This content is solely based on the treatment guidelines provided by National Institute of Health (NIH). NIH claims that there are no Food and Drug Administration (FDA)-approved drugs for the treatment of COVID-19. Various potential drugs are under evaluation for the management of COVID-19. The drugs are used on the basis of the severity of the disease since the disease range from mild to moderate and that of severe cases leading to the death of patient. The drugs are administered based on the preliminary clinical trial data. The COVID-19 Treatment Guideline Panel recommends the administration of the investigational antiviral agents. Such agents are discussed in this section. The panel has given ratings on recommendation viz. A refering to strong, B refering to moderate and C refering to optimal recommendations followed by rating of evidence as I, II and III. Rating I is given for one or more randomized trials with clinical outcomes and/ or validated laboratory endpoints. Rating II is designated for one or more well-designed, non-randomized trials or observational cohort studies and III refers to expert opinion [1].
No agent is given for pre-exposure and post-exposure prophylaxis known to be effective for preventing SARS-CoV-2 infection. Patients with SARS-CoV-2 experiences a range of clinical manifestations from no symptoms to critical illness. Patients with COVID-19 can be group into the following illness categories:
i) Asymptomatic or Presymptomatic Infection: Individuals who test positive for SARS-CoV-2 but have no symptoms
ii) Mild illness: Individuals who have any of various signs and symptoms (e.g., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath, dyspnea, or abnormal imaging
iii) Moderate illness: Individuals who have evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SpO2) >93% on room air at sea level
iv) Severe illness: Individuals who have respiratory frequency >30 breaths per minute, SpO2 ≤93% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300, or lung infiltrates >50%
v) Critical illness: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction
The treatment can be categorized into two categories. First category includes the potential antiviral drugs and the second category includes to immune based therapy. Both of these alternatives are under evaluation for the treatment of COVID-19.
A) Potential drugs under evaluation
The potential drugs under evaluation are Remdesivir, Chloroquine or Hydroxychloroquine and Lopinavir/Ritonavir and other HIV Protease Inhibitors.
The panel recommends Remdesivir in the severe cases of the disease. Severe cases are defined as the cases in which patients have oxygen saturation (SpO2) ≤ 94% on ambient air (at sea level), requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO, also called as extracorporeal life support, ECLS). Remdesivir is not approved by FDA.
Remdesivir is a nucleotide prodrug of an adenosine analog. It has been reported this drug has demonstrated in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and both in vivo (in animal models) and in vitro activity against SARS-Co-V and Middle East respiratory syndrome coronavirus (MERS-CoV)[2-5]. Remdesivir binds to the viral RNA-dependent RNA polymerase. This binding will halt the viral replication through premature termination of RNA transcription.
There are reports showing remdesivir in improving disease outcomes and reducing levels of SARS-CoV in mice [3]. It also reduced MERS-CoV levels and lung injury in mice. Taking about the rhesus macaque model, remdesivir prevented MERS-CoV clinical disease [5]. Giving remdesivir 12 hours after inoculation with MERS-CoV, reduced viral replication and the severity of lung disease in treated animals compared to control animals. Likewise, in a rhesus macaque model of SARS-CoV-2, the adminstration of the drug soon after inoculation had lower lung virus level and less lung damage than the control one [6].
Remdesivir is a nucleotide prodrug of an adenosine analog. It has been reported this drug has demonstrated in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and both in vivo (in animal models) and in vitro activity against SARS-Co-V and Middle East respiratory syndrome coronavirus (MERS-CoV)[2-5]. Remdesivir binds to the viral RNA-dependent RNA polymerase. This binding will halt the viral replication through premature termination of RNA transcription.
There are reports showing remdesivir in improving disease outcomes and reducing levels of SARS-CoV in mice [3]. It also reduced MERS-CoV levels and lung injury in mice. Taking about the rhesus macaque model, remdesivir prevented MERS-CoV clinical disease [5]. Giving remdesivir 12 hours after inoculation with MERS-CoV, reduced viral replication and the severity of lung disease in treated animals compared to control animals. Likewise, in a rhesus macaque model of SARS-CoV-2, the adminstration of the drug soon after inoculation had lower lung virus level and less lung damage than the control one [6].
2. Chloroquine and its derivatives
Chloroquine is an antimalarial drug developed during 1930s. Hydroxychloroquine is an analogue of chloroquine developed in 1940s and were used to treat autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Chloroquine and its less toxic derivates hydroxychloroquine have been utilized in management of patients with mild, and in some cases, moderate cases of COVID-19. However, these drugs are dubious regarding their recommendation in the lack of sufficient clinical data. The panel is against the combination therapy of hydroxychloroquine plus azithromycin because of the potential for their toxicities. The panel recommends against using high-dose chloroquine for the treatment of COVID-19.
Choloroquine and hydroxychloroquine increase the endosomal pH that inihibits the fusion of SARS-COV-2 with the host cell membranes [7]. In addition, chloroquine inhibits glycosylation of the cellular angiotensin-converting enzyme 2 (ACE2) receptor which interfere with binding of SARS-CoV-2 to the cell receptor [8]. In vitro activity of chloroquine and hydroxychloroquine have been reported to block the transport of SARS-CoV-2 from early endosomes to endolysosomes that prevents the release of viral genome in cytosol [9]. According to the guideline, both of these drugs have immunomodulatory effect.
Chloroquine is an antimalarial drug developed during 1930s. Hydroxychloroquine is an analogue of chloroquine developed in 1940s and were used to treat autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Chloroquine and its less toxic derivates hydroxychloroquine have been utilized in management of patients with mild, and in some cases, moderate cases of COVID-19. However, these drugs are dubious regarding their recommendation in the lack of sufficient clinical data. The panel is against the combination therapy of hydroxychloroquine plus azithromycin because of the potential for their toxicities. The panel recommends against using high-dose chloroquine for the treatment of COVID-19.
Choloroquine and hydroxychloroquine increase the endosomal pH that inihibits the fusion of SARS-COV-2 with the host cell membranes [7]. In addition, chloroquine inhibits glycosylation of the cellular angiotensin-converting enzyme 2 (ACE2) receptor which interfere with binding of SARS-CoV-2 to the cell receptor [8]. In vitro activity of chloroquine and hydroxychloroquine have been reported to block the transport of SARS-CoV-2 from early endosomes to endolysosomes that prevents the release of viral genome in cytosol [9]. According to the guideline, both of these drugs have immunomodulatory effect.
There are reports that illustrated serious dysrhythmias in patients with COVID-19 treated with chloroquine or hydroxychloroquine. These medicine are often used in combination with azithromycin.
3. Ritonavir/ Lopinavir
Replication of SARS-CoV-2 depends on the cleavage of polyprotein into RNA-dependent RNA polymerase including a helicase [10]. The enzymes responsible for this cleavage are two proteases 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro).
Lopinavir/ritonavir has been demontrated with inhibition of SARS-CoV-2 3CLpro in vitro [12,13]. The panel doesn't recommends to use ritonavir/lopinavir or other HIV protease inhibitors to be used in combination. This is because use of these drugs in combination are unfavorable pharmacodynamically and negative clinical trial data.
B) Immune- based therapy under evaluation
Similarly, immune-based therapy includes Convalescent Plasma and Immune Globulins, Interleukin-1 Inhibitors, Interleukin-6 Inhibitors and other immuno-modulators. Endogenous IL-1, a proinflammatory cytokine, induces IL-6 in monocytes and macrophages and is elevated in COVID-19 patients. The Janus kinase (JAK) family of enzyme regulate signal transduction in immune cells. JAK inhibitors play a major role in inhibiting and blocking cytokine release. Blockage of IL-6 and IL-1 and inhibition of JAK have been proposed to treat the systemic inflammation associated with severe COVID-19 illness .
Lopinavir/ritonavir has been demontrated with inhibition of SARS-CoV-2 3CLpro in vitro [12,13]. The panel doesn't recommends to use ritonavir/lopinavir or other HIV protease inhibitors to be used in combination. This is because use of these drugs in combination are unfavorable pharmacodynamically and negative clinical trial data.
B) Immune- based therapy under evaluation
Similarly, immune-based therapy includes Convalescent Plasma and Immune Globulins, Interleukin-1 Inhibitors, Interleukin-6 Inhibitors and other immuno-modulators. Endogenous IL-1, a proinflammatory cytokine, induces IL-6 in monocytes and macrophages and is elevated in COVID-19 patients. The Janus kinase (JAK) family of enzyme regulate signal transduction in immune cells. JAK inhibitors play a major role in inhibiting and blocking cytokine release. Blockage of IL-6 and IL-1 and inhibition of JAK have been proposed to treat the systemic inflammation associated with severe COVID-19 illness .
REFERENCES:
| 1 | https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/ |
| 2 | Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32020029. |
| 3 | Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396). Available at: https://www.ncbi.nlm.nih.gov/pubmed/28659436. |
| 4 | Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222. Available at:https://www.ncbi.nlm.nih.gov/pubmed/31924756. |
| 5 | de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020;117(12):6771-6776. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32054787. |
| 6 | Williamson BN, Feldmann F, Benjamin Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. bioRxiv. 2020;[Preprint]. Available at: https://www.biorxiv.org/content/10.1101/2020.04.15.043166v2.full.pdf. |
| 7 | Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32020029. |
| 8 | Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318. |
| 9 | Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. Available at: https://www.ncbi.nlm.nih.gov/ pubmed/32194981. |
| 10 | Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15(5):327-347. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26868298. |
| 11 | Tahir ul Qamar M, Alqahtani SM, Alamri MA, Chen L. Structural basis of SARS-CoV-2 3CLpro and antiCOVID-19 drug discovery from medicinal plants. Journal of Pharmaceutical Analysis. 2020. [In press]. Available at: https://www.sciencedirect.com/science/article/pii/S2095177920301 |
| 12 | Liu X, Wang XJ. Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines. J Genet Genomics. 2020;47(2):119-121. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32173287. |
| 13 | Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-1034. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32192578. |
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