Remdesivir is an adenosine analog that works as an antiviral agent in cultured cells and animal models against various RNA viruses, including SARS/MERS. It was initially an experimental antiviral drug used to treat Ebola and is now under the cooperation of Gilead Sciences Inc. with researchers and clinicians in China. It can cause the RNA chains of the viral to terminate before it reaches its mature stage and therefore fulfills its antiviral function [40]. A previous study showed that Remdesivir could effectively suppress the infection of the virus in a highly sensitive human cell line (human liver cancer Huh-7 cells) [41]. From their detection, Remdesivir functions in one stage after virus entry [41]. The EC₉₀ value of Remdesivir against the SARS-CoV-2 infection of E6 cells was 1.76 μM. Meanwhile, the EC₅₀ value is 0.77 μM (SI  >  129.87) [41]. In America, the first SARS-CoV-2 patient was treated with Remdesivir and was already cured [42]. Moreover, in France, a patient was treated with Remdesivir and cured [43]. However, Fan et al. [44] reported that administrating Remdesivir to mice with a daily dose of 150 μg/mice can cause a significant decrease in sperm count and motility and a significant increase in abnormal sperm rate, indicating that the administration of Remdesivir may cause testicular toxicity. Since the experiment was only carried out on mice, more experiments are needed to confirm the result [44]. Moreover, on April 29, 2020, the results of three clinical trials of Remdesivir for COVID-19 were announced simultaneously. These studies reported contradicting results on the efficacy of Remdesivir in treating COVID-19. The first report was from the first clinical trial to evaluate Remdesivir in the treatment of COVID-19, initiated by NIH [45]. In this randomized controlled trial with 1063 patients, preliminary data analysis revealed that advanced COVID-19 patients who received Remdesivir recovered more quickly than comparable patients who received a placebo. Another study evaluated the 5-day and 10-day treatment courses of Remdesivir for COVID-19 patients and found no significant difference (no significant adverse effect), and all patients’ clinical conditions showed a similar improvement [46]. However, the third study presented a conclusion that conflicted with the findings of the first two research works. It was a randomized, double-blinded, placebo-controlled study to evaluate Remdesivir’s effectiveness in treating patients with severe COVID-19 [47]. Their result showed no statistically significant difference in clinical improvement time between the group receiving Remdesivir and the group receiving a placebo. The result is surprising, as the two previously mentioned trials had at least shown some benefits in treating the disease. According to a study, Remdesivir treatment reduces mortality in SARS-CoV-2-infected individuals. In this study of 342 patients, Raltegravir was given to 60 patients in the control group and 18 in the case group (35.1% vs. 10.5%, p < 0.0001). Remdesivir therapy can decrease SARS-CoV-2 mortality [48]. A randomized, double-blind, placebo-controlled trial validated the safety of Remdesivir in a three-day treatment [49]. Some studies have confirmed that a three-day outpatient course of Remdesivir significantly reduces the risk of hospitalization or death. In a retrospective matched-pair study to evaluate the contributions of Remdesivir and vaccination in reducing severe clinical outcomes, patients who received a three-day course of Remdesivir after receiving ambulatory vaccination were 75% less likely to end up in the hospital and 95% less likely to experience respiratory failure. Neither intubations nor fatalities occurred [50].

A broad-spectrum antiviral drug called arbidol hydrochloride prevents enveloped viruses from infecting host cells by preventing the fusion of the virus with the cell membrane. Including FLU-A, RSV, HRV 14, and CVB3, Arbidol exhibits strong inhibitory efficacy against both enclosed and non-enveloped RNA viruses. According to the records of 252 COVID-19 patients, patients who received Arbidol experienced a clinical improvement rate that was noticeably higher than that of patients who did not. Clinical improvement rates in the Arbidol group were 95.6% and 81.7%, respectively, in moderately and severely ill patients, which was considerably greater than in the no-Arbidol group (66.6% and 53.8%). However, there was no discernible difference among critically ill individuals. Additionally, results show that Arbidol works well in treating COVID-19 patients and may be a useful antiviral therapeutic option for those with mild to moderate COVID-19 symptoms [51].

A powerful inhibitor of viral RNA polymerase, favipiravir is phosphor-ribosylated by cellular enzymes to produce favipiravir-ribofuranosy l-5′-triphosphate, which is its active form (RTP). When used to treat influenza, the guanine analog favipiravir effectively inhibits RNA viruses’ RNA-dependent RNA polymerase. With an IC50 of 341 nM, favipiravir-RTP blocks influenza viral RNA-dependent RNA polymerase (RdRP) activity [52].

A recent study reported its activity in SARS-CoV-2 [53]. A randomized trial of favravavir in combination with interferon-α (CHICTR090029) and barbituric (CHICTR09009554) for SARS-CoV-2 has been conducted [54].

The medication baricitinib particularly inhibits Janus-activated kinase 1 and 2 (JAK1/2), which mediate signaling for cytokines and growth factors involved in hematopoiesis, inflammation, and the immune response. Suppressing JAK1 and JAK2’s enzymatic activity could modify intracellular signaling by reducing STAT phosphorylation and activation. An observational, long-term experiment involved treating patients with 4 mg of baricitinib once a day for 7 days after receiving 4 mg twice daily for 2 days. Serum-derived cytokine and antibodies against SARS-CoV-2 were assessed and linked with changes in the immunological phenotype and phosphorylated STAT3 (p-STAT3) expression in blood cells (anti-SARS-CoV-2) [55]. A single treated patient with altered myeloid cell functional activity was assessed. According to the findings, patients using baricitinib experienced significantly lower levels of IL-6, IL-1, and TNF in their serum, rapid recovery in the frequency of circulating T and B cells, and increased antibody production against the SARS-CoV-2 spike protein. By altering the patients’ immunological environment, baricitinib prevented the viral infection from progressing to a severe, extreme form, and these modifications were linked to a safer, better clinical result for COVID-19 pneumonia patients. Recently, baricitinib (Olumiant) received U.S. Food and Drug Administration approval as the first immunomodulatory treatment for COVID-19 [56].

The JAK family of kinases is effectively and selectively inhibited by tofacitinib. Tyrosine-protein 2 kinases (Tyk2) and JAK1, JAK2, and JAK3 are less activated when treated with tofacitinib [57]. Tofacitinib blocks the signaling of hetero-dimeric cytokine receptors in human cells, which have higher functional selectivity to bind JAK3 and/or JAK1 but not homodimer JAK2. Tofacitinib reduces interleukin signaling, including IL-2, IL-4, IL-6, IL-7, IL-9, IL-15, and IL-21, and interferon type I and II, and modifies immunological responses. A total of 289 patients were randomly assigned at 15 sites around Brazil [34]. In particular, 89.3% of the patients received glucocorticoids during hospitalization. By day 28, 18.1% of deaths or respiratory failures were noted in the tofacitinib group and 29.0% in the placebo group. Moreover, by day 28, 2.8% of patients in the tofacitinib group and 5.5% of patients in the placebo group had died from any cause. When comparing tofacitinib to a placebo, the proportional chances of having a lower score on the eight-level ordinal scale were 0.60 on day 14 and 0.54 on day 28. Twenty patients (14.1%) using tofacitinib and 17 (12.0%) taking a placebo experienced serious adverse events. By day 28, tofacitinib resulted in a lower risk of death or respiratory failure among patients hospitalized with COVID-19 pneumonia compared to those treated with a placebo [58].

The ribonucleoside analog EIDD-1931 has a prodrug called molnupiravir that is orally bioavailable. Several coronaviruses, including SARS-CoV-2, MERS-CoV, and SARS-CoV, are resistant to the antiviral effects of molnupiravir, which has a broad spectrum of antiviral activity [59]. The potential of molnupiravir was assessed in a study of COVID-19 and seasonal and pandemic influenza. In contrast to the placebo group (16.7%), viruses could only be isolated from a few of the 202 patients taking 800 mg molnupiravir (1.9%) on day 3 (p = 0.02). Compared to 11.1% of participants taking a placebo on day 5, viruses could not be isolated from persons taking 400 or 800 mg of molnupiravir (p = 0.03). Overall, molnupiravir was well tolerated, and the side effects were consistent across all groups [60]. In a propensity score matching analysis, the risk of the composite outcome was non-significantly lower when using molnupiravir: the hazard ratio was 0.83 (95% confidence interval, 0.57–1.21). Molnupiravir was correlated with a substantial reduction in the risk of a compound outcome in elderly patients, at 0.54 (0.34–0.86); in women, at 0.41 (0.22–0.77); and in patients with insufficient COVID-19 immunization, at 0.45 (0.25–0.82), according to a subgroup analysis. Statistics indicate that molnupiravir may reduce the risk of severe COVID-19 and COVID-19-related death [61]. Moreover, it was reported that complications are factors in the effectiveness of molnupiravir treatment. The mean age of the 192 patients on molnupiravir was 70.4 ± 15.4 years, and regarding comorbidities, the most prevalent were active cancer (51, 26.6%), obesity (51, 26.6%), chronic lung disease (56, 29.2%), and cardiovascular disease (96, 50.0%). Overall, 13 patients died: six died due to COVID-19, and seven died due to complications during treatment. Notably, of these patients, one had sepsis due to a urinary tract infection, two had traumatic brain injuries, one had heart failure, and four had metastatic cancer [62]. In addition, patients treated in the first three days after the onset of COVID-19 clinical symptoms have a lower risk of developing severe illness [62].

Anakinra is an approved 17-kD recombinant nonglycosylated human IL-1 receptor antagonist in treating rheumatoid arthritis. By inhibiting the action of IL-1, it may be useful as an adjuvant therapeutic option in individuals with severe COVID-19. In a randomized controlled clinical trial, 30 individuals were enrolled, and 15 received anakinra. Eleven patients were female (36.7%), and 19 were male (63.3%). The patients’ average age was 55.77 + 15.89 years. Compared to the control group, the intervention group’s need for invasive mechanical ventilation was significantly lower (20.0% vs. 66.7%, p = 0.010). Additionally, these patients’ hospital stays were considerably shorter (p = 0.043). There was no discernible increase in the rate of infection. According to the findings, patients were referred to critical care units because severe COVID-19 required less mechanical ventilation when anakinra was used as an immunomodulatory drug. The drug shortened the patient’s time in the hospital. Furthermore, there was no discernible rise in the risk of infection. These results require confirmation in additional randomized placebo-controlled trials with a larger sample size [63].

Nirmatrelvir/ritonavir is another oral antiviral (OA) medication that helps to prevent mild to moderate COVID-19 patients from developing severe COVID-19. Nirmatrelvir is an oral protease inhibitor that can help to block the replication of the virus. Ritonavir is used as a booster for the former, slowing down the rate of decomposition and metabolism of nirmatrelvir in the liver to maintain the concentration of nirmatrelvir in the plasma and make it more effective. To date, some real-world investigations have shown that the nirmatrelvir/ritonavir combination is effective against mutant strains. It is thought to be a therapy that will alter the present outbreak prevention and control strategy. One retrospective cohort study assessed the clinical outcomes of nirmatrelvir/ritonavir in mild-to-moderate hospitalized patients [64]. Using propensity score matching, 890 recipients of nirmatrelvir and ritonavir were matched with 890 placebo recipients. When compared to controls, recipients of nirmatrelvir/ritonavir reportedly had a reduced incidence of all-cause death (p < 0.0001), progression of composite disease (p < 0.0001), and requirement for oxygen therapy (p = 0.032). Furthermore, a quicker reduction in viral burden in nirmatrelvir/ritonavir recipients was observed [64].

However, some are concerned that the addition of ritonavir, a CYP3A4 enzyme inhibitor, leads to interactions with various medications and impairs liver and kidney function, thereby restricting its usage among the general population and raising the risk of harm in the elderly and those with underlying conditions. In another real-world retrospective research study by Gentile et al., 111 mild to moderate patients who were older or had significant comorbidities were enrolled and received the nirmatrelvir/ritonavir combination. Despite their age and comorbidities, throughout a 14-day follow-up, only one patient was reported hospitalized. The proportion of reported ADRs was low, and no recipients stopped their therapy due to adverse drug reactions. Moreover, participants with two or more comorbidities experienced similar risks of hospitalization (1.4%) versus those with no or one comorbidity (1.6%). Although they concluded that obesity was the most prevalent comorbidity for the development of severe COVID-19, these older-aged, OA-treated recipients with comorbidities were shown to have a low hospitalization rate, mortality, and ADRs [65].

In short, oral antiviral medications nirmatrelvir/ritonavir have demonstrated significant therapeutic benefits. The World Health Organization (WHO) and National Institute of Health (NIH) have already announced on their official websites that nirmatrelvir, in combination with ritonavir, may be used in mild to moderate patients who are at high risk for developing severe COVID-19 [66].

The antibody (mAb) combination AZD7442 was created with two anti-spike monoclonal antibodies: Cilgavimab (AZD1061) and Tixagevimab (AZD8895). It was claimed to be both therapeutic and suitable for pre-exposure prophylaxis. Cilgavimab and Tixagevimab are classified as receptor-binding motif (RBM) class II and class III mAbs and are capable of binding to epitopes that overlap ACE2 and limiting the motion of the spike protein, respectively [66]. Data on their effectiveness and safety in immunized individuals during the Omicron waves are currently only available from a few retrospective cohort studies.

In a trial in Israel by Kertes et al., participants were randomly assigned to receive one dosage of the cocktail (150 mg of Tixagevimab and 150 mg of Cilgavimab). Those who received the cocktail showed a 69% lower chance of COVID-19 symptoms or death from any cause (p = 0.002, 95% CI 36–85) in a median follow-up of 83 days. Only one (0.1%) of the cocktail recipients needed hospitalization, compared to 27 (0.6%) of the controls (p = 0.07) [67]. Some additional cohort clinical studies were conducted on organ transplant recipients wherein BA.2 was the immune strain, with all these studies reporting increased neutralization and a decreased infection rate [68,69].

Since the cocktail was developed before the prevalence of Omicron, a 150 mg dosage has been reported to be insufficient against BA.1 and BA.1.1. Hence, an increased dosage using 300 mg of Tixagevimab plus 300 mg of Cilgavimab to elicit greater neutralization is proposed and is now listed as one of the recommended treatments by the National Institutes of Health (NIH) [66,67]. However, research examining its efficacy against the current BA.4/BA.5 variants of concern is lacking, and no clinical trials have yet been conducted [66].

The first antibody cocktail therapy to be commercially licensed in China was a cocktail composed of Amubarvimab and Romlusevimab. These two anti-COVID-19 monoclonal antibodies were obtained in early 2020 during the pandemic. According to the trial results from NIH’s ACTIV-2 randomized, blinded clinical trial, a total of 837 mild–moderate, non-hospitalized adult patients participated in the trial. In the 7-day follow-up, recipients of Amubarvimab and Romlusevimab reported fewer hospitalizations (12 vs. 45) and deaths (1 vs. 9), while the 28-day follow-up revealed a 78% decrease in both hospitalization and mortality. Additionally, fewer adverse events were reported in the cocktail-receiving group compared to the placebo group (3.8% vs. 13.4%). Due to its safe and effective treatment of COVID-19, it is now listed as one of the Emergency Use Authorizations by the FDA [70].

The SARS-CoV-2 spike protein targets the powerful neutralizing IgG1 mAb known as Bamlanivimab (LY-CoV555). It prevents viral attachment to human cells and penetration, neutralizing the virus and perhaps preventing and curing COVID-19 [39]. According to studies, prophylactic dosages such as 2.5 mg/kg suppressed viral proliferation in the upper and lower respiratory tract in samples obtained on research day 6 following viral injection in a rhesus macaque challenge model. A range of COVID-19 indications, including prevention and therapy, are being assessed for this antibody and it has begun clinical testing [71].

Etesevimab (JS016 or LY-CoV016) is another humanized neutralizing mAb. It can selectively bind to the virus’s surface protein receptor-binding domain (RBD) and efficaciously prevent it from attaching to the ACE-2 receptors on the host cell surface [72].

Etesevimab and Bamlanivimab are frequently used in tandem. In one phase 2 randomized clinical trial involving 577 non-hospitalized patients by Gottlieb et al., individuals with mild to moderate illness receiving combination treatment of 2800 mg Bamlanivimab and 2800 mg Etesevimab showed a significantly higher reduction in virus load at day 11, compared to the placebo group. The difference in viral log load change from baseline at day 11 compared with placebo was −0.57 (95% CI, −1.00 to −0.14; p  =  0.01). Furthermore, with only one incidence of COVID-19-related hospitalization or emergency department visit, combination treatment showed the best performance compared to sole Bamlanivimab or placebo treatment [73].

In another phase 3 trial, 1035 mild or moderate patients randomly received a Bamlanivimab/Etesevimab combination or placebo treatment in a one-to-one ratio. At day 7, patients who were administered Bamlanivimab with Etesevimab reported a higher viral log load decrease than in the placebo group (95% CI, 1.46 to 0.94; p = 0.001). At day 29, 36 of 517 (7.0%) placebo recipients and 11 of 518 (2.1%) Bamlanivimab/Etesevimab recipients experienced a hospitalization or COVID-19-related death. While 10 mortality cases were recorded in the placebo group, none were recorded in the Bamlanivimab/Etesevimab group [73].

Although the combination of Bamlanivimab and Etesevimab seemed successful for mild or moderate patients in the two clinical studies mentioned above, their application was discontinued in June 2021 because this combination could no longer provide sufficient efficacy against the newly emerged Omicron variant.

Casirivimab and Imdevimab are two other human monoclonal antibodies used in combination. The neutralizing cocktail composed of them is called REGN-COV2. They act to prevent virus attachment by interacting with the virus’s spike protein RBD area [74]. Weinreich et al. conducted a phase 1–3, randomized, double-blind clinical study to examine the effectiveness of REGN-COV2. A total of 275 non-hospitalized patients were randomly assigned to one of three treatment groups: placebo, low-dose (2.4 g), or high-dose REGN-COV2 (8.0 g). As a result, 6% of participants in the control group and 3% of those who received REGN-COV2 in the entire study population reported having at least one medical visit. Moreover, this REGN-COV2 combination was observed to decrease the viral load in patients, with a larger impact on individuals whose immune response had not yet begun to react or in those with high viral loads at baseline. However, the proportion of recipients who experienced adverse effects (e.g., hypersensitivity response) was comparable to that of the placebo control group [75].

As with the Bamlanivimab/Etesevimab combination, REGN-COV2 has also been considered non-therapeutic due to the current prevalence of the Omicron strain and its substrains. Therefore, it is also now listed as a treatment option that is not recommended.

The anti-spike-neutralizing monoclonal antibody Sotrovimab was applied to treat mild to moderate COVID-19 in outpatient settings. It is resistant to all key protein mutations in Omicron mutant strains. Sotrovimab is currently approved in approximately 12 countries, including the U.S. In clinical trials, patients with mild to moderate new coronary arteries experienced a 79% reduction in the risk of hospitalization and mortality. In an interim analysis of the ongoing COMET-ICE research, the effectiveness of Sotrovimab was assessed. Patients received either a placebo (N = 292) or a single 500 mg infusion of Sotrovimab over 1 h. The whole randomized population’s median age was 53 years (range: 18–96). Compared to the placebo group, Sotrovimab patients’ clinical COVID-19 advancement was reduced by 85% on day 29 (p = 0.002) [76].

Tocilizumab, a recombinant humanized IgG1 mAb, binds exclusively to membrane-bound and solubilized IL-6 receptors (sIL-6R and mIL-6R), blocking the signaling cascade and lowering IL-6’s pro-inflammatory activity. Between March and August 2021, retrospective cohort research was carried out involving persons with severe SARS-CoV-2 pneumonia. A total of 101 individuals were included, of whom 46 received corticosteroids and 55 received corticosteroids together with tocilizumab. The findings revealed a 58-year-old median age and a 63.9% female population. Obesity and high blood pressure were observed in 36.1% and 54.6%, respectively. The cohort’s survival rate was 81.4%, and the average hospital stay was 19.0 days. In the cohort, secondary infections were observed in 47.4% of cases. Patients in the tocilizumab group had shorter hospital stays, lower C reactive protein (CRP) levels at discharge, a decreased likelihood of multiple organ failure, and higher functional status. According to a bivariate study, there were no differences in mortality rate or secondary infection occurrence. There was a significant difference in the variability of the clinical state as measured by the WHO Ordinal Scale from deterioration to discharge (or 14 days), demonstrating a better functional status in patients receiving tocilizumab [77].

Bebtelovimab is a mAb with newly identified antiviral activity against the prevalent Omicron strain and its substrains. Although clinical data are still lacking, it has been listed as one of the recommended therapies for non-hospitalized adults with mild to moderate COVID-19 symptoms [78]. In a retrospective cohort study, despite being, on average, 10 years older than the control group, the Bebtelovimab-treated group saw fewer hospitalizations or fatalities (3.1% vs. 5.5%). In other words, Bebtelovimab can bring an even lower rate of hospitalization or death despite patients being older, in poorer health conditions, and more likely to be immunocompromised [79].