Clinical Management of COVID-19: A Review of Pharmacological Treatment Options

Since the outbreak and subsequent declaration of COVID-19 as a global pandemic in March 2020, concerted efforts have been applied by the scientific community to curtail the spread of the disease and find a cure. While vaccines constitute a vital part of the public health strategy to reduce the burden of COVID-19, the management of this disease will continue to rely heavily on pharmacotherapy. This study aims to provide an updated review of pharmacological agents that have been developed and/or repurposed for the treatment of COVID-19. To this end, a comprehensive literature search was conducted using the PubMed, Google Scholar, and LitCovid databases. Relevant clinical studies on drugs used in the management of COVID-19 were identified and evaluated in terms of evidence of efficacy and safety. To date, the FDA has approved three therapies for the treatment of COVID-19 Emergency Use Authorization: convalescent plasma, remdesivir, and casirivimab/imdevimab (REGN-COV2). Drugs such as lopinavir/ritonavir, umifenovir, favipiravir, anakinra, chloroquine, hydroxychloroquine, tocilizumab, interferons, tissue plasminogen activator, intravenous immunoglobulins, and nafamosat have been used off-label with mixed therapeutic results. Adjunctive administration of corticosteroids is also very common. The clinical experience with these approved and repurposed drugs is limited, and data on efficacy for the new indication are not strong. Overall, the response of the global scientific community to the COVID-19 pandemic has been impressive, as evident from the volume of scientific literature elucidating the molecular biology and pathophysiology of SARS-CoV-2 and the approval of three new drugs for clinical management. Reviewed studies have shown mixed data on efficacy and safety of the currently utilized drugs. The lack of standard treatment for COVID-19 has made it difficult to interpret results from most of the published studies due to the risk of attribution error. The long-term effects of drugs can only be assessed after several years of clinical experience; therefore, the efficacy and safety of current COVID-19 therapeutics should continue to be rigorously monitored as part of post-marketing studies.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared the infectious agent of the global pandemic coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO) on 11 March 2020 [1]. Originating from its epicenter in Wuhan, China, SARS-CoV-2 quickly spread to other countries, with the first U.S. case reported in January 2020 in Washington state. At the time of this authorship, more than 166 million confirmed cases worldwide and over 3.4 million deaths in 222 countries have been attributed to COVID-19 [2]. In the absence of gold standard treatments, the disease can progress rapidly and lead to pneumonia, resulting in long-term organ damage and even death in some patients.

Results
Since the discovery of SARS-Cov-2 and the declaration of COVID-19 as a global pandemic, numerous studies have evaluated different pharmacological agents against the novel virus. Figure 1 summarizes the study selection process and the search results. The initial search returned a total of 2999 articles which were screened for inclusion criteria. A total of 70 articles were reviewed in this study. In Table 1, a summary of the clinical findings on the effectiveness of current therapeutics for COVID-19 is presented. The approved and repurposed drugs are from different chemical and pharmacological classes, reflecting the diversity of the mechanisms of action and potential therapeutic benefits ( Figure 2). . The Oxford-AstraZeneca prophylactic (AZD1222), an adenoviral vector-based vaccine, is being used in the United Kingdom. While vaccines constitute a critical part of the public health strategy to reduce disease burden, the management of the disease will continue to rely heavily on pharmacotherapy. Therefore, the aim of this paper is to provide an updated overview of pharmacological agents that have been repurposed, evaluated, or developed for COVID-19 management, including a review of published data for evidence (or lack thereof) of efficacy and safety with regard to identified agents.

Results
Since the discovery of SARS-Cov-2 and the declaration of COVID-19 as a global pandemic, numerous studies have evaluated different pharmacological agents against the novel virus. Figure 1 summarizes the study selection process and the search results. The initial search returned a total of 2999 articles which were screened for inclusion criteria. A total of 70 articles were reviewed in this study. In Table 1, a summary of the clinical findings on the effectiveness of current therapeutics for COVID-19 is presented. The approved and repurposed drugs are from different chemical and pharmacological classes, reflecting the diversity of the mechanisms of action and potential therapeutic benefits ( Figure 2).   Clinical improvement by day 14 was similar in both groups.
Safety profiles was similar in tests and placebo. Significant reduction in viral load was associated with the drug compared to the placebo.

Approved Therapeutics
To date, the FDA has approved three therapies for the treatment of COVID-19 under EUA: convalescent plasma, remdesivir, and casirivimab/imdevimab (regeneron). Several drugs, including antiviral and antiparasitic agents, have been repurposed for the treatment of COVID-19. Supportive therapies including immunosuppressants have also been used.

Convalescent Plasma
Convalescent plasma (CP), obtained from recovering patients, provides passive immunity in actively infected patients. CP has been utilized in previous viral pandemics.
For example, CP demonstrated efficacy and superiority over placebo (58.3% vs. 15.6%, p < 0.001) in an earlier study with patients suffering from SARS-CoV infection [54]. CP has also been used for the prevention and/or treatment of such viral infections as poliomyelitis [55], measles [56], and mumps [57]. Case series suggested the efficacy of CP in the treatment of Machupo virus associated with Bolivian hemorrhagic fever [58], Lassa fever in Nigeria [59], Junin virus associated with Argentinian hemorrhagic fever [60], and Ebola viral infection [61]. Use was safe and effective against influenza [62], influenza A (H5N1) infection [63], and H1N1 pandemic influenza [64].
On 23 August 2020, the FDA approved an EUA for CP to treat hospitalized patients with COVID-19. Compared with other blood products and therapeutics for COVID-19, CP had a clear scientific basis for use. For severely ill COVID-19 patients, CP appeared to be a potential therapy with no serious adverse effects reported [50,52,65]. However, concerns persist regarding dosing and the need for standardization due to varying donor titer amounts [49,50,52].
Cases and case reports have highlighted the utility and efficacy of CP in the treatment of COVID-19 (Table 1). Clinical improvement has been reported for patients who were immunocompromised at the time of contracting SARS-CoV-2 [46], patients who were refractory to antiviral and supportive care [44], and a pediatric patient with severe COVID-19 whose previous treatment with antiviral drugs and immune modulators failed [40]. As a biologic, concerns about safety across patient populations have been raised. However, CP has been well tolerated based on several published clinical reports (Table 1). Jafari et al. [39] reported the use of CP in a 26-year-old COVID-19 patient who was pregnant with twins. CP was infused following caesarian section, and treatment failure with meropenem, azithromycin, and hydroxychloroquine. Given on the sixth day of hospitalization, CP administered with favipiravir was associated with improved clinical outcomes and the patient was discharged two weeks after admission. However, efficacy across all patients has not been established for CP.
In an open-label, multi-center, randomized controlled trial involving 103 COVID-19 patients with severe or life-threatening symptoms, CP used as adjunctive therapy did not cause any significant difference in 28-day mortality compared to standard therapy [53]. Difference in time spent before discharge was also not significant. The study was terminated early, without reaching the planned 200 recruits. Overall, although CP may offer clinical benefits in COVID-19 treatment, current data are mixed and largely inconclusive. Published case reports and case series often combine CP use with other therapies, making it difficult to attribute efficacy to CP. More controlled studies are required to establish the efficacy of CP in COVID-19 treatment.

Remdesivir
Remdesivir is a monophosphoramide nucleoside analog with broad-spectrum antiviral activity. Once activated by host cellular kinases, the active remdesivir triphosphate exerts antiviral activity by inhibiting the viral RNA-dependent RNA polymerase, competing with adenosine triphosphate for incorporation into the viral RNA and terminating viral RNA synthesis. Prior to the current pandemic, in vitro studies demonstrated that remdesivir exhibits strong antiviral activity [66]. Previously developed to treat Ebola virus infection [67,68], remdesivir has selective cytotoxic activity against SARS-CoV-2 [69]. Other preclinical animal studies have shown that remdesivir reduces viral load in lung tissues, while enhancing pulmonary functions [70].
Remdesivir was one of the drugs used to treat the first case of COVID-19 in the United States, with remarkable results [71]. Since then, there have been numerous case reports on the use of remdesivir in COVID-19 with documented improvements in viral loads and symptomatology (Table 1). Particularly noteworthy was the use of remdesivir in a pregnant woman in her third trimester, resulting in significant clinical response and patient home discharge, without requiring emergency delivery [34]. Another important case report involved an immunocompromised patient who received a two 10-day courses of remdesivir starting at day 24 and day 45 after the onset of symptoms [36]. Not only did symptoms improve, but the patient subsequently tested negative for the virus after some episodes of relapse. These studies demonstrated the safe and effective use of remdesivir in pregnant and immunosuppressed patients.
In a prospective open-label study, remdesivir was effective in treating COVID-19 pneumonia in patients with severe symptoms [32]. This study, which enrolled 35 critically ill COVID-19 patients (18 ICU and 17 infectious disease ward (IDW) patients), recorded significant clinical responses following remdesivir use such that 6 and 14 patients had been discharged from the ICU and IDW, respectively, by day 28. Another clinical trial that evaluated the efficacy of remdesivir examined 5-and 10-day courses in a population of 397 randomized COVID-19 patients. In this study, 200 and 197 patients received intravenous remdesivir for 5 or 10 days, respectively (200 mg on day 1 and subsequently 100 mg daily) with both groups showing similar levels of clinical improvements by day 14 [38].
Two major randomized, double-blind, placebo-controlled, multicenter clinical trials have been reported for remdesivir. In the first report by Wang et al. [47], a total of 237 patients were enrolled, with 158 and 79 randomized to the remdesivir and placebo groups, respectively. Patients were allowed concurrent use of other antivirals and corticosteroids. Although patients taking remdesivir had faster clinical improvement, there was no statistically significant difference in the time to clinical improvement in the two groups. In the trial conducted by Beigel et al. [37], 1062 patients were randomized, with 541 receiving remdesivir and 521 receiving the placebo. Median recovery time with remdesivir was 10 days compared to 15 days for the placebo group. A summary of clinical experience with remdesivir is provided in Table 1. Although responses to remdesivir have been mixed, the drug appears to be safe with overall clinical benefit sometimes attributable to co-treatment with other therapies. Approved previously for use in Japan, Taiwan, India, Singapore, and the United Arab Emirates, remdesivir received a one-year conditional marketing authorization from the European Commission in July 2020. In October 2020, remdesivir was approved by the FDA for use in adult and pediatric patients (≥12 years of age and weighing at least 40 kg) for the treatment of COVID-19 requiring hospitalization.

Casirivimab/Imdevimab
The casirivimab/imdevimab combination (REGN-COV2) was granted an EUA for outpatient use in November 2020. REGN-COV2 combines two recombinant human monoclonal antibodies (mAb) which were initially reported as a new antibody cocktail capable of targeting the spike protein of SARS-CoV-2 and withstanding antibody resistance [72]. The two mAbs were further characterized to be potent, with strong affinity for the receptor-binding domain of the spike protein [73]. In two animal models-rhesus macaque and golden hamster for mild and severe COVID-19, respectively-prophylactic casirivimab/imdevimab reduced viral load in the respiratory tract and limited disease progression, indicating therapeutic potential of REGN-COV2 in humans [74].
Analysis of casirivimab/imdevimab revealed a greater reduction in viral load for patients whose immune response had not yet started or who had a viral load at their baseline visit [15]. This longitudinal study, which analyzed 275 patients randomized equally into three groups (placebo and 2.4 g or 8.0 g of casirivimab/imdevimab), monitored the immune response to the virus. Safety profiles were similar in tests and placebo. Clinical experience with casirivimab/imdevimab is limited, and published clinical studies are sparse.

Lopinavir-Ritonavir
Lopinavir-ritonavir (LPV/r) is a common antiretroviral combination which acts against the viral protease enzyme and prevents the cleavage of the precursor polyprotein at the late stage of viral replication. Ritonavir is used in the LPV/r fixed combination as a potent inhibitor of the efflux p-glycoprotein and cytochrome P450 3A4 enzymes, thus enhancing the overall plasma exposure to LPV. During the 2003 SARS outbreak, LPV/r was one of the therapeutic agents explored as treatment and showed some in vitro activity against strains of SARS-CoV [75]. The authors at the time also compared the clinical efficacy of ribavirin-lopinavir/r combination (41 patients) with ribavirin alone (111 patients) against SARS-CoV and reported a better outcome with LPV/r use. Specifically, LPV/r significantly reduced the incidence of acute disease and death by day 21. Use of LPV/r was also associated with decreased intubation rate and mortality in a multicenter study of SARS-CoV [76]. This, and other limited evidence of LPV/r efficacy in combating SARS, spurred interest in exploring LPV/r for the treatment of COVID-19.
Several case reports and case series on the use of LPV/r show mixed results on its efficacy in COVID-19 treatment. While the reported clinical improvement and negative conversion in several patients were partially attributed to LPV/r, a number of the published cases showed otherwise. Two published clinical trials also showed mixed data. The study by Ye et al. [77] associated a faster clinical response and shorter course of the disease to LPV/r use. This open-label study assigned 47 hospitalized COVID-19 patients to the group receiving either the standard COVID-19 care alone (control) or the group receiving LPV/r in addition to the standard care. The control group was given interferon inhalation and umifenovir, while antibiotics and other remedies were used when indicated. The small sample size and the influence of as-needed antibiotics and multicomponent adjuvant treatment likely limited the conclusions that could be drawn from this study. In a second clinical study by Cao et al. [78], LPV/r neither shortened the time to clinical improvement nor reduced mortality at 28 days. A total of 199 patients who were hospitalized for severe COVID-19 were randomized for a 14-day treatment with either LPV/r plus the standard care (99 patients) or standard care alone (100 patients). Virological response was similar in both groups, suggesting that LPV/r may not be more effective for viral cure. Overall, LPV/r lacks convincing data to support widespread use in the treatment of COVID-19. More robust and varied clinical studies are needed to generate conclusive data.

Umifenovir
Umifenovir (Arbidol) is an indole carboxylic acid derivative with broad-spectrum antiviral activity and is currently approved in China and Russia for the prevention and treatment of infections caused by influenza type A and B viruses [79]. It acts by inhibiting the fusion of the virion with the host cell membrane. In vitro studies have shown umifenovir to be active against a wide spectrum of viruses, including human herpesvirus, hepatitis C virus, and Ebola virus [80]. Umifenovir also has demonstrated in vitro activity against SARS-CoV and SARS-CoV-2, engendering scientific interest in this drug as a potential treatment modality for COVID-19 [81,82].
The limited clinical data that exist on the use of umifenovir in COVID-19 treatment is mixed. In a retrospective study of 33 patients who were treated with either the umifenovir-LPV combination (16 patients) or LPV/r only (17 patients), the use of umifenovir appeared to have produced a significant clinical response. By day 7 of treatment, negative conversion occurred in 75% of patients in the combination group compared to 35% in the LPV/r group, with the numbers increasing to 94% and 53%, respectively, after 14 days. Additionally, chest CT scan improvement was better with the combination therapy [83]. In another retrospective analysis of COVID-19 patients treated with LPV/r (34 cases) vs. umifenovir (16 cases), viral cure at day 14 was 56% and 100%, respectively, although disease progression was halted in both groups [84]. A third study that showed potential efficacy of umifenovir was an analysis of 62 hospitalized COVID-19 patients who received adjuvant treatment alone (20 patients) vs. umifenovir (42 patients). The results showed that the use of umifenovir was associated with a shorter course of disease and reduced the duration of hospitalization [85].
Not all studies have shown promising results for umifenovir. Two other retrospective analyses concluded that umifenovir was not associated with better viral cure or any other clinical outcome in COVID-19 treatment [86,87]. In a more elaborate randomized open-label controlled multicenter trial, 240 patients were randomized (1:1) to receive conventional COVID-19 therapy along with either umifenovir or favipiravir. Clinical recovery by day 7 was not significantly different between the groups, but umifenovir was associated with a slower rate of clinical recovery and symptom improvement [88]. With conflicting findings from these limited studies, data from multiple ongoing studies will hopefully provide more definitive conclusions with regard to the efficacy of umifenovir for COVID-19 treatment.

Favipiravir
Favipiravir (FPV) is a broad-spectrum antiviral agent for the treatment of SARS and MERS. It is a purine analog prodrug which is phosphorylated in situ and competitively inhibits the viral RNA-dependent RNA polymerase. FPV was reported to be effective in the treatment of Ebola virus infection in mice [89]. A recent study also demonstrated that FPV had in vitro inhibitory activity against SARS-CoV-2 [69]. Cai [88]. Although the in vitro and limited clinical data are promising, more clinical evaluation and experience is desirable to ascertain the efficacy of FPV in COVID-19 treatment.

Chloroquine and Hydroxychloroquine
Hydroxychloroquine (HCQ) and its parent compound, chloroquine (CQ), are aminoquinoline drugs with a long history of use in the treatment of protozoal infections, especially malaria and intestinal amebiasis. Both drugs have been used as disease-modifying agents for immunological disorders such as rheumatoid arthritis and lupus erythematosus. They were widely popularized for COVID-19 treatment, especially in the early days of the pandemic. Data from in vitro studies are mixed regarding the antiviral activity of CQ and HCQ. Earlier studies have demonstrated in vitro activities of the aminoquinolines against certain viral strains. In a study reported by Li et al., the replication of Epstein-Barr virus in infected cells was enhanced by CQ [91]. In other studies, CQ inhibited the vertical transmission of the Zika virus in infected mice [92]. The in vitro inhibition of Ebola virus replication by CQ did not translate into an in vivo improvement in infected guinea pigs [93,94]. This pattern was repeated with a promising inhibitory effect of CQ on the in vitro replication of dengue virus which did not translate to any significant clinical response in humans [95,96]. Reports of in vitro inhibition of SARS-CoV-2 replication by CQ and HCQ, besides the known immunomodulatory effects of these two drugs, led to speculations that the aminoquinolines may be an effective treatment for COVID-19 [97].
Apart from a few case reports and case series, most clinical studies have not found HCQ to be efficacious in the management of COVID-19. An initial clinical study of 100 patients claimed that chloroquine showed efficacy in the treatment of pneumonia associated with COVID-19 [98]. This study appeared isolated and was not corroborated by other clinical findings. Subsequent popularization of HCQ along with azithromycin, a staple macrolide antibiotic, for the treatment of COVID-19 generated a significant number of clinical reports with mixed inferences. In an open-label, non-randomized study reported by Gautret et al. [99], 20 hospitalized COVID-19 patients treated with HCQ (and azithromycin when necessary) had significantly reduced viral loads by day 6 of treatment compared to the untreated control group. However, in multiple randomized and/or control studies, HCQ was not associated with reduced incidence and duration of illness, a higher rate of negative conversion, or any other clinical measure of improvement [100][101][102][103]. Lack of supporting data has thus weakened the argument for the continued use of CQ/HCQ in the treatment of COVID-19, and has led to the withdrawal of the previously approved EUA [104].

Anakinra
Anakinra is an immunosuppressive biologic that functions as an interleukin-1 receptor antagonist. The combination of ARDS and hyperinflammation-induced multi-organ failure caused by a cytokine storm is primarily responsible for COVID-19 deaths [105]. The biochemical and immunopathological changes observed in COVID-19 share similarities with immune-mediated disorders for which drugs such as anakinra have been used [106].
In several case studies, anakinra was found to be safe as an adjunct treatment for COVID-19. In patients with signs of inflammation, anakinra, when used with other treatments, is effective in alleviating symptoms, reducing the need for mechanical ventilation, and improving general clinical outcomes [107][108][109][110][111][112][113].
In an observational cohort study, for example, 120 hospitalized COVID-19 patients with associated hyperinflammation were monitored for the effect of a high-dose anakinramethylprednisolone combination on 28-day survival [114]. The study, which compared 65 treated patients with 55 untreated historical controls, reported a significant reduction in mortality in the treatment group (13.9%) compared with controls (35.6%). Another retrospective cohort study analyzed outcomes in 29 patients managed with standard treatment (antiviral and HCQ) and anakinra, with 16 others managed with standard treatment only [115]. Use of anakinra was associated with better outcomes compared to the control group, as demonstrated by greater improved respiratory function (72% vs. 50%) and day 21 survival (90% vs. 56%). In both studies, anakinra was not associated with reductions in bacteremia. A third study reported no significant differences in the need and duration of mechanical ventilation use or length of ICU stay, although the study found a better clinical response with anakinra use [116]. Currently, there are several ongoing clinical trials related to the use of anakinra in the treatment of COVID-19. A recently published prospective, open-label, interventional study showed interesting and promising results [117]. A total of 45 patients in the intervention group received anakinra in addition to standard therapy compared to 24 historical controls. The use of anakinra was associated with a reduced need for mechanical ventilation, shorter duration of required oxygen therapy, and reduction in inflammatory biomarkers. The findings of this study presented some of the strongest evidence for the efficacy of anakinra in enhancing clinical outcomes in patients with severe COVID-19.

Corticosteroids
Corticosteroids, such as methylprednisolone and dexamethasone, are standard treatments for inflammation-associated disorders. The severe inflammatory responses that often accompany SARS-CoV-2 infection have made the use of corticosteroids popular in the treatment of COVID-19. Expectedly, high-dose, short-term corticosteroid therapy in early respiratory distress has been associated with better prognosis [118]. Several clinical reports have demonstrated that the use of corticosteroids in severe COVID-19 provides multiple clinical benefits, including reductions in the need for and duration of invasive ventilation [119][120][121][122].
In a single-blind, randomized controlled trial with 34 patients in each arm to receive standard treatment with or without methylprednisolone, clinical improvement and survival was significantly better with the use of methylprednisolone (94.1% vs. 57.1%) [123]. However, these findings were not supported by the data from a double-blind placebo-controlled trial which randomized 416 patients to receive either methylprednisolone (194 patients) or a placebo (199) [124]. In the latter study, survival rate at day 28 was not different between the two groups, although a sub-analysis showed higher survival rate among patients who were over 60 years of age.
Similar results have been reported for dexamethasone. In a case series of 21 patients who had COVID-19 with pneumonia and worsening hypoxemia and were treated early with short-course dexamethasone, significant clinical improvements were reported, and none of the patients deteriorated to the point of requiring mechanical ventilation [125]. The RECOVERY trial, a controlled open-label study of 6425 hospitalized COVID-19 patients, provides the most elaborate study on the efficacy of dexamethasone [126]. The patients were randomized (1:2) to receive a 10-day course of dexamethasone or the usual care. Overall, 28-day mortality (22.9% vs. 25.7%) was only slightly lower in the dexamethasone group. However, sub-analysis showed that survival was better with dexamethasone for patients who were on mechanical ventilation (70.7% vs. 59.6%) and those receiving noninvasive oxygen support (76.7 vs. 73.8%). Cano et al. [127] performed a meta-analysis of the 73 available clinical studies covering the use of corticosteroids in 21,350 COVID-19 patients and concluded that mortality benefits were shown in patients who were severely ill. Thus, although corticosteroids do not have direct antiviral activity, their ability to suppress the deleterious acute inflammatory response associated with SARS-CoV-2 infection has made them clinically important in the management of COVID-19.

Tocilizumab
Tocilizumab (TCZ) is an immunosuppressive monoclonal antibody used for the treatment of immune-mediated disorders. It is a potent antagonist of the interleukin-6 receptor. Similarly to anakinra and corticosteroids, TCZ has been employed as supportive therapy in COVID-19 to manage symptoms of hyper-inflammation and other immune responses. Several published case series and reports observed remarkable clinical responses following the use of TCZ in COVID-19 patients, including the clinical resolution of septic shock, reduction in the markers of inflammation, enhanced negative conversion, and reduced need for invasive mechanical ventilation [128][129][130][131][132][133][134][135][136][137][138][139].

Interferons
Interferons (IFNs) are immunomodulators that can decrease the inflammatory response. They have been part of the standard treatment for hepatitis B and C viral infections. By enhancing the host's immunological defense against the virus, interferons may act to suppress the replication of SARS-CoV-2 and provide anti-inflammatory effects as well. In particular, IFN-α2b, IFN-β1b, and IFN-β1a have been explored for therapeutic benefits in COVID-19 patients, although very few clinical studies have examined efficacy. In a cohort study, 7, 24, and 46 hospitalized patients received nebulized IFN-α2b, umifenovir, or an IFN-α2b-umifenovir combination (standard of care), respectively. The use of IFN-α2b alone or in combination was associated with significantly higher viral clearance and reduction in circulating biomarkers (IL-2 and CRP) of inflammation [140]. Similar positive results have been reported for IFN β-1a and IFN β-1b [141][142][143]. It is anticipated that INFs will continue to play at least supportive roles in COVID-19 treatment while more clinical data are being collected.

Tissue Plasminogen Activator
Tissue plasminogen activator (TPA) is a thrombolytic agent that has been used as supportive treatment for severely hypoxic COVID-19 patients. It is hypothesized that TPA administration may help patients who are experiencing thrombus formation by immediately lysing and diffusing the thrombus, thereby improving oxygen levels [144]. Apart from the significant bleeding risk anticipated from this biochemical mechanism, convincing therapeutic benefits have not been reported with the use of TPA in COVID-19 patients. In the few published case series, only temporary clinical improvement was observed with TPA use [145,146]. As our understanding of COVID-19 disease progression improves, better treatment options may relegate TPA to only occasional symptom-dependent support therapy.

Intravenous Immunoglobulin
Intravenous immunoglobulin (IVIG) is a blood product which is used to supplement antibodies produced by the patient to enhance the immunological suppression of pathogens. In a published report of the first COVID-19 case in Bhutan, LeVine et al. [147] attributed a dramatic clinical response in an immunocompromised 76-year-old patient to a three-day course of IVIG. The patient's condition had deteriorated despite treatment with oseltamivir, ceftriaxone, and doxycycline. Similar dramatic responses have been attributed to IVIG [148][149][150]. While questions on dosing and safety will need to be addressed through further studies, IVIG may continue to offer a treatment option for refractory cases of COVID-19.

Nafamostat
Nafamostat is a proteolytic enzyme inhibitor approved and marketed in Japan for the treatment of pancreatitis and coagulation disorders. In vitro activity of nafamostat against the MERS coronavirus has been reported previously [151,152]. Some anecdotal reports have associated nafamostat with enhanced clinical outcomes, especially when used along with other treatments [153]. According to clinical reports on eleven COVID-19 cases, nafamostat has been reported to reduce viral replication and enhance recovery when used in combination with FPV [154]. However, while nafamostat may be a potential treatment, little clinical experience exists for its use in COVID-19 therapy.
The summary of the clinical experience with repurposed and off-label-use drugs for the treatment of COVID-19 is provided in Table 2. Table 2. Clinical experience with repurposed and off-label-use drugs for the treatment of COVID-19.

Drug and Study Type Description Findings References
LPV/r, case report Index (54-year-old) patient in a Korean hospital treated with LPV/r 10 days after disease onset.
Significant decrease in viral load after LPV/r administration. LPV might have played a role. [155] LPV/r, case report 65-year-old HIV/AIDS patient being treated with LPV/r who contracted SARS-CoV-2. Support treatment was added.
Patient improved and was discharged after 34 days. LPV/r was thought to play a role in recovery. [156] LPV/r, case report 35-year-old patient treated with LPV/r for 10 days, along with supportive therapies. Virological cure was confirmed, and patient was discharged. [157] LPV/r, case series 5 cases of COVID-19 with 2 patients treated with LPV/r while 3 patients served as controls for the analysis.
The rate and duration of SARS CoV-2 shedding was not different with or without LPV/r. [158] LPV/r, case series 3 patients received LPV/r for 3, 10, and 12 days, several days after the onset of illness. All patients recovered, tested negative, and were discharged. [159] LPV/r, azithromycin, HCQ; case series Two cases of immunosuppressed patients who were managed with drug combinations.
Despite being recipients of kidney transplants, both patients recovered after drug treatments. [160] LPV/r, AZM and HCQ combination; case report Severe COVID-19 case in a 41-year-old who was treated with the combination therapy.
Most multi-organ symptoms resolved within 10 days and patient was discharged after 2 weeks of hospitalization. [161] LPV/r, controlled open-label 47 hospitalized COVID-19 patients were grouped to either receiving or not receiving LPV/r in addition to their adjuvant therapies.
LPV/r was associated with faster clinical response and a shorter disease course. [77] LPV/r, randomized, controlled, open-label trial 199 hospitalized severe COVID-19 patients were randomized to receive either a 14-day course of LPV/ritonavir in addition to standard care or standard care alone.
LPV/r neither shortened the time to clinical improvement nor reduced mortality at 28 days. Virological response was similar in both groups. [78] LPV/r, HCQ, and interferon β-1b combination; case series 5 patients with severe cases of COVID-19 treated with the combination therapy, in addition to corticosteroids for associated inflammation.
Clinical improvement and resolution of symptoms were observed. All 5 patients were discharged. [162] LPV/r, ribavirin and interferon combination; open-label, randomized, phase 2 trial 127 patients were randomized 86:41 to receive a 14-day course of either the combination or the control LPV/r only.
The combination therapy was associated with shorter duration of viral shedding and hospitalization. [163] Umifenovir, case control Retrospective analysis of 50 cases of COVID-19 patients treated with LPV/r (34 cases) or umifenovir (16 cases).
Disease progression was halted in both groups. Viral cure at day 14 was 100% and 56%in umifenovir and LPV/r groups, respectively.

Drug and Study Type Description Findings References
Umifenovir, case control 62 hospitalized COVID-19 patients were analyzed based on whether they received adjuvant therapy alone (20, control) or with umifenovir (test, 42).
The use of umifenovir was associated with a shorter course of disease and reduced duration of hospitalization. [85] Umifenovir; retrospective cohort study Analysis of patients treated with umifenovir-LPV/r combination (16 patients) compared to LPV/r only (17 patients).
By day 7 of treatment, negative conversion occurred in 75% of the patients in the combination group compared to 35% in LPV/r group. There was better chest CT scan improvement with the combination. [83] Umifenovir, case control A retrospective analysis of 81 hospitalized patients treated for COVID-19 (45 umifenovir and 36 control). Clinical outcomes were not better with umifenovir. [87] Umifenovir, randomized controlled trial 86 patients randomized as follows: 34 LPV/r, 35 to umifenovir, and 17 control, no antiviral medication.
Viral cure rate and clinical responses were not significantly different in the groups. [86] Umifenovir; randomized open-label controlled trial 240 patients were randomized (1:1) in a multicenter study to receive conventional COVID-19 therapy plus either umifenovir or favipiravir.
Clinical recovery by day 7 was not significantly different between the groups, but umifenovir was inferior to favipiravir in shortening the duration of symptoms. [88] HCQ; case report 60-year-old who was taking HCQ for 6 months for Sjogren's syndrome contracted SARS-CoV-2 and had illness. Chronic use of HCQ did not prevent COVID-19. [164] HCQ, tocilizumab; case report 61-year-old immunocompromised transplant recipient diagnosed with COVID-19 and treated with HCQ and tocilizumab.
Patient experienced significant clinical improvement and was discharged 13 days after diagnosis. [165] HCQ, AZM; case report 74-year-old COVID-19 patient with significant comorbidities was managed in the ICU with HCQ and AZM.
Patient recorded significant clinical improvement and was extubated by day 5 and moved to the floor. [166] HCQ, AZM; open-label Analysis of 1376 hospitalized patients treated with one or a combination of HCQ and AZM AZM alone was associated with reduced mortality compared to no treatment. HCQ did not affect mortality. [167] HCQ; case series 3 cases of chronic HCQ users who contracted SARS-CoV-2 and had serious symptoms. Chronic HCQ use did not prevent COVID-19. [168] HCQ observational study Analysis of 1446 patients to establish association between HCQ use and intubation or death.
HCQ did not reduce or increase the need for intubation or incidence of death. [100] HCQ, AZM; Open label, non-randomized study 20 hospitalized COVID-19 patients treated with HCQ (and AZM when necessary) with outcome of viral load suppression compared to untreated patients.
HCQ and AZM were associated with significantly reduced viral load by day 6 of treatment compared to untreated control. [99]

Drug and Study Type Description Findings References
HCQ; randomized, double-blind, placebo-controlled trial 821 participants who had been exposed to COVID-19 but were asymptomatic were randomized to receive either HCQ or placebo for post-exposure prophylaxis.
HCQ did not reduce the incidence of illness, but rather was associated with a higher incidence of side effects. [101] HCQ; randomized open-label, multicenter, controlled trial 150 hospitalized COVID-19 patients randomized (1:1) to receive HCQ or not, in addition to standard care.
The use of HCQ was not associated with a higher rate of negative conversion of SARS-CoV-2. HCQ was associated with higher incidence of side effects [102] CQ and tocilizumab, case report 63-year-old hospitalized for COVID-19 and treated with a 7-day course of CQ and single IV tocilizumab.
Patient experienced significant clinical improvement, recovered, and was discharged. [169] CQ, randomized phase II trial Patients were enrolled in a study to compare the efficacy and safety of high-dose (81 patients) vs. low-dose (40 patients) CQ as adjunct therapy for severe COVID-19.
High CQ dose was associated with higher incidence of side effects. High-dose CQ did not have a better effect on viral load than low CQ dose. [103] AZM; open-label, randomized multicenter Study of randomized 397 hospitalized patients with severe COVID-19 to either receive (214) or not (183) receive AZM in addition to standard treatment which included HCQ.
AZM was not associated with significant clinical improvement. [170] TCZ, case report 42-year-old cancer patient who had respiratory failure as a complication of COVID-19 despite treatment with LPV/r. He was treated with two infusions of TCZ.
Patient experienced rapid clinical improvement and was fully discontinued on oxygen 5 days after TCZ infusions. Patient later fully recovered. [128] TCZ; case report Critically ill 57-year-old with COVID-19 who was refractory to standard treatment and treated with TCZ to inhibit cytokine storm.
Significant and progressive clinical response was observed in response to TCZ. [129] TCZ; case report 54-year-old with severe respiratory symptoms from COVID-19 who did not respond to antiviral drugs and was infused with TCZ.
Remarkable clinical improvement was observed only 4 days after TCZ administration. [130] TCZ; case report 36-year-old severe COVID-19 patient whose symptoms did not improve with HCQ and antiviral drugs. A single-dose TCZ was infused.
Progressive improvement was observed after TZC use, with subsequent negative conversion and recovery. [131] TCZ; case report 46-year-old patient in ICU whose COVID-19 illness was refractory to HCQ, and other supportive therapy was treated with TCZ.
Patient experienced remarkable recovery and was discharged to home 5 days after TCZ use. [133] TCZ; case series 5 critically ill COVID-19 patients whose illness was refractory to standardized treatment.
Marked clinical improvement was observed in all patients except one. Recovery and negative conversion were reported. [134] TCZ; case series Two patients whose COVID-19 was complicated by cytokine release syndrome were treated with TCZ.
Progression to secondary hemophagocytic lymphohistiocytosis was observed in both patients, with viral myocarditis in one, despite the treatment.
[135] TCZ was associated with significant clinical improvement and the amelioration of cytokine storms in COVID-19 patients. [136] TCZ, case series A retrospective analysis of 5 patients with severe COVID-19 illness requiring ICU admissions who were treated with TCZ.
All patients had significant improvement and were discharged from ICU after 13-26 days, with 2 discharged home. [137] TCZ; case series 3 patients admitted and treated with HCQ and AZT with no significant clinical improvement. All 3 received doses of TCZ.
Patients had sufficient clinical improvement to avoid intubation, and ultimately recovered. [138] TCZ; case series 2 patients whose symptoms worsened after treatment with HCQ, AZM and other supportive therapies were administered with TCZ.
Drastic improvement in respiratory symptoms and markers of inflammation were observed following TCZ use. Both patients recovered and were discharged. The use of IFN-α2b alone or in combination was associated with significantly higher viral clearance and reduction in circulating biomarkers (IL-2 and CRP) of inflammation. [140] IFN-β-1a; prospective non-controlled study Observation and analysis of 20 patients treated with IFN-β-1a in addition to conventional treatment (HCQ and LPV/r).
Significant clinical response including viral clearance and symptom relief. Recovery after 14 days, with no serious adverse events in any patient. [141] IFN-β-1a; randomized controlled trial Patients (n = 44) were treated with IFN-β-1a in addition to standard treatment and compared with controls (39) who received standard treatment only.
Mortality at day 28 was significantly lower in patients treated with IFN-β-1a compared to control (19% vs. 43.6%). IFN-β-1a did not shorten the time to clinical response. [142] IFN-β-1b, randomized, open-label trial Patients received IFN-β-1b in addition to standard treatment (n = 33) and were compared to controls who received only the standard treatment (n = 33).

Vaccines
The Pfizer/BioNTech (BNT162b2) and Moderna (mRNA-1273) COVID-19 vaccines, both of which contain nucleoside-modified RNAs encoding the SARS-CoV-2 spike protein, were the first to be approved by the U.S. FDA under Emergency Use Authorization in December 2020. Following successful phase 3 clinical trials, the vaccines' preliminary efficacy (95%) and safety data supported a two-dose regimen [172]. The Oxford/AstraZeneca (AZD1222) vaccine, developed as a viral vector vaccine, was first approved in Europe for a two-dose regimen, having demonstrated an initial efficacy of 82.4%. Similar adenovirus vector vaccines that have been developed and approved for public use include the Sputnik

Adjunctive and Supplementary Medicines
The role of vitamins and herbal products as complementary therapies in the management of COVID-19 has been the subject of several recent publications [174,175]. Vitamins serve as antioxidants and enhance immunity. They may also help to accelerate a patient's recovery from the multi-dimensional symptomatology of COVID-19.
Multiple case reports and case series suggest that high-dose vitamin C may enhance the recovery from COVID-19 [176][177][178]. A retrospective study of 76 patients reported that the use of vitamin C in COVID-19 patients was associated with modest clinical benefits, including reductions in 28-day mortality and improvements in oxygen support status [179]. However, more elaborate clinical studies did not demonstrate therapeutic benefits of highdose vitamin C in patients with COVID-19 [180][181][182][183]. Similarly, vitamin D supplementation may be of potential benefit in ameliorating the effects of COVID-19, but there are currently no clinical studies to support this suggestion [184].
There are anecdotal reports on the therapeutic efficacy of herbal medicines. Traditional Chinese medicine (TCM) is perhaps the most studied in this regard. There are several ongoing clinical trials examining the therapeutic effects of some of these herbal products. Beyond traditional use, none of these products have been officially approved for in-patient treatment of COVID-19. A detailed review of herbal therapies in COVID-19 treatment is beyond the scope of the current paper.

Discussion
The response of the global scientific community to the COVID-19 pandemic has been impressive. The use of repurposed drugs for clinical management of the disease, the testing of new drugs in clinical trials, and the successful development of several efficacious vaccines within one year are the results of a monumental worldwide effort to restrict SARS-CoV-2 infection. While the experimental development and regulatory approval of current drugs and vaccines have been rapid and fast-tracked, sufficient clinical data have been generated to warrant their use in the prevention and management of COVID-19. However, the long-term effects of drugs can only be assessed after several years of clinical experience. The efficacy and safety of current COVID-19 therapeutics should continue to be monitored as part of a rigorous pharmacovigilance process.
Several repurposed and supportive drugs have shown mixed data on efficacy and safety. Interpreting the published studies can be challenging due to multiple confounding factors, of which the most prominent factor is the lack of effective standard COVID-19 control treatment. The use of multiple regimens as standard control therapy blurs the line of the attribution of efficacy to the test drugs. In addition, the sample sizes in most of the studies were too small, and the consequent small statistical power limits the inferences that can be drawn from the results. The presence of comorbidities and the severity of COVID-19 in many of the studied patients also complicates understanding the pathophysiology of the disease as well as the pharmacodynamic response.
Although the advent of vaccines will continue to reduce the spread and the global burden of COVID-19, the disease may not be totally eradicated due to a combination of viral mutation and refusal of individuals to be vaccinated. Therefore, a reliance on pharmacotherapy in COVID-19 management will likely continue. It is evident that targeted antiviral treatment and multiple supportive therapies, including immunomodulation and antibody supplementation, will continue to play significant pharmacological roles in the treatment of COVID-19. Prudent use of these available drugs will hopefully continue to benefit patients while more effective therapeutics are being developed.