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‘Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2)’ has caused the current pandemic of ‘Corona Virus Disease-2019 (COVID-19)’. It has affected 2.5 crore individuals worldwide with current active cases of 6.9 Lac. It has claimed 8.5 Lac lives as of 1st September, 2020.[1] As it is completely new virus, there is no proven treatment at the start of the pandemic in January 2020 and search for the effective treatment continues since then.

Drug re-purposing

The health care professionals have tremendous pressure to curb the COVID-19 across the world including India. In the absence of specific antiviral agents, scientific community responds with the re-purposing of various existing drugs based on their in-vitro (cell lines and cell culture) data against SARS-CoV-2. Drugs being explored are antimalarials (hydroxychloroquine, chloroquine), antiinfluenza drugs (arbidol, favipiravir), anti-retroviral drugs (lopinavir/ritonavir), anti-hepatitis C drug (remdesivir), broad spectrum antiviral drug (ribavirin), interferon beta1b and anti-helmenthic agents (ivermectin). They are being given priority due to known safety records of use in human population and to overcome the burden of time consuming traditional drug discovery process.

The clinical evidence about the utility of re-purposed drugs as specific antiviral drugs against COVID-19 is limited. The early trends suggest their limited benefits over supportive care. Some of the drugs shown to have a detrimental effect on the clinical outcome. In case of hydroxychloroquine, higher rate of occurrence of QT prolongation and ventricular arrhythmia especially with concomitant use of azithromcin is reported. The recent meta-analysis suggest hydroxychloroquine do not reduce the mortality of COVID-19. On 24th April, 2020, US FDA advises cautions against the use of hydroxychloroquine outside of the hospital setting or a clinical trial due to risk of cardiac arrhythmia in COVID-19 patients. Subsequently, on June 15, 2020, US FDA revokes emergency use authorization for hydroxychloroquine in COVID-19. The Government of India continues to advocate the use of hydroxychloroquine in all severity COVID-19 patients. Hydroxychloroquine in Indian populations. The other commonly used antiviral drugs in COVID-19 are remdesivir and favipiravir. Both are the RNA dependent RNA polymerase inhibitors. They are not backed with the good quality evidences. Three randomized controlled trials are.

published so far for remdesivir.Two of them did not observe any significant benefit of its usage in improving clinical outcomes. Only one RCT showed earlier clinical recovery in terms of reduced hospital stay (~ 4 days) with remdesivir as compared to placebo.[8] Similar story exit for favipiravir. A small sample sized RCT did not observe the benefits of the use of favipiravir in the treatment method of mild to moderate COVID-19 cases. Both remdesivir and favipiravir are quite costly.

Drugs targeting pathophysioloy of COVID-19

The other way to respond is to understand the pathophysiology behind the severity of COVID-19 and associated inflammatory reactions. The most severe cases are associated with the cytokine storm due to over activity of T-cells and subsequently higher levels of proinflammatory cytokines and chemokine like IL-1B, IFNγ, C-X-C motif chemokine ligand 10 (CXCL10), IL-6, TNFα and chemokine C-C motif ligand 2 (CCL2).

The various anti-cytokine and anti-inflammatory drugs are re-purposed to treat moderate to severe COVID-19 patients. The commonly used drugs in India are corticosteroids, tocilizumab and itolizumab. They are suggested to control the inflammatory cytokine release and helps to control cytokine storm.

The good quality evidence is only available for the corticosteroid. As compared to supportive care only, dexamethasone treated patients had experienced lower mortality in invasive mechanical ventilation and oxygen receiving arm patients in recovery trial of the UK. However, it does not affect the outcome among patients who do not require any respiratory support. A recent metaanalysis observed that corticosteroid reduces all cause mortality in COVID-19 patients. However, difference in outcome was observed among individual corticosteroids. Dexamethasone showed a better effect than hydrocortisone and methylprednisolone. The latest published guideline of WHO recommends the use of corticosteroids in severe and critical cases but not in non-severe cases.

The evidences are limited in case of other commonly used drugs like tocilizumab and itolizumab. There are no published randomized controlled studies so far for these drugs. They are being used to block the IL-6 and subsequent cytokine storm. The observational studies suggest improved survival in patients of COVID-19 pneumonia.

COVID-19 drugs and political dilemma

The current COVID-19 pandemic has put pressure on political leadership across the world to curb its consequences. The effective drugs and vaccines are possible solutions that they expect from the researchers and medical fraternities. They cannot be exercised without patience and discipline. The frequent change in policies does not address it. Hydroxychloroquine was promoted by US and Indian Government based on preliminary evidence. The hypocrisy was observed while debating the efficacy and safety hydroxychloroquine and remdesivir. On one hand, promotion of hydroxychloroquine was largely criticized on the basis of lack of clinical evidence on COVID-19, possible cardiac adverse effects and potential shortage of supply for its approved use like rheumatoid arthritis and systemic lupus.

However, similar outrage was not seen while evaluating off label use of remdesivir, which is an anti-hepatitis C drug. Like hydroxychloroquine, remdesivir was promoted based on in-vitro data against SARS-CoV-2. The leakage of its phase 3 data was largely published by the media and applauded as an effective solution of COVID-19. Till today, its therapeutic utility is questionable based on the data of randomized controlled trials and limited safety information is available. All currently used drugs in COVID-19 should only be debated based on scientific merits and demerits. The recently published letter in journal “The Lancet” on 5th September, 2020 raises the questions over the uncertainty in India’s COVID-19 mortality data.

The article stat that “Information about whether state data on deaths include suspected and probable cases is not in the public domain and the Indian Ministry of Health and Family Welfare did not respond to The Lancet’s requests for clarification.” The Government agencies should be proactive in responding to such request. Such data should be there in the public domain. It is to be understood that Government agencies are in tremendous pressure and working tirelessly to combat this unprecedented situation. In spite of more than 35 Lac cases in India, we do not have sufficient number of scientific publications telling the world about the way of management of COVID-19 in India and still relying on Western data on managing the patients. The academic institutes should also play a bigger role in this.

Summary

In summary, various existing drugs are currently explored as a re-purposed agent due to unavailability of specific antiviral drugs. The current evidence about their clinical utility is limited except for dexamethasone against COVID-19.

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Author

– Dr. Tejas K. Patel

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