In late 2019, a mysterious virus causing infection consisting of dry cough, fever tiredness, and last pneumonia first appeared in Wuhan, China. The world health organization (WHO) named the disease as Coronavirus 2019 (Covid-19). Interestingly, Covid-19 and flu (caused by influenza virus) share the common disease progression asymptomatic (no symptoms), mild symptoms fever or chills, body ache, cough, fatigue, headache, and pneumonia (fluid in the lungs). The only difference between them is shortness of breath and loss of taste and smell that appears in Covid-19 [1].

Several risk factors that contribute to severe illness may include but are not restricted to, old age, and underlying medical ailments which include respiratory disorders, asthma, heart conditions, diabetes, and a weak immune system. When the body trying to fight the infection, the immune system may go into overdrive and cause excessive immune response leading to complications and ultimately acute respiratory distress syndrome (ARDS) [1].

Symptomatic treatment for Covid-19:

A patient with mild symptoms can be managed at home and treating symptoms symptomatically. The patient should be isolated in a separate room and monitored for breathlessness.

Mild - severe Covid-19 needs hospitalization for oxygen support, intravenous drugs, and possibly ventilator support.

The main aim of available Covid-19 treatment options is to reduce viral load, improve host immune status, and breathing.

Drug Therapies Undergoing Clinical Trials

As no conclusive therapy is available for clinical management of COVID-19, existing drugs are being repurposed for treatment. The drugs used for treatment are based on three approaches: drugs that affect the virus's ability to enter inside the host cell, drugs that interfere with host immunity, and the use of antibodies. Currently, various drugs are prescribed for symptomatic management of disease (Table 1) [2].   

Antiviral drugs:

Remdesivir

Remdesivir (GS-5734; Gilead Sciences, Inc) is a broad-spectrum antiviral drug approved by US-FDA under emergency use authorization (EUA) for severe COVID-19 hospitalized cases. Two pharma companies, Cipla and Hetero introduced remdesivir (licensed from Gilead Sciences) in India under the brand name 'CIPREMI' and 'COVIFOR' for emergency use of a drug in the country. Also, the Cadila healthcare of India has launched a lyophilized Remdesivir injection (100 mg) in August 2020 [3, 4].

Favipiravir

Favipiravir, another patented antiviral drug (tested on Ebola infection) of Gilead Sciences, has been approved as EUA for treatment of COVID-19 infection is mild to moderate condition. The drug selectively blocks the enzyme responsible for the multiplication of the virus. Japan and the USA conducted phase 3 and phase 2 clinical trials of favipiravir in COVID-19 patients. Glenmark Pharma (India) announced the results of the Phase-3 clinical trial conducted on mild to moderate patients who were administered with a favipiravir tablet. The results showed 28.6% faster virus clearance in overall participants and 69.8% of patients achieved clinical cure on day 4. Currently, different brands such as 'Covihalt' (Lupin), 'PiFLU' (FDC), and 'Avigen' (Dr. Reddys) are launched in India [5, 6].

Tocilizumab

During the progression of COVID-19 from severe to critical condition, the body produces an excessive amount of proinflammatory cytokines (cytokine release syndrome) which leads to ARDS followed by shock and multiple organ failure. Therefore, to rescue sever patient Tocilizumab is approved by US-FDA for cytokine release syndrome. India approved the use of Actemra (Tocilizumab) injection only for certain COVID-19 cases [7].      

Itolizumab

In July 2020, Biocon Ltd. received the Drugs Controller General of India's node for emergency use of Itolizumab (ALZUMAb®) injection for the treatment of CRS and severe acute respiratory distress syndrome associated with COVID-19. Itolizumab, which was launched in 2013 as an anti-CD6 IgG1 monoclonal antibody for the treatment of chronic plaque psoriasis repurposed in severe COVID-19 complications. Currently, dexamethasone is under phase 3 and phase 4 trial for the treatment of hypoxia and respiratory distress syndrome.  Also, IV infusion of itolizumab is in phase 2 trial for the treatment of complications associated with Covid-19. [8].

Dexamethasone

Dexamethasone (corticosteroid) showed improved recovery rate and reduced death by one third in the UK recovery trial among hospitalized patients. The drug acts by dampening the body’s immune response which becomes too aggressive, produce cytokines and damages own body cells in many terminally ill Covid-19 patients. In June 2020, the Health Ministry of India added dexamethasone as an alternative to methylprednisolone in moderate to severe cases. Currently, the Intranasal administration of Dexamethasone is in phase 2 clinical trial as an adjuvant in Covid-19 patients [9].

Supplementary therapy

Micronutrient such as Vitamins and trace elements (Vitamin D, Vitamin C & zinc) plays a crucial role in developing and maintenance of immunity system of the body. Supplementation of vitamins and trace elements in Covid-19 treatment found to beneficial in improving clinical outcomes.

Zinc (daily intake 8 to 11 mg/day) is necessary for the maintenance of innate and adaptive immunity as increased intracellular concentration helps in impairment of virus replication and thereby prevents multiplication. Currently, various clinical trials of zinc supplementation along with other treatment option is in phase 4 and phase 2 stage [10, 11].

Daily supplementation with vitamin D (daily intake 2000 IU/day) and vitamin C (daily intake 200mg/day) reduce the risk of upper and lower respiratory tract infections. A clinical trial involving hydroxychloroquine treatment with vitamin supplementation for the prevention of Covid-19 symptoms is in phase 2 [12].

Antibiotics - Azithromycin, Ivermectin

Antibiotics such as azithromycin and ivermectin are found to be effective in the treatment of COVID-19. Ivermectin is a broad-spectrum anti-parasitic drug that displayed its efficacy against SARS-CoV2 during in vitro study. It acts by blocking the nuclear import of viral and host proteins thereby preventing viral replication inside the host.  Another drug, azithromycin (macrolide antibiotics) displayed therapeutic efficacy against SARS-CoV2 viral pneumonia in a study performed by the New Mexico University research group. However clinical trials need to be conducted on azithromycin as it can act as prophylactic in a declining rate of infection [13]. 

Hydroxycholoroquine

In the initial phase, US-FDA, EMA, or other regulatory approved drugs are available for the treatment of COVID-19 patients. On 22nd March 2020, the Indian council of medical research association (ICMR) recommended hydroxychloroquine as prophylactic for asymptomatic health care workers and an asymptomatic patient who came in contact with laboratory-confirmed patients of COVID-19. Furthermore, the FDA granted the use of chloroquine or hydroxychloroquine for the treatment of COVID-19 on March 28, 2020. However, FDA discontinued use on July 4, 2020, as it shows little or no effect on patient mortality during the trial. Both drugs block the entry of the virus by interfering with receptors present in the body for SARS-CoV-2. However, prophylactic studies of these anti-malarial drugs show benefits but they are not conclusive [14, 15]. 

Convalescent Plasma (CP) Therapy

The convalescent plasma therapy or passive antibody therapy was used first time in the treatment of the Spanish influenza pandemic that appeared from 1918 to 1920.  Therapy involves the collection of CP from previously infected patients in order to transfer antibodies to protect or treat humans from infection. After the outbreak of SARS-CoV2, researchers and healthcare professionals started searching for the possibility of CP therapy in infection. During the trial, CP has shown limited and moderate success and can be used as a short term solution for the suppression of the mortality rate. In March 2020, US-FDA approved the use of CP therapy in severe infection. Maharashtra government has launched convalescent plasma therapy-cum-trial project for treatment of critical COVID-19 in which severe patients will receive two doses of 200 ml of convalescent plasma free of cost [16].

Future Direction:

Different drug targets are presently under investigation for the treatment of Covid-19. Immunity against the virus is a major focus in these studies as the immune system helps us to fight against different viral infections. Various drugs that can improve our immunity in the Covid-19 condition are in clinical trials. Nivolumab, an anticancer drug, is in phase 2 investigation for its efficacy in adaptive immunity. Another drug, Sargramostim, is investigated for stimulating antiviral immunity action in Covid-19 and is currently in phase 2. Drugs Isotretinoin, which is used in different skin conditions is in phase 3 clinical trial for its immunity-boosting action in body. The mixture of Hesperidin and Diosmin, which improve host immunity against the virus is presently in phase 1. Apart from this, some herbal drugs such as Nigella sativa (phase 2 and 3), Ayurvedic kadha, Colchicine (phase 2), Caesalpinia spinosa (phase 2 & 3) are also being evaluated in clinical trials for their action against Covid-19.

As no specific treatment or vaccine is available for COVID-19, only symptomatic management of using antiviral drugs, immunomodulators, or plasma therapy is used by healthcare professionals. Preventions will help us to break the infection chain of the virus. To protect ourselves and family from COVID-19 wear a mask, clean your hands properly using soap and water, use alcohol-based hand sanitizers, don't touch your eyes, nose, or mouth. If you have a fever, cough, or difficulty in breathing consult your doctors. Wear a mask, stay home and save lives.

References:

1. CDC. Interim guideline of Management of Patients with confirmed Coronavirus Disease (COVID-19) CDC.
2. Chen, Y., Guo, Y., Pan, Y., & Zhao, Z. J. (2020). Structure analysis of the receptor binding of 2019-nCoV. Biochemical and biophysical research communications.
3. Wang, Y., Zhang, D., Du, G., Du, R., Zhao, J., Jin, Y., ... & Hu, Y. (2020). Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet.
4. Cipla launches Cipremi (remdesivir lyophilised powder for injection 100 mg), the only U.S. FDA approved Emergency Use Authorisation (EUA) treatment for patients with severe COVID-19 disease
5. Cai, Q., Yang, M., Liu, D., Chen, J., Shu, D., Xia, J., ... & Shen, C. (2020). Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering.
6. Glenmark becomes the first pharmaceutical company in India to receive regulatory approval for oral antiviral Favipiravir, for the treatment of mild to moderate COVID-19
7. Actemra (Tocilizumab): A New Important Identified Risk: Hepatotoxicity
8. CLINICAL MANAGEMENT PROTOCOL: COVID-19
9. The Study of Quadruple Therapy Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected With COVID-19
10. A Study of Hydroxychloroquine, Vitamin C, Vitamin D, and Zinc for the Prevention of COVID-19 Infection (HELPCOVID-19)
11. Choudhary, R., & Sharma, A. K. (2020, May 1). Potential use of hydroxychloroquine, ivermectin and azithromycin drugs in fighting COVID-19: trends, scope and relevance. New Microbes and New Infections. Elsevier Ltd.
12. WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19
13. Zou, L., Dai, L., Zhang, X. et al. Hydroxychloroquine and chloroquine: a potential and controversial treatment for COVID-19. Arch. Pharm. Res. 43, 765–772 (2020).
14. Focosi D, Anderson AO, Tang JW, Tuccori M. 2020. Convalescent plasma therapy for COVID-19: state of the art. Clin Microbiol Rev 33:e00072-20

Table 1: Clinical management of COVID-19