POTENTIAL/CURRENTLY USED COVID19 THERAPEUTICS
Version 1: 01-04-2020
Please note that there are currently no clear guidelines for antiviral therapies for COVID-19. The following summaries have been compiled based on studies currently available, and the recommendations are rapidly evolving as studies and clinical trials results are published. There also many more drugs that are currently being investigated – the drugs mentioned here are the most commonly mentioned (other than Teicoplanin). To further read the studies cited please refer to references below.
BEFORE use of investigational or off-label medicinal drugs ensure you have:
Provided patient optimal supportive care
Informed patient about uncertain efficacy and toxicities of drugs
Received consent (oral or signed)
MAJOR DRUGS CONSIDERED IN COVID-19 TREATMENT
A major question is whether corticosteroids are recommended as a systemic adjunctive treatment. Current interim guidelines from WHO (Jan 28th, 2020) recommend against corticosteroid use (unless required for another associated condition such as chronic obstructive pulmonary disease, asthma and autoimmune disease (in which case corticosteroids is considered a supported component of treatment). For example, low dose corticosteroids may be indicated in the case of advanced stage disease, high IL-6, and lack of response to tocilizumab. 
Evidence for COVID-19 treatment:
A review published in The Lancet on Feb 7th 2020 by Russell et al., examined literature for evidence for and against use of steroids, and found that patients with COVID-19 infections will not benefit from steroids, and indeed may be more likely to be harmed. Corticosteroids were found to delay clearance of MERS and SARS-CoV viral RNA and cause complications in SARS-CoV and Influenza patients. In a retrospective observational study conducted on 309 patients who were critically ill with MERS, patients who were given corticosteroids were more likely to be placed on mechanical ventilation, and require vasopressors, nitric oxide, neuromuscular blockers, and renal replacement therapy.
Should inhaled corticosteroids be used for COPD/Asthma in COVID-19 patients?
On March 17th 2020, Massachusetts General Hospital released a COVID-19 Treatment Guidance document. It recommends discontinuing inhaled corticosteroids as it suppresses the immune system plus promotes viral replication, and therefore should only be used in acute exacerbations.
A non peer-reviewed paper published by Matsuyama et al. found through screening a chemical library that Ciclesonide, an inhaled corticosteroid, suppressed human coronavirus replication in cultured Vero cells whereas the normally prescribed systemic steroids, such as cortisone and prednisolone (systemic steroids) and fluticasone (an inhaled corticosteroid) did not. However, the authors state that the drug suppressed anti-viral activity similar to the efficacy of lopinavir. Given the mixed results that have been found with lopinavir/ritonavir treatment, the evidence from this study is not conclusive. However, for situations in which patients may need inhaled corticosteroids, this could be considered an alternative treatment option for acute exacerbations.
NEURAMINIDASE INHIBITOR TREATMENT (E.G. OSELTAMIVIR/TAMIFLU)
Treatment of SARS-CoV-2 with neuraminidase inhibitors is controversial. BMJ best practice guidelines published on March 12th 2020 asks to consider treatment until influenza is ruled out based on WHO guidelines. If no confirmed influenza infection and confirmed COVID19 would discontinue neuraminidase inhibitors, given no evidence of efficacy. 
Chloroquine phosphate is a broad-spectrum antiviral drug traditionally used in the treatment of malaria, as well as an anti-inflammatory agent used in rheumatoid arthritis and SLE. On Feb 17th 2020, China State Council announced that the drug has marked safety & efficacy in COVID-19 treatment associated pneumonia validated through multi-centre trials.  Based on current guidelines for several European countries, chloroquine (and more so hydroxychloroquine) is usually considered the first choice treatment for mild/moderate to severe COVID-19 disease (though Remdesivir appears to be preferred for more critical disease), due to its “defined safety profile as an antimalarial drug”.
Mechanism of action: There are multiple mechanisms through which chloroquine may work against viruses. It may prevent virion-binding to cell surface receptors, [7,9] inhibit pH-dependent endosome-mediated viral entry as well as interfere with post-translational modification of viral proteins. For detailed review of mechanisms please refer to review published by Deveaux et al.
Evidence for COVID-19 treatment:
In vitro studies: Chloroquine has been tested against SARS-CoV-2 in African green monkey kidney (Vero) cells and was found to prevent viral entry at low-micromolar concentration (EC50 value of chloroquine against the virus was 6.90 µM which can be achieved clinically in patient’s plasma with a dosage of 500 mg as seen in rheumatoid arthritis patients).
Clinical Studies: There have been ~20 clinical trials (consisting >100 patients) conducted in China to study the efficacy of chloroquine (and hydroxychloroquine) in 10 hospitals in China. Chloroquine phosphate was found to reduce pneumonia exacerbation, reduce fever, improve lung computed tomography (CT) images, increase virus-negative conversion, and decrease the duration of the disease.
Administration Dosage: Chloroquine base: 600 mg (10 mg/kg) at diagnosis, 300 mg (5mg/kg) BID upto day 5. Chloroquine phosphate: 1000 mg at diagnosis and 500 mg 12 hrs later, followed by 300 mg BID.
Hydroxychloroquine is an analog of chloroquine, with the same mechanism of action and a similar pharmacokinetic profile. The major structural difference is the presence of a hydroxyl group. Compared to chloroquine, hydroxychloroquine is more potent, and therefore lower dosages can be used. Even though there have been no in vivo experiments or clinical trials been conducted for hydroxychloroquine, because of the low dosage, similarity to chloroquine, and the fact that therapy is usually required for older patients and/or those with more severe disease, hydroxychloroquine is preferred to chloroquine.
Mechanism of action: Antiviral mechanism is similar to chloroquine. It also works by controlling the cytokine storm in critically ill SARS-CoV-2 infected patients.
Administration Dosage: 400 mg BID P.O., maintenance dose 200 mg BID for 4 days  (Please note this varies very slightly compared to the dosage recommended by the Belgian guidelines - which recommends second dose on the first day to be 12h later from initial dose).
Evidence for COVID-19 treatment:
In vitro studies: A study by Yao et al. tested the pharmacological activity of chloroquine and hydroxychloroquine in vitro in SARS-CoV-2-infected Vero cells. They found that hydroxychloroquine had EC50 of 0.72 µM making it more potent than chloroquine.
Clinical studies: Clinical trials are currently ongoing for hydroxychloroquine.
Remdesivir is a novel broad-spectrum antiviral drug that works against filoviruses, coronaviruses, and paramyxoviruses (e.g. resp syncytial viruses). It is NOT authorized in any country; however, it is currently used in clinical trials or through compassionate use. It has been investigated previously in non-human primates for the treatment of Ebola virus infections. Based on current evidence remdesivir appears to be one of the more promising drugs for the treatment of COVID-19. It is currently recommended as the first-choice drug for use in severe and critical COVID-19 disease in countries such as Belgium, Italy, France, and Switzerland.
Mechanism of action: Remdesivir is an analog of adenosine triphosphate. It inhibits RNA polymerases by integrating into viral RNA chains and resulting in early RNA termination.
Evidence for COVID-19 treatment:
In vitro studies: Studies conducted in Vero cells found that the EC90 value of remdesivir was 1.76 µM. Based on previous studies against Ebola in non-human primate models, the authors suggest that this EC90 value can be achieved in nonhuman primates to block SARS-CoV-2 post-infection.
In vivo studies: Studies conducted with MERS CoV-infected humanized transgenic mice found that remdesivir significantly reduced viral loads in lung tissue, reduced lung hemorrhage, and acute lung injury.
Clinical Studies: Furthermore, recently a patient in US was successfully treated with Remdesivir; the patient had mild/moderate symptoms upon presentation (cough, subjective fever), previous history of hypertriglyceridemia, and rhonchi, but otherwise had no other abnormalities. On the 5th day, his respiratory status dropped to 90% and imaging found evidence of pneumonia. Upon treatment with supplemental Oxygen (2L/min) and IV Remdesivir on day 7, the patient successfully recovered from the disease. There is currently a phase III double blind, multicenter trial being conducted using COVID-19 patients in China. Patients in the experimental group are receiving 200 mg of remdesivir following by 100 mg for 6 days via IV (+ routine treatment). Patients in the control group receive routine treatment + placebo. Results are expected to be published in April 2020.
Lopinavir/ritonavir are protease inhibitors used for HIV patients (adults and children >14 years). Since the outbreak of the novel coronavirus, LPV/r has been of potential interest for treatment. However, the evidence for LPV/r treatment has been mixed. There are current guidelines for countries such as Belgium, Italy, France to use LPV/r as a second- or third-line treatment, but given the currently rapidly evolving recommendations (especially the recently published NEJM randomized control trial results) these guidelines may change.
Evidence for COVID-19 treatment:
In vivo studies: Studies conducted comparing LPV/r-IFNβ in MERS-CoV humanized transgenic mice found that LPV/r-IFNβ treatment only modestly reduced viral loads and did not reduce lung hemorrhage or acute lung injury. Compared to LPV/r-IFNβ, remdesivir reduced lung injury as evidenced by decreased cellular debris and inflammatory cells when compared to controls. A pathological hallmark of acute lung injury is the diffuse alveolar damage (DAD) score, which was significantly reduced in remdesivir but not in LPV/r-IFN treatment.
Clinical Studies: To note, as of 18th March 2020, a randomized, control trial of 199 patients published in NEJM comparing LPV/r to standard treatment found no significant difference in time to clinical improvement and reduction in viral loads. There was a slight decrease in mortality in the treatment group, however these results could be confounded by the fact that the standard treatment group was sicker at baseline compared to the treatment group.[15,16]
Arbidol is a small indole-derivative molecule used to treat influenza A and B. It is also being considered for treatment of COVID19-pneumonia, however the current evidence for use is very limited.
Mechanism of action: Arbidol inhibits viral fusion and entry into target cells.
Evidence for COVID-19 treatment:
Clinical studies: A retrospective cohort study conducted on 69 patients in Wuhan between January 16th and 29th 2020 found that Arbidol appeared to decrease the discharge and mortality rate in patients in mild- severe disease categories (severe = Sp<90%). All the patients who died were in the arbidol-treated group. The study found that 12 of 36 patients were discharged in the arbidol-treated group, compared to 6 of 31 patients in the non-treated group. The study recommends conduction of a randomized control trial to assess safety and efficacy of the use of the drug before incorporating it into SARS-CoV-2 treatment.
Another retrospective cohort study of 111 patients assigned 49 patients to empiric treatment + Arbidol group and 62 patients to empirical regimens only. They found that Arbidol reduced the need for high flow nasal catheter oxygen therapy, improved focal absorption on radiological images, and enhanced viral clearance. These effects were more predominant in patients with mild illness.
A study conducted in 33 adults between Jan 17th and Feb 13th 2020 compared giving combination therapy (Arbidol + LPV/r) versus monotherapy (oral LPV/r) for 5-21 days. They assessed outcome through negative viral conversion rates on days 7 & 14, and CT outcomes on day 7. After 14 days, SARS-CoV-2 was not detected in 15 of 16 patients in the combination therapy group compared to 9 of 17 in the monotherapy group (P<0.05). CT scans improved in 11/16 patients in combination therapy compared to 5/17 in monotherapy groups after 7 days (P<0.05). One critical limitation of this study was that 1/16 (6%) received corticosteroids in the combination therapy group, whereas 7/17 (41%) in the monotherapy group received corticosteroids, which could have potentially confounded the results. Nevertheless, arbidol may be useful in reducing viral loads and abrogating formation of lesions, and information from randomized-clinical trials could be beneficial in informing COVID-19 treatment.
Tocilizumab is a humanized receptor antibody developed and approved in Japan for the use in the treatment of autoimmune diseases such as rheumatoid arthritis.
Mechanism of action: IL-6 antagonist 
Evidence for COVID-19 treatment:
In respiratory viral infections such as H5N1 Influenza and SARS, the excessive inflammatory reaction known as a cytokine storm has been found to be implicated in severe disease states such as acute respiratory distress syndrome and multiple organ dysfunction syndrome. A key characteristic of COVID-19 patients is lymphopenia. Lymphocytes, especially CD8+ T cells are critical in fighting viral infections. In a retrospective cohort study of 522 patients conducted by Diao et al., they found that the cytokines TNF-α, IL-6, and IL-10 were enhanced in COVID-19 patients, which was negatively correlated with total T cells. Chronic synthesis of IL-6 in response to an infection has been found to be pathological and contribute to dysregulated inflammation. Tocilizumab has been shown to act against the cytokine storm when used with treatments for acute lymphoblastic leukemia. Therefore, the rational for Tocilizumab is that it may help prevent the loss of T cells in COVID-19 patients through downregulation of IL-6 signaling. There is currently a multicentre, randomized control trial of tocilizumab approved for COVID-19 patients who have elevated IL-6.
In China’s preprint open source database, ChinaXiv, an abstract has recently been published, in which Xu et al. have found that treating severe or critical COVID-19 patients with Tocilizumab had significant recovery upon treatment with Tocilizumab. 15 of 20 patients had reduction in the need for oxygen therapy, lung lesion opacity decreased in 19 patients, increased C-reactive protein was reduced in 84% of patients, and lymphopenia was resolved in 50% of patients by 5th day of treatment. Importantly, 19 of the patients were discharged by a mean of 13.5 days post-initiation of treatment with Tocilizumab.
Ribavirin is a nucleoside analogue that is described to have broad antiviral properties. The current evidence for the use of ribavirin is limited. A study conducted on 41 SARS-infected patients found that ARDS and mortality was reduced in patients treated with LPV/r plus ribavirin as opposed to ribavirin treated patients only.
Favipiravir is a drug which was approved for treatment of influenza on February 15th 2020. It is a broad-spectrum antiviral drug (RNA-dependent RNA polymerase (RdRp) inhibitor), preventing replication of flavi-, alpha-, filo-, bunya-, arena-, and other RNA viruses. A multicenter clinical trial of 80 patients found that Favipiravir had more potent antiviral effect than LPV/r and less adverse effects than LPV/r. However, the study citing this clinical trial used a newspaper article as a source, and therefore these results should be taken with caution.
Teicoplanin is a glycopeptide antibiotic commonly used in treating gram-positive infections such as staphylococcal infections. Zhou and colleagues found that in coronaviruses, teicoplanin acts early in viral replication by preventing the cleavage of the viral spike protein by cathepsin L in late endosomes, preventing the release of viral RNA, and hence interrupting viral replication. These same authors recently published that this activity is preserved on SARS-CoV-2. An important finding of these studies was the concentration of drug needed to inhibit 50% of the virus in vitro was 1.66 µM, which is much lower than the concentration reached in human blood (8.78 µM for the daily dose of 400 mg). It would be useful to pursue this drug in randomized clinical trials.
CONVALESCENT PLASMA/SERUM THERAPY
On the 26th of March, it was reported that the US FDA has approved the use of convalescent plasma therapy (CP) to treat critically ill patients with COVID-19.
It should be noted that no clinical trials have been conducted for the use of CP therapy against COVID-19, but given the public health emergency, countries (as seen with the US) are considering it a treatment option for severely ill patients.
CP is a classic adaptive immunotherapy that has been used for infectious diseases for more than 100 years. Upon individuals contracting and recovering successfully from an infection such as SARS-CoV-2, their immune system would have generated virus-specific virus-neutralizing antibodies which circulate in their blood. These individuals’ blood can be drawn, screened for antibodies, and upon identification of high-titres, be transferred to high-risk confirmed COVID-19 patients for treatment or prophylaxis. Rationale for treatment with CP is based on studies from other diseases such as H1N1 influenza, SARS, and MERS which have shown passive antibody therapy reduces hospital stay and mortality.[30,34] It is also considered to be relatively cheap and has not been linked to significant adverse risks. CP has been recommended as most efficacious when used prophylactically or earlier in symptom development. Serum therapy is considered safer than plasma therapy; plasma has proteins such as albumin, fibrinogen and clotting factors which could be considered sensitizing antigens and cause further complications.
Evidence for COVID-19 Treatment:
A study conducted in China found that when 5 critically ill patients (diagnosed with ARDS as well as on mechanical ventilation, antiviral agents, and methylprednisolone) were administered convalescent plasma with a SARS-CoV-2-specific antibody (IgG) (1:1000); they had normalization of body temperature, decrease in SOFA score, increase in PaO2/FiO2, decrease in viral loads, and increase in neutralizing antibody titres. Of the 5 patients 3 were discharged from hospital, and 2 were in stable condition upon time of publishing the study.
Another non-peer reviewed study published in medRxiv found that when 10 severe COVID-19 patients were given CP, patients had maintained or increased levels of neutralizing antibody, significant increase in oxyhemoglobin saturation, varying levels of lung lesion absorption in radiography, and undetectable viral loads post-transfusion in 7 patients. Furthermore, they compared outcomes to a previous historic control group and found that outcomes were better in the CP treated group in terms of mortality and discharge. However, they recommend dosing and efficacy to be tested through randomized clinical trials.
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