover, age is also found to cause an exponential variation in the fatality rate. The Korean Center for Disease Control and Prevention states that the COVID-19 fatality rate is significantly higher in the elderly (7.19% in patients 70–79 years of age and 20.46% in patients more than 80 years old) at the beginning of November 2020 (8). Earlier, in a previous analysis of 44672 COVID-19 cases in China, a similar pattern of higher mortality in the elderly was found (8.0% in patients 70–79 years of age and 14.8% in patients more than 80 years old) (9). The similar pattern of age-related mortality was also found in a report conducted by the Higher Institute of Health in Italy (16.9% in patients 70–79 years old and 24.4% in patients more than 80 years old) (10). Some studies also observed that multiple comorbidities tend to be associated with a higher case fatality rate. In a study in China, authors observed that confirmed COVID-19 patients with diabetes and hypertension as comorbidities demonstrated a 7.3% and 6% mortality rate, respectively (9). A similar result of comorbidity-related mortality was also found to be observed in another retrospective study where authors found a higher mortality (21.1% vs. 7%) among those with diabetes than non-diabetic COVID-19 cases (11).

A pandemic always has an inherent challenge of conducting clinical trials urgently to decrease the fatality rate. Accordingly, various treatment modalities and molecules with a wide variety of mechanisms have been proposed for the treatment of COVID-19. Over 200 clinical trials are ongoing to test the potency and safety of antiviral agents against SARS-CoV-2. There are several previously approved as well as experimental antiviral drugs found to have potential therapeutic effects. The aim of this narrative review was to outline and summarize the clinical trials of the proposed and investigational drugs in treating COVID-19. We present the following article in accordance with the Narrative Review checklist (available at http://dx.doi.org/10.21037/apm-20-1755).

Therapeutic interventions

Lopinavir/ritonavir

The combination of lopinavir/ritonavir is a broadly discussed antiviral combo in many literatures and thought to have a promising potency in the treatment of COVID-19. Lopinavir is a protease inhibitor and known for decreasing the viral load by preventing viral replication in host cells (12,13), while ritonavir is used with lopinavir to improve the efficacy and half-life of lopinavir by inhibiting cytochrome p450 (14). This combination therapy was previously registered for the treatment of HIV and MERS infection, which was found to be potent in inhibiting SARS-CoV (15).

Several clinical trials were conducted recently to test its efficacy and safety against COVID-19. Among these, one trial recruited 199 laboratory confirmed cases of COVID-19. This study showed that the duration of clinical improvement between the treatment group and the standard group was only one day with a similar mortality and viral clearance rate. The study also showed that there was no obvious treatment benefit of lopinavir/ritonavir combination against the SARS-CoV-2 infection (16). A similar result regarding virus clearance duration was indicated in another retrospective study (17). On the contrary, a small sample-sized (n=47) retrospective study revealed a faster clinical improvement and shorter duration of virus clearance (18). Apart from these studies, some published case reports found lopinavir/ritonavir therapy beneficial in the clinical improvement along with shortening the duration of viral shedding (19,20), but another descriptive case series showed no definite clinical benefit of using lopinavir/ritonavir as treatment (21). These studies showed an inconclusive result for the potency of lopinavir/ritonavir in the treatment of COVID-19; however, due to some limitations such as a small sample size and lack of randomization, its effect in the treatment of COVID-19 needs further exploration (Table 1).

Table 1 Clinical trials of lopinavir/ritonavir
Full table

Arbidol

Arbidol {ethyl-6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-indole-3-carboxylate hydrochloride monohydrate} is a small indole derivative licensed in China and Russia as a prophylactic and therapeutic agent for the treatment of influenza A and B infections along with other respiratory viral infections (22). Arbidol exerts its antiviral effect by inhibiting the fusion of viral envelope with host cell membrane through the inhibition of endocytosis, thus preventing the entry of virus into host cells (23,24). Due to its broad-spectrum antiviral activities, arbidol was found to have some potency in the treatment of COVID-19 through some small sample-sized clinical studies.

Li et al. found little benefit of arbidol therapy in the rate and duration of negative conversion of SARS-CoV-2 nucleic acid along with the rate of clinical improvement and chest imaging over lopinavir/ritonavir therapy and standard supportive therapy (25). Unlike this study, a retrospective study found that arbidol therapy could improve symptoms, chest imaging, virus clearance, and hospital discharge rate as well as mortality rate among COVID-19 patients (26). Similarly, in another retrospective study, authors found arbidol as a superior therapeutic agent in the negative conversion of patients for SARS-CoV-2 nucleic acid and shorter duration of positive RNA test over lopinavir/ritonavir therapy (27). In addition, arbidol therapy was also found to be efficient in the improvement of pneumonia-associated symptoms and chest imaging in another retrospective study (n=4) while it was given in combination with some other antiviral and Chinese medicine (28) (Table 2).

Table 2 Clinical trials of arbidol
Full table

Favipiravir

Favipiravir is an investigational generic prodrug licensed for the treatment of influenza in Japan and also suggested for the treatment of the Ebola virus infection along with other viral infections (29-32). It is metabolized into its active form, favipiravir-ribofuranosyl-5'-triphosphate, and inhibits viral replication by inhibiting RNA-dependent RNA polymerase (RdRp) needed for viral transcription in host cells (33). As RdRp-mediated transcription is an important mechanism of SARS-CoV-2 replication in human body cells, favipiravir is assumed to have potential therapeutic efficiency in the treatment of COVID-19 patients.

To evaluate its efficiency in the treatment of COVID-19 patients, Cai et al. conducted an open-label nonrandomized control study and found a shorter median time (4 days) of viral clearance among patients treated with favipiravir than the median time of 11 days in those who received lopinavir/ritonavir. Favipiravir also was found superior in the improvement rate of chest imaging over the control group (91.43% vs. 62.22%). In the study, favipiravir showed to have greater efficiency in the treatment of COVID-19 with minimal adverse reactions (34). Due to its potential efficacy, it was approved for urgent and clinical trial use in the treatment of COVID-19 patients in China (35) (Table 3).

Table 3 Clinical trials of favipiravir
Full table

Remdesivir

Remdesivir (GS-5734) is a prodrug of 1'-cyano-substituted nucleotide analogue with broad spectrum antiviral activity against several RNA viruses by inhibiting viral replication through inhibiting RdRp (36,37). It was previously targeted for Ebola, SARS, and MERS and now has been accessed for its efficiency against COVID-19 (38,39). Many in vitro studies observed remdesivir to have a potent inhibiting effect against SARS-CoV-2 (14,40,41). Apart from its efficiency to inhibit SARS-CoV-2 in different in vitro studies, in a randomized, double-blind, placebo-controlled multicenter study with 237 COVID-19 patients, authors found a 2-day benefit with regard to time to clinical improvement in the remdesivir group over the placebo group with similar mortality in both groups. In this study, remdesivir seemed to have no difference but numerically associated with a rapid improvement of the clinical conditions of COVID-19 patients, while remdesivir was terminated early because of adverse events in more patients than the placebo (42). Supplementary to the above-mentioned studies, another most recently published double-blind, randomized, placebo-controlled trial also supported the efficacy and safety of remdesivir in the treatment of COVID-19. The study found remdesivir to be associated with a median of a 4-day shorter recovery time and 4.8% less mortality rate than the placebo (43). The inconsistent results might be due to the different severity of the enrolled patients, who were much more severe in the former study. In another study, researchers found overall clinical improvement and oxygenation in a total of 68% patients who received remdesivir on compassionate use basis (44). In a case report of the first COVID-19 patient in the USA, remdesivir was found to be associated with good clinical improvement along with the discontinuation of oxygen supplementation (45). Recently, the Food and Drug Administration had authorized the emergency use of remdesivir in the treatment of COVID-19 (46). Now, hundreds of COVID-19 patients in the USA and Europe are receiving remdesivir as an antiviral therapy but due to the uncertain efficiency and safety, remdesivir needs to be explored with larger sample-sized, randomized, controlled clinical trials (Table 4).

Table 4 Clinical trials of remdesivir
Full table

Chloroquine (CQ) and hydroxychloroquine (HCQ)

CQ and HCQ are easily accessible and cheaper drugs approved for the treatment of malaria for more than 70 years. They are also known for their immunomodulatory property as well as their broad-spectrum antiviral activity. The antiviral activity was found to be achieved through the increment of lysosomal PH leading to the inhibition of endocytic cell entry of viruses (47,48) along with the alteration of the glycosylation process of angiotensin converting enzyme 2 (ACE2) receptor preventing viral fusion with host cells in both the pre- and post-infection situations (49). Many in vitro studies showed their (CQ and HCQ) effectiveness in viral inhibition against SARS-CoV-2 with a superior safety profile for HCQ than CQ (41,50,51).

Besides in vitro studies, Chen et al. conducted a randomized control trial to explore the efficacy of HCQ therapy in COVID-19 treatment. Researchers found that 80.6% of patients in the treatment group showed improvement in pneumonia while only 54.8% of patients in the control group showed such improvement. The study gave the impression that HCQ had great potency for the reduction in duration of clinical improvement as well as pneumonia (52). Additionally, in a small sample-sized (n=36) open-label, non-randomized clinical trial, researchers observed HCQ as the most potent agent for positive to negative conversion of SARS-CoV-2 nucleic acid in COVID-19 patients when its effect was increased by the co-administration of azithromycin (53). The antiviral activity of azithromycin against SARS-COV-2 is hypothesized to be attributed to its interaction with CD147. CD147 is recognized as a receptor along with ACE2 receptor used by SARS-COV-2 to infect host cells (54). Azithromycin was also found to exert a synergistic effect in combination with HCQ in an in vitro study (55). Furthermore, it is found as a potential candidate against SARS-COV-2 in a bioinformatics analysis due to its ability to exert its antiviral effects via autophagy. However, another small sample-sized prospective study reported no strong antiviral activity of HCQ with azithromycin in terms of clinical improvement (56). In another small sample-sized retrospective study, authors also found no association in reduction of risk of mechanical ventilation or overall mortality (57). In addition, a separate cohort study also did not find any significant reduction in intensive care unit admission or the development of acute respiratory distress syndrome along with hypoxemic pneumonia in hospitalized COVID-19 patients who received HCQ (58). Furthermore, a pilot prospective study also reported that there was no improvement in the virus clearance rate, time to clinical improvement, and radiological progression in COVID-19 patients, when compared with those who received only conventional therapy (59). Moreover, in a separate observational study, HCQ seemed to have no association to either increased or reduced risk of intubation or death (60). In another open-label, randomized control trial, authors observed a good rate of negative conversion of viruses among those with mild to moderate disease, but HCQ therapy had no significantly higher probability of negative conversion over standard therapy (61) (Table 5).

Table 5 Clinical trials of chloroquine and hydroxychloroquine
Full table

Ribavirin

Ribavirin is another broad-spectrum nucleoside analogue antiviral drug, previously approved for the management of infections caused by respiratory syncytial viruses and hepatitis C virus (62,63). It was extensively used during the SARS outbreak in Hongkong but the therapy had faced much criticism on its efficacy and safety in the treatment of SARS (64). However, a study supported its efficiency in inhibiting SARS-CoV replication in various animal cells as well as humans inoculated with a strain of SARS-CoV (65,66). However, its efficacy against SARS-CoV-2 is uncertain until present, and a clinical trial (reg no. NCT04276688) is under way to explore its efficacy and safety profile against SARS-CoV-2 in the treatment of COVID-19.

Oseltamivir

Oseltamivir is a neuraminidase inhibitor and a prodrug of oseltamivir carboxylate with superior inhibiting effect against Influenza A and Influenza B infections (67). However, no study was published on database showing its efficacy against COVID-19 despite of one silico identification study to explore its efficacy against COVID-19 which stated that oseltamivir had a potent inhibitory effect on the protease of SARS-CoV-2 (68). In addition, it was reported for its administration in China during the COVID-19 epidemic along with other molecule like antibiotics or glucocorticoids (69). To prove its efficacy and safety against COVID-19, several trials are ongoing, along with other therapeutic molecules under reg no. NCT04303299, NCT04338698, NCT04255017, NCT04261270 and NCT04371601.

Ivermectin

Ivermectin (ivermectin is a semisynthetic derivative of avermectin B1) is a broad-spectrum and well-tolerated anti-parasitic agent and presently approved for the treatment of onchocerciasis, lymphatic filariasis, strongyloidiasis and/or scabies (70). Its antiviral activity was tested by Australian researchers in an in vitro study through infecting a Vero/hSLAM cell with clinically isolated SARS-CoV-2 strain Australia/VIC01/2020 and they found ivermectin as an intense potent agent for the inhibition of SARS-CoV-2 (71). We found 18 ongoing clinical trials to explore its efficacy and safety in the treatment of COVID-19, some of which are in phase III (72).

Nitazoxanide

Nitazoxanide is a broad-spectrum anti-helminthic drug with broad-spectrum antiviral activity. It is indicated for the treatment of cryptosporidiosis, giardiasis, and influenza and have shown a potent antiviral effect against MERS-CoV in an in vitro study (73,74). Most recently, the drug is also found to have a potent inhibitory effect against SARS-CoV-2 in a separate in vitro study which warranted further exploration in the treatment of COVID-19 (41).

Monoclonal antibody (tocilizumab)

Pathogen-associated molecular pattern and damage-associated molecular pattern trigger the production of IL-6 from immune cells, mesenchymal cells, epithelial cells, and fibroblasts. IL-6 triggers acute phase immune response and is involved in the pathogenesis of several autoimmune diseases including cytokine release syndrome (CRS). In a retrospective study, researchers found a high level of IL-6, IL-1, and other cytokines in severe COVID-19 cases (75). As severe COVID-19 cases showed a cytokine pattern similar to CRS, tocilizumab has been hypothesized for treating severe COVID-19. Tocilizumab is a humanized monoclonal antibody and approved for the treatment of rheumatoid arthritis and several other autoimmune diseases. It is directed towards IL-6 receptor and controls effects of over production of IL-6 (76). Although it has no direct antiviral effects, it exerts its antiviral potential as adjunct therapy through the inhibition of proinflammatory responses mediated by viruses (77). Its potential therapeutic effect in COVID-19 is being tested in several clinical trials.

A rapid resolution of clinical symptoms, normalization of all inflammatory markers, improvement of oxygenation, and negative conversion of SARS-CoV-2 nucleic acid in COVID-19 patients was observed following administration of tocilizumab in various small sample-sized studies (78-81). For further exploration of its efficacy and safety, clinical trials with reg no. ChiCTR2000030196, ChiCTR2000030442, and ChiCTR2000029765 are already on their way in different phases of progression. Nonetheless, tocilizumab is also recommended by the National Health and Family Planning Commission of China for the treatment of seriously ill COVID-19 patients (82).

In addition to the above-mentioned role of IL-6 in the pathogenesis of severe COVID-19 including its approach in blocking its production and managing COVID-19 cases, there is another alternative way towards the management of severe COVID-19 sharing similar manifestations with CRS. As IL-1 causes induction of IL-6 response and other cytokines, IL-1 also mediates the initiation of cytokine pattern similar to that of CRS and macrophage activation syndrome in severe COVID-19 patients (83). Thus, it was hypothesized that early blocking of IL-1 production with IL-1 receptor antagonist anakinra can significantly reduce the activity of proinflammatory cytokines including IL-6. Anakinra was previously approved for the treatment of several autoinflammatory disorders including macrophage activation syndrome. In a retrospective cohort study, authors found that 72% of patients who were treated with high dose anakinra showed a significant reduction in the level of C-reactive protein and a good respiratory improvement with 21 days survival of about 90% (84). A similar result was found in another retrospective study, which showed all patients who received anakinra as treatment improved clinically without any mortality (85).

Convalescent plasma therapy

In the absence of definitive therapeutic agent and vaccine, a passive immunotherapy like convalescent plasma therapy, which were previously fruitfully engaged in the treatment of SARS, MERS, and influenza, is deemed to be efficiently beneficial for the treatment of severely ill COVID-19 patients during the first week of the disease when viremia is thought to be at its peak. Convalescent plasma contains neutralizing antibodies which prevent virus cell penetration, as well as induction of phagocytosis for the clearance of viral structure and activate natural killer cells to eliminate infected cells (86-89).

A prospective cohort study on 10 seriously ill COVID-19 patients showed rapid improvement of clinical symptoms and oxygenation along with chest radiography in the majority of patients following administration of convalescent plasma containing neutralizing antibodies against SARS-CoV-2. The researches transfused 200 mL of convalescent plasma containing neutralizing antibody titer of >1:640 and found a rapid increment in the level of neutralizing antibody titer in five patients while other five maintained a high titer of >1:640 (90). In addition to the above study, there were several independent case reports which also supported the excellent recovery from COVID-19 symptoms along with the negative conversion of SARS-CoV-2 nucleic acid following administration of convalescent plasma. In a preliminary uncontrolled case series, authors found rapid normalization of body temperature along with the improvement of ARDS and decreased oxygen demand following transfusion of convalescent plasma containing neutralizing antibody titer of >1:1,000 (91,92). A similar result on the reduction of oxygen requirement and an improved survival rate following transfusion of convalescent plasma containing neutralizing antibody >1:320 was described in another retrospective study (93). In a recent randomized control trial, authors have not found a significant difference in the 28^th day of clinical improvement as well as mortality and discharge from hospital among those who received convalescent plasma transfusion with S protein receptor-binding domain (s-RBD) specific IgG titer >1:640 from patients who received only standard therapies (94). Convalescent plasma therapy has also received clinical permission for its emergency use and investigational administration in seriously ill COVID-19 patients from the Food and Drug Administration of the United States (95) (Table 6).

Table 6 Clinical trials of convalescent plasma therapy
Full table

Interferon

The antiviral properties of interferon have been explored during viral interference studies. Several stimuli such as viral infection triggers human interferon system to synthesize interferon and establish an antiviral state. There are two types of interferons, namely type 1 or viral interferons and type 2 or immune interferons. Type 1 interferons include IFN-α, IFN-β, and IFN-ω. Type 2 interferon includes IFN-γ. Viral infections induce the production of type 1 interferons. Interferons induce the synthesis of direct antiviral effector molecules like RNA dependent protein kinase, 2',5'-oligodenylate synthetase, and Mx protein GTPases to exert their antiviral effects (96). Interferon response occurs earlier than immune response to provide an early host defense. Interferon is an immune enhancer used in several observational studies for its effectiveness against SARS-CoV and MERS-CoV (97,98). When combined with other approved antiviral drugs, it was found to be a total inhibitor of cytopathic effects of SARS-CoV in vitro (99). Although it proved its effectiveness against SARS-CoV and MERS-CoV, several clinical trials are ongoing to prove its efficacy against SARS-CoV-2 with favipiravir under clinical trial reg no. chiCTR2000029600 and with ribavirin under reg no. chiCTR2000029387.

Janus kinase inhibitor (baricitinib)

Janus kinase is an intercellular signaling pathway responsible for the production of various cytokines in the manifestation of viral infections (100,101). Janus kinase inhibitors like baricitinib presently are approved drugs for the treatment of rheumatoid arthritis (102). Baricitinib exerts its antiviral effect by inhibiting AP2-associated protein kinase which is needed for entrance of SARS-CoV-2 into host cells as well as inhibition of abnormal production of cytokines like IL-6 (103). Due to its hypothetical potency, it was suggested for trial in appropriate human populations (104,105).

Miscellaneous

Besides the above-discussed antiviral agents, several other antiviral agents like zanamivir, darunavir, galidesivir, peptide like EK1, and camostat mesylate might be effective in the treatment of COVID-19 but these need further exploration.

Conclusions

At present, we are facing SARS-COV-2 which emerged as a despicable virus with high infectivity. Currently, there is no specific molecule or drug regimens specified for the treatment of COVID-19. Many drugs or molecules which showed their potency in vitro or hypothesized to be effective against SARS-COV-2 are being clinically tested for their safety and efficacy. Remdesivir seems to have a potential antiviral activity against SARS-COV-2. Additionally, favipiravir and arbidol, along with a combination of azithromycin and HCQ, also seem to have acceptable potency as alternate antiviral treatments for COVID-19. Nonetheless, some biologics including tocilizumab, anakinra, interferons, and convalescent plasma therapy containing neutralizing antibody are also found to be potential agents for the treatment of severe COVID-19 cases complicated by an abnormal cytokine pattern. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to some limitations in this review. We feel the need for a multicentered, large sample-sized, randomized, placebo-controlled trial on appropriate COVID-19 patients to reach a proper conclusion on the most promising antiviral agent.

Acknowledgments

Funding: This study was supported by the National Natural Science Foundation of China (No. 82070102 and 81770097), the Project of Science and Technology Commission of Shanghai Municipality (No. 20ZR1451500 and 17411970800), the Fund of Shanghai Youth Talent Support Program, the Fund of Shanghai Municipal Health Commission for Excellent Young Scholars (No. 2018YQ01), and the Shanghai Sailing Program (No. 19YF1444100).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/apm-20-1755

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm-20-1755). The authors have no conflicts of interest to declare.

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