What are the current anti-COVID-19 drugs? From traditional to smart molecular mechanisms – Virology Journal – Virology Journal

Different drug classes have emerged during the COVID-19 pandemic, and multiple drugs (with other indications) have been repurposed and showed substantial efficacy against the virus. These drugs can be classified as antivirals, anti-SARS-CoV-2 antibody agents (monoclonal antibodies, convalescent plasma, and immunoglobulins), anti-inflammatory, and immunomodulators (Fig.1B).

In this review, we discuss and summarize the different drug classes used for the treatment of COVID-19, with special emphasis on their targets, mechanisms of action, adverse effects, and drug interactions (summarized in Table 1). Additionally, we spotlight the latest important guideline recommendations October 2023 of NIH [38], IDSA [39], and NICE [40] and FDA approval or authorization regarding the use of these drugs in the management of COVID-19 (summarized in Additional file 1: Table 1).

This class of drugs works by interfering with the SARS-CoV-2 replication cycle to reduce the viral load and its subsequent pathological effects. Antiviral drugs inhibit the entry of the virus through the ACE2 receptor and/or TMPRSS2, the viral membrane fusion and endocytosis, or the viral proteases and RdRp. This class of drugs has a vital role in preventing COVID-19 illness progression because viral replication is more active during early infection [41].

Remdesivir is the first FDA-approved antiviral drug against COVID-19. It is a nucleotide prodrug, and its active metabolite, which is an adenosine analog, can bind to viral RdRp and inhibit viral replication through premature termination of RNA transcription [42].

In 2020, the WHO recommended against the use of remdesivir in COVID-19 patients regardless of disease severity due to the lack of evidence at that time that remdesivir could improve survival or any other clinical outcomes. In April 2022, following the emergence of new data from clinical trials, the WHO updated its recommendations and suggested the use of remdesivir in mild or moderate COVID-19 patients who are at high risk of hospitalization [43, 44].

The FDA and the latest guideline (NIH, IDSA, and NICE) versions recommend the use of remdesivir in hospitalized and non-hospitalized adult and pediatric (aging28 days and weighing3 kg) patients with mild to moderate COVID-19 to reduce the risk of disease progression. Additionally, NIH recommends the co-administration of remdesivir with dexamethasone for hospitalized COVID-19 patients requiring O2 supplementation [38,39,40].

Remdesivir is administered by intravenous (IV) route at a dose of 200 mg infused over 30120 min on day 1 (loading dose) followed by 100 mg/day. For pediatric patients (less than 40 kg), the loading dose is 5 mg/kg on day one, followed by 2.5 mg/kg/day. The most common adverse effect of remdesivir is nausea. It may also elevate liver transaminases and prothrombin time and induce hypersensitivity reactions. Chloroquine and hydroxychloroquine reduce remdesivir antiviral effectiveness; therefore, their coadministration is not recommended. Remdesivir dose should be adjusted in patients with renal insufficiency. Its use is not recommended in patients with an estimated glomerular filtration rate (eGFR)<30 mL/min. Remdesivir is well tolerated during pregnancy, with a low rate of serious adverse effects [45].

Paxlovid is the first FDA-approved oral antiviral drug against COVID-19 [46]. It is a combination of nirmatrelvir, which inhibits the main protease (Mpro) of SARS-CoV-2, and ritonavir, the inhibitor of cytochrome P450-3A4, thus slowing down nirmatrelvir metabolism. This combination allows a longer half-life of nirmatrelvir, allowing a 12-h dosing interval. It is the first oral anti-viral drug approved for COVID-19 [46].

The FDA and the latest guideline (NIH, IDSA, and NICE) versions recommend the use of Paxlovid in non-hospitalized adult and pediatric (12 years and40 kg) patients with mild to moderate COVID-19 to reduce the risk of disease progression [38,39,40, 46].

Paxlovid side effects include diarrhea, impaired taste, hypertension, and myalgia. It is not recommended for patients with severe renal or hepatic impairment. It should be used cautiously in patients with liver diseases, abnormal liver enzymes, or hepatitis [39]. Using Paxlovid in people with uncontrolled or undiagnosed HIV-1 infection may induce HIV-1 drug resistance [47].

Paxlovid is contraindicated in patients with a history of clinically significant hypersensitivity reactions. As it is a CYP-3A4 inhibitor, it is contraindicated in patients receiving drugs metabolized by CYP-3A4, like alfuzosin, colchicine, propafenone, amiodarone, ergotamine, statins, sildenafil, midazolam, and triazolam [47]. The dose of Paxlovid should be adjusted in patients with eGFR60 mL/min. Paxlovid is not recommended for patients with eGFR<30 mL/min [39].

Molnupiravir is another oral antiviral drug that targets viral replication. It is a prodrug that is converted to -D-N4-hydroxycytidine (NHC), which is incorporated into viral RNA strands mimicking nucleoside cytidine or uridine and leading to error catastr5phe during viral replication [48].

The FDA and the guidelines of NIH, IDSA, and NICE recommend the use of molnupiravir in non-hospitalized adult patients with mild to moderate COVID-19 to reduce the risk of disease progression only when Paxlovid or remdesivir cannot be used [38,39,40, 49]. The dose of molnupiravir is 800 mg orally every 12 h for 5 days, starting within 5 days of symptom onset [38].

The most common side effects of molnupiravir are nausea, diarrhea, and dizziness. Neither drug interactions nor contraindications were reported, as the available data is limited. However, it is not authorized for patients18 years with COVID-19 due to bone and cartilage growth affection and is not recommended in pregnant or lactating females. Additionally, molnupiravir is not FDA-authorized for pre- or post- exposure prophylaxis of COVID-19. Due to its lack of clinical benefit, molnupiravir is not authorized for the treatment of hospitalized COVID-19 patients [39].

This antiprotozoal agent was first approved by the FDA for the treatment of Giardia duodenalis and cryptosporidium parvum in adults and children>1 year [50]. It is a prodrug that is actively metabolized to its active form, tizoxanide, which interferes with the pyruvate: ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction necessary for the anaerobic metabolism in anaerobic organisms. It has shown in vitro anti-viral activity against multiple viruses like the influenza virus, Rotavirus, Norovirus, hepatitis B and C, Ebola virus, MERS-CoV, and COVID-19 [50,51,52].

Nitazoxanide inhibits host enzymes, which impairs the post-translational processing of viral proteins. It also has an inhibitory effect on pro-inflammatory cytokine production. The NIH recommends against the use of nitazoxanide for the treatment of COVID-19, except in a clinical trial [38]. Interestingly, multiple clinical trials highlighted the role of nitazoxanide in reducing the risk of COVID-19 progression, decreasing the median time for clinical recovery, and reducing the SARS CoV-2 viral load [53,54,55]. Indeed, the nitazoxanide/azithromycin combination has been suggested as a new protocol for early management of COVID-19 [56].

Nitazoxanide is a well-tolerated drug; however, it is associated with some side effects, including nausea, vomiting, and abdominal pain, and urine and ocular discoloration (rare). Nitazoxanide is highly bound to plasma protein (>99.9%); therefore, drug-drug interactions may occur when nitazoxanide is concurrently administered with other highly plasma protein-bound drugs due to the competition for plasma protein binding sites [57].

Azithromycin is a macrolide broad-spectrum antibiotic that mediates its anti-bacterial effects via protein synthesis inhibition [58]. It has shown anti-viral activity against multiple viruses, including Ebola and Zika viruses [58,58,59,60]. However, its anti-viral mechanism is not yet clearly identified [60]. Moreover, macrolides have been shown to exhibit an anti-inflammatory effect [61, 62].

As regards COVID-19, which is characterized by exacerbated inflammation, azithromycin was shown to suppress pro-inflammatory cytokine production. It also inhibits T cells by inhibiting calcineurin signaling, mammalian target of rapamycin activity (mTOR), and NFB activation [63].

The NIH, the IDSA, and the NICE guidelines do not recommend azithromycin for the treatment of COVID-19 in the absence of other indications [38,39,40].

Adverse effects include allergy, hepatotoxicity, QT prolongation, ventricular tachycardia, and gastrointestinal upset, which need to be taken into consideration, especially in the outpatient setting where frequent ECG monitoring may not be possible [39]. Although azithromycin has a minimal risk for cytochrome P450 interactions, serious drug interactions with other antivirals or drugs that induce QT interval prolongation should be considered [39].

It is a RdRp inhibitor like remdesivir. It is a prodrug purine analog, and its activated phosphor-ribosylated form (favipiravir-RTP) inhibits viral RNA polymerase activity and genome replication [64]. Favipiravir was approved in 2014 for the treatment of influenza viruses in Japan [64, 65]. Due to the urgency of the situation of COVID-19, favipiravir was repurposed and used (off-label) for the treatment of mild non-hospitalized cases of COVID-19 [66, 67]. However, the NIH, the IDSA, and the NICE guidelines do not recommend or approve using favipiravir for COVID-19 treatment.

In vitro studies revealed that favipiravir may be effective against SARS-CoV-2 [66]. Nevertheless, there is controversy regarding its effectiveness against COVID-19 in clinical trials [67, 68]. A meta-analysis showed that favipiravir reduced the mortality rate by 30%, but this finding was not statistically significant. Moreover, favipiravir treatment induced a significant clinical improvement compared to the control group after 7 days post-hospitalization. On the other hand, after 14 days post-hospitalization, clinical improvement was 10% higher in the favipiravir group, but this finding was also not statistically significant [69]. Clinical evidence supports the safety and tolerability of short-term use of favipiravir [67]. The most reported adverse effect of favipiravir is the elevation of liver transaminases, bilirubin, and uric acid, as well as gastrointestinal disturbances, chest pain, and teratogenicity; therefore, it is contraindicated in pregnancy [70].

Lopinavir/ritonavir is a protease inhibitor approved by the FDA in 2000 for the treatment of HIV [71]. Ritonavir is added as it is a cytochrome P450-3A4 inhibitor to slow lopinavir metabolism. This combination exhibited in-vitro inhibition of SARS-CoV-1 and MERS-CoV replication [72, 73] and reduced ARDS mortality in clinical trials [74].

In the early phase of COVID-19, a triple combination of interferon beta-1b, ribavirin, and lopinavir/ritonavir shortened the duration of hospital stay in patients with mild to moderate COVID-19 in an open-label, randomized, phase II trial [75].

Lopinavir/ritonavir did not show clinical efficacy among non-hospitalized patients with COVID-19 in two RCTs [76, 77]. The NIH and the IDSA strongly recommend against the use of lopinavir/ritonavir for the treatment of COVID-19 in hospitalized or non-hospitalized patients or for post-exposure prophylaxis [38, 39].

The most common reported side effects include nausea, vomiting, diarrhea, abdominal pain, loss of appetite, bloating, metallic taste, paresthesia, itching, prolonged QT interval, and hepatotoxicity, in addition to drug interactions due to its CYP3-A4 inhibiting activity [39].

Chloroquine and its analog hydroxychloroquine, are used to treat malaria as well as autoimmune diseases like systemic lupus erythematosus and rheumatoid arthritis due to their effect on cytokines like IL-1 and IL-6 [78]. Evidence suggests that these agents may exhibit an effect against multiple viruses, including coronaviruses [79].

They have shown in vitro activity against SARS-CoV-2 within the range of predicted achievable tissue concentrations. This in-vitro effect, the wide use for other diseases, and the common availability of the drug made it a great option for the treatment of COVID-19 [41, 80, 81].

Chloroquine increases the endosomal pH, thus inhibiting the fusion between SARS-CoV-2 and the cell membrane [78]. It also inhibits glycosylation of the ACE2 receptor, which interferes with virus binding [81]. In vitro studies suggest that chloroquine and hydroxychloroquine block the transport of SARS-CoV-2 from endosomes to endolysosomes, thus possibly preventing the release of viral genetic material [82]. Also, hydroxychloroquine inhibits the cytokine storm induced by SARS-CoV-2 via suppressing T-cell activation [83].

However, the NIH and the IDSA guidelines recommend against the use of chloroquine and hydroxychloroquine for the treatment of COVID-19 in hospitalized or non-hospitalized patients due to the lack of clinical benefit among the different RCTs established [38, 39].

Adverse effects of both chloroquine and hydroxychloroquine are nausea, vomiting, dyspepsia, abdominal pain, pruritis, skin rash and discoloration (contraindicated in psoriasis), retinal degeneration and corneal opacities, quinidine-like action with QT prolongation, and hemolytic anemia in G6PD-deficient subjects. In addition to the reported drug interactions, including CYP-2D6 inhibition leading to decreased antiviral activity of remdesivir, therefore, co-administration of these drugs is not recommended [39].

It is an anti-parasitic FDA-approved drug used in diseases like onchocerciasis, head lice, scabies, strongyloids, ascariasis, and filariasis. It is also used in malaria by killing the mosquito, thus preventing the transmission of the infection [84]. Its antiparasitic mechanism is the opening of glutamate-gated and gamma-aminobutyric acid (GABA)-gated chloride channels, leading to an increase in chloride ion conductance, which induces motor paralysis in parasites. However, its mechanism in COVID-19 infection is different; it inhibits the virus binding to the host cell membrane via interfering with ACE-2 receptors and reducing virus/cell fusion [85]. It also inhibits viral nuclear accumulation by blocking the importin / protein receptor, which is responsible for the nuclear transport of viral proteins, leading to an efficient antiviral response [86].

Ivermectin was reported to have an anti-inflammatory effect, which was useful in COVID-19 patients [87,88,89]. Despite having in vitro activity against viruses, e.g., HIV, yellow fever, Zika virus, and dengue fever, no clinical trials have reported clinical significance [90, 91].

In April 2020, the FDA issued a statement concerning the self-administration of ivermectin against COVID-19 and highlighted that those in vitro studies are not sufficient and further trials are needed to confirm the safety and efficacy of ivermectin for its use in COVID-19 patients [92].

The NIH, the NICE, and the IDSA guidelines do not recommend ivermectin for the treatment of COVID-19 except in clinical studies [38,39,40]. Ivermectin is tolerated; adverse effects of ivermectin include dizziness, pruritis, nausea, or diarrhea [38, 39].

The target of this group is to decrease the viral load in the upper and lower respiratory airways of the infected host, resulting in reduced virus-induced pathology [93, 94]. This group includes anti-SARS-CoV-2 monoclonal antibodies, convalescent plasma, and SARS-CoV-2 specific immunoglobulins.

They target the S protein, the main protein used by the virus to attach and fuse to the human cell membrane, thus blocking viral entry into host cells. There are 5 anti-SARS-CoV-2 mAbs, including 3 double mAbs, which are bamlanivimab/etesevimab, casirivimab/imdevimab (REGEN-COV), and tixagevimab/cilgavimab (Evusheld), and 2 single mAbs, which are sotrovimab and bebtelovimab [93].

Bamlanivimab (700 mg)/etesevimab (1400 mg) is administered as a single IV injection. They bind to different (but overlapping) epitopes of the S-protein receptor binding domain (RBD). Reported adverse effects of bamlanivimab/etesevimab are nausea, dizziness, pruritis, and hypersensitivity reactions (anaphylaxis and infusion-related reactions) [95].

Casirivimab (600 mg)/imdevimab (600 mg) is administered as a single IV or subcutaneous (SC) injection. They bind to non-overlapping epitopes of the S protein RBD of SARS-CoV-2. Allergic and injection site reactions are the most common adverse effects encountered with casirivimab/imdevimab [96].

Sotrovimab was originally identified in 2003 from SARS-CoV survivors derived from memory B-cells. It is administered at a dose of 500mg as a single IV infusion. It binds to a conserved epitope on the S-protein RBD of SARS-CoV-2. The reported adverse effects include rash, diarrhea, anaphylaxis, and infusion-related reactions [97].

Tixagevimab co-packaged with cilgavimab (Evusheld) represent other monoclonal antibodies that can bind to non-overlapping epitopes of the S-protein RBD. These drugs were the first FDA-authorized anti-SARS-CoV-2 monoclonal antibodies for the pre-exposure prophylaxis of COVID-19 in adults and pediatric individuals (12 years). Evusheld is administered as an initial dose of tixagevimab (300 mg) and cilgavimab (300 mg) as 2 separate consecutive intramuscular injections, followed by the repeat dosage of tixagevimab (300 mg) and cilgavimab (300 mg) every 6 months. The most frequently encountered adverse effects of Evusheld were headache, fatigue, cough, hypersensitivity reactions, and anaphylaxis [98].

Between November 2020 and February 2022, multiple anti-SARS-CoV-2 monoclonal antibodies were FDA-authorized for the treatment/prevention of COVID-19 in adults and pediatric patients (12 years of age) [95,96,97,98,99]. Unfortunately, the extensive mutations of the S protein of the Omicron variant and the subsequent high prevalence of Omicron subvariants resulted in a marked resistance to the action of the therapeutic neutralizing mAbs. Consequently, all clinically authorized therapeutic mAbs targeting the Omicron variant, especially the BQ and XBB subvariants, have been rendered ineffective and are no longer FDA-authorized for treatment, pre-exposure, or post-exposure prevention of COVID-19 [100,101,102,103,104].

The updated guidelines (NIH, IDSA, and NICE) recommend against the use of anti-SARS-CoV-2 neutralizing monoclonal antibodies for the treatment or post-exposure prophylaxis against COVID-19. Only the NICE guideline still recommends sotrovimab as an option for the treatment of COVID-19 in adult and pediatric (12 years) patients with an increased risk of disease progression only if Paxlovid treatment is not applicable [38,39,40].

For years, the CP has been used for the treatment of many severe acute viral infections, such as SARS, MERS, and influenza outbreaks, and recently in the treatment of COVID-19 [105]. CP is collected from patients who have recovered from a viral infection to transfuse virus-neutralizing antibodies (Abs) to give the recipient a sort of passive immunity [106]. The main components of CP are neutralizing antibodies (IgM and IgG), clotting factors, anti-inflammatory cytokines, protein C, and protein S, which help to ameliorate the infection [107].

Anti-SARS-CoV-2 neutralizing Abs in CP might have multiple potential mechanisms of action in COVID-19. The Abs are directed against the RBD of the S protein to interfere with its interaction with the ACE2 receptor, thus preventing viral entry into the host cell. Abs in CP also inhibit the complement factors C3a and C5a and decrease immune complex formation [108]. The transfused IgG in CP can also neutralize cytokines such as IL-1 and TNF and limit the inflammatory response triggered by excessive complement activation. Additionally, CP is found to enhance dendritic cell anti-inflammatory functions, which could be important in cases of excessive inflammation due to infection [109].

The NIH and the IDSA guidelines recommend against the use of CP for the treatment of COVID-19 in hospitalized patients, especially if this CP was collected prior to the emergence of the Omicron (B.1.1.529) variant [38, 39].

Adverse effects of CP are transfusion reactions such as allergic reactions, anaphylactic reactions, febrile nonhemolytic reactions (<1% of all transfusions) [39], transfusion-associated circulatory overload, transfusion-related acute lung injury, transfusion-transmitted infections (e.g., HIV, hepatitis B, hepatitis C), hypothermia, metabolic complications, and post-transfusion purpura [110,111,112].

Intravenous immunoglobulin (IVIg) is used as an adjunctive treatment for many diseases, including, but not limited to, GuillainBarre syndrome, myasthenia gravis, immune-cytopenias, vasculitis, SLE, and Kawasaki syndrome. Also, they have been used in the treatment of some infections, such as the Parvovirus B19 infection [113]. A systematic review of four clinical trials and three cohort studies concluded that the use of IVIg in the critical subgroup (ARDS, sepsis, septic shock requiring MV) could decrease mortality compared to the control group, but no significant differences were reported in the severe (respiratory rate>30 BPM, PaO2/FiO2300mmHg) or non-severe subgroups [114].

Currently, no sufficient clinical data is available on the use of these agents in COVID-19. The NIH recommends against using SARS-CoV-2-specific immunoglobulin for the treatment of patients with acute COVID-19. Potential risks may include transfusion reactions. Theoretical risks may include antibody-dependent enhancement of infection [38].

COVID-19 is characterized by an exacerbated inflammatory response with an increased incidence of a cytokine storm which represents the major mechanism of organ damage in COVID-19. Hence, anti-inflammatory/immunomodulator drugs may be of immense importance in the management of COVID-19-associated inflammatory damage. In this section, we discuss the most widely used anti-inflammatory/immunomodulator drugs during the COVID-19 pandemic.

Patients with COVID-19 could experience a systemic inflammatory response that may cause lung injury and multi-organ dysfunction; corticosteroids, with their known effective anti-inflammatory action, are thought to prevent these outcomes. Favourable effects were reported with the use of corticosteroids in patients with lung infections like Pneumocystis jirovecii pneumonia with hypoxemia [115]. Using corticosteroids in patients with ARDS accelerated clinical improvement and reduced mortality rates [116, 117].

This class is used for the control of many auto-immune diseases and to maintain graft survival after organ transplantation due to their strong anti-inflammatory properties. They were found to be beneficial with COVID-19, especially in hospitalized patients who required O2 therapy, mostly due to their role in ameliorating the COVID-19-induced systemic inflammation [118].

The NIH, the IDSA, and the NICE guidelines recommend the use of dexamethasone in hospitalized patients with severe COVID-19 [38,39,40]. The recommended dose of dexamethasone is 6mg IV or PO for 10days or until discharge. If it is not available, an alternative corticosteroid with an equivalent dose may be used, such as prednisone 40mg, methylprednisolone 32mg, or hydrocortisone 160mg, which are used in the management of shock in COVID-19 patients (as dexamethasone lacks mineralocorticoid activity, which renders it less effective for sodium and fluid retention) [119]. The pediatric dose of dexamethasone is 0.15mg/kg/dose (maximum dose: 6mg) once daily for up to 10days [38].

Patients receiving a short course of steroids may experience hyperglycemia, neuropsychiatric symptoms, an increased risk of opportunistic fungal infections (e.g., mucormycosis, aspergillosis), and reactivation of latent infections (e.g., HBV, herpesvirus infections, tuberculosis). Patients who are receiving inhaled corticosteroids may develop oral candidiasis [119]. During corticosteroid treatment, we should monitor patients (especially if taken with other immunosuppressant drugs) for adverse effects with systemic forms like opportunistic infections such as mucormycosis [120, 121] and dormant infections [38].

Mucormycosis, or the deadly black fungus, is a life-threatening fungal infection caused by mucormycetes. It has been associated with conditions where low immunity takes place, such as in the case of diabetes, neutropenia, organ transplantation, burns, hematological malignancies, steroid use, IV drug usage, renal disease, and the use of broad-spectrum antibiotics. It is becoming common among COVID-19 patients, where factors such as high body temperature, high osmolarity, and hypoxia are present. Moreover, wearing O2 masks or being on a ventilator could provide an entry path to the body for the fungus [122].

Treatment of mucormycosis associated with COVID-19 does not differ from non-COVID patients. Treatment options include early and aggressive surgical resection and debridement of the affected tissues. The drug of choice for first-line therapy of mucormycosis is liposomal amphotericin B. It needs to be initiated early and is strongly recommended at a dose of 5 mg/kg per day in 200 ml of 5% dextrose over 23 h for 36 weeks [123]. Other antifungals, such as posaconazole or isavuconazole, have also been described for the treatment of mucormycosis associated with COVID-19[124].

Interleukin-6 is a pro-inflammatory cytokine released by inflammatory cells such as lymphocytes and monocytes and is found to be produced in excessive amounts by the epithelial cells during SARS-CoV infection [125].

It is thought that by modulating the extent of IL-6 activity, the course of COVID-19 illness, duration, and severity could be modified. Tocilizumab and sarilumab are humanized anti-interleukin-6 receptor mAbs that are thought to exhibit potent anti-inflammatory effects with improvements in morbidity and mortality in patients with COVID-19 [38].

In December 2022, tocilizumab was FDA-approved for the treatment of COVID-19 in hospitalized adults who require supplemental O2, mechanical ventilation, or ECMO [126]. NIH, IDSA, and NICE guidelines recommend the use of tocilizumab in addition to dexamethasone for the treatment of hospitalized patients with progressive severe or critical COVID-19 who have elevated markers of systemic inflammation. Sarilumab could be used if tocilizumab could not be used [38,39,40].

Indeed, multiple trials demonstrated that tocilizumab treatment did not exhibit clinical improvement in patients with COVID-19-associated pneumonia, with concerns regarding its safety [127,128,129]. On the other side, multiple studies demonstrated that tocilizumab plus standard of care therapy was associated with a significant reduction in progression to mechanical ventilation and death [130]. In general, tocilizumab is not recommended as routine therapy for patients with COVID-19; rather, it should be considered for selected critical cases [43].

Tocilizumab and sarilumab adverse effects include elevated liver enzymes (dose-dependent), infusion-related reactions, and hypersensitivity reactions [131,132,133]. Other adverse effects, such as a runny nose, sore throat, sinus infection, headache, and increased blood pressure, were reported. Very rarely, GIT perforations may occur [133].

These mAbs actively cross the placenta with the greatest level in the third trimester and may affect the immunity of the fetus, however, no sufficient data indicates whether they lead to abortion or major birth defects or not. Hence, currently, it is not recommended to use them during pregnancy, and there is no sufficient data for justification of their use in children [134].

Tocilizumab and sarilumab should be used cautiously in patients who are immunosuppressed or receiving immunosuppressive drugs, their ALT levels>5 times the upper limit of normal, are at elevated risk for gastrointestinal perforation, have an uncontrolled serious infection other than COVID-19, their absolute neutrophil counts<500 cells/L, their platelet counts<50,000 cells/L, or the presence of hypersensitivity to these drugs [131, 132].

The endogenous IL-1 is found to be elevated in COVID-19 patients [135, 136]. Il-1 released due to respiratory epithelial damage leads to the recruitment of inflammatory cells with more generation of pro-inflammatory cytokines. IL-1 receptor blockers such as anakinra or drugs that block IL-1 signalling like canakinumab can interrupt this cycle and are under investigation for COVID-19 [137].

Anakinra is a recombinant human IL-1 receptor antagonist. It is FDA-approved for the treatment of rheumatoid arthritis and cryopyrin-associated periodic syndromes [138]. The NIH does not recommend for or against its use in COVID-19 due to the limited clinical evidence [38]. The IDSA guideline suggests against its routine use in hospitalized patients with severe COVID-19 [39]. In November 2022, anakinra was FDA-authorized for the treatment of COVID-19 in hospitalized adults with pneumonia requiring supplemental O2 who are at high risk of disease progression and have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR) [139].

With anakinra, there is an increased risk of infection reported if this drug is used with TNF- blockers for a prolonged time, but not with short-term use. Headache, nausea, vomiting, and elevation of liver enzymes are commonly reported side effects of anakinra [140]. The American College of Rheumatology (ACR) recommends against the use of anakinra during pregnancy [141].

Canakinumab is a human monoclonal antibody against the beta subunit of IL-1. It is FDA-approved for the treatment of systemic juvenile idiopathic arthritis and Stills disease. Its common adverse effects are hypersensitivity reactions, neutropenia, nasopharyngitis, headache, abdominal pain, nausea, vomiting, diarrhea, musculoskeletal pain, injection site reactions, and elevation of liver enzymes with an increased risk of infections, including respiratory tract infections, bronchitis, gastroenteritis, and pharyngitis [142]. Due to the lack of clinical evidence, the NIH recommends against the use of this agent for the treatment of COVID-19 [38].

Cytokines play key roles in controlling cell functions like cell growth, survival, and immune response. They work by activating specific cytokine receptors that rely on the Janus kinase family in their signal transduction. Janus kinase acts through the phosphorylation of activated cytokine receptors, which in turn activate the signal transducer and activator of transcription (STAT) proteins, which modulate gene transcription [143]. Accordingly, inhibiting Janus kinase activity will lead to the blockade of cytokine signalling, thus decreasing the immune response in many diseases, such as rheumatoid arthritis [144]. As COVID-19 is characterized by a cytokine storm, the use of Janus kinase inhibitors may play a role in decreasing such a hyperinflammation state to achieve clinical improvement for COVID-19 patients.

Baricitinib is FDA-approved for the treatment of rheumatoid arthritis [145]. It acts through inhibition of JAK1/JAK2, thus inhibiting the inflammatory cascade; it also shows inhibition of IL-6-induced STAT3 phosphorylation. Additionally, it has a direct antiviral effect through inhibition of viral entry into the host cell [146].

In May 2022, baricitinib was FDA-approved for the treatment of COVID-19 in hospitalized adults requiring supplemental O2, mechanical ventilation, or ECMO [147]. The NIH, IDSA, and NICE guidelines recommend the use of baricitinib in addition to dexamethasone (or remdesivir) for the treatment of hospitalized adult and pediatric (2 years) patients with severe COVID-19 [38,39,40].

Adverse effects of baricitinib may include hypersensitivity reactions, infections such as respiratory and urinary tract infections, reactivation of herps, myelosuppression, thrombosis, elevation of liver enzymes, GIT perforation (in rare cases), and serious cardiac-related events (myocardial infarction and stroke). Baricitinib needs dose adjustment in renal patients. It is a CYP-3A4 substrate with drug interactions with CYP-3A4 inducers and inhibitors [146].

Tofacitinib is another JAK inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis [148]. Its use was associated with serious adverse reactions, including cardiovascular events, stroke, and death [149]. It is also a CYP-3A4 substrate, so the dose should be monitored in cases where it is co-administered with CYP-3A4 inhibitors, and it is not recommended to be used with CYP-3A4 strong inducers [149]. A complete blood count and liver and kidney functions should be requested before initiating JAK inhibitors. Screening for viral hepatitis and tuberculosis is recommended [150].

The NIH guideline states that oral tofacitinib could be used instead of oral baricitinib if baricitinib therapy is not applicable [38]. The IDSA guideline suggests tofacitinib for hospitalized adults with severe COVID-19, not on mechanical ventilation [39].

The activation of complement pathways is thought to play pivotal roles in immune activation and cellular damage manifested in COVID-19. The complement component C5a is a potent anaphylatoxin that attracts neutrophils, macrophages, and monocytes to the site of infection, which triggers tissue damage via oxidative radical formation, histamine release, and exaggerated cytokine release [151]. Vilobelimab is a monoclonal antibody against C5a that is thought to reduce immune system activation through inhibition of lung injury [38].

In April 2023, vilobelimab was FDA-authorized for the treatment of hospitalized adults with severe COVID-19 when initiated within 48h of receiving invasive mechanical ventilation, or ECMO [152]. Due to insufficient evidence, the NIH guideline does not recommend either for or against the use of vilobelimab for the treatment of COVID-19 [38].

The commonest adverse effects of vilobelimab included pneumonia, sepsis, and infections such as herpes simplex, enterococcal infection, and bronchopulmonary aspergillosis, in addition to pulmonary embolism, deep venous thrombosis, hypertension, thrombocytopenia, elevated liver enzymes, and rash [38].

NSAIDs were often used in the early stages of the COVID-19 pandemic to treat fever, body aches, and headaches, which are frequently encountered symptoms in COVID-19 patients [153]. However, at that time, some reports suggested that the use of NSAIDs was linked to worsened infection severity and poorer clinical outcomes, which was postulated to be due to the upregulation of angiotensin-converting enzyme (ACE) 2 expression, which may facilitate viral host cell invasion [23, 154]. Over time, and with the emergence of many well-designed studies, it was revealed that NSAIDs do not influence the expression of this enzyme [155], and it was shown that there is no evidence supporting these assertions; this is reflected in the current recommendations from the major authorities across the world, which encourage the use of NSAIDs as analgesics and antipyretics during COVID-19 [153]. Many studies reported favorable effects of ibuprofen in attenuation of symptoms, reduction of hospital length, incidence of ICU admission, and improvement of leucocytic/lymphocytic count in patients with COVID-19 [156, 157].

Colchicine is an anti-inflammatory drug used in diseases like gout, pericarditis, and familial Mediterranean fever (FMF) [158]. It was also shown to reduce cardiovascular events in patients with coronary artery disease [159]. Colchicine disrupts microtubule assembly, thus inhibiting neutrophil chemotaxis. It also inhibits inflammasome signalling and decreases cytokine formation like IL-6 and IL-1 [160]. Having these anti-inflammatory properties added to its relative safety and limited immunosuppressive effects favored the use of colchicine in the early times of the COVID-19 pandemic. However, at the current time, the NIH, IDSA, and NICE guidelines recommend against the use of this agent for the treatment of COVID-19 [38,39,40].

Colchicine has side effects like nausea, vomiting, diarrhea, and abdominal cramping, but, in rare cases, it may cause neurotoxicity, myopathy, and bone marrow depression. It should be avoided in patients with severe renal insufficiency, and it should be monitored in patients with moderate renal insufficiency. Colchicine should be cautiously used with other drugs that are CYP-3A4 or P-glycoprotein inhibitors, as such interaction will increase the level of colchicine in plasma, raising the risk of adverse effects. There is an increased risk of myopathy if co-administrated with statins due to competition on the CYP-3A4 and P-glycoprotein pathways [160, 161].

It crosses the placenta, and due to its anti-mitotic effect, it was thought to have a teratogenic effect; however, a meta-analysis concluded that the use of colchicine during pregnancy did not cause major fetal malformations [162].

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