We are in the midst of a global pandemic of novel SARS CoV-2 viral infection which
have affected more than 2.6 million people in 180 countries and has already claimed
nearly 180,000 lives.[1] The magnitude of devastation and sense of fear and uncertainty caused by the pandemic
is unprecedented. It is extremely motivating to see the efforts by everyone to win
over this global crisis; such as governments trying to flatten the curve and trading
off between loss of human lives and big jolt to their economies; health care workers
providing care to their patients and adapting to their new attire (personal protective
equipment [PPE]); scientists, both fundamental and clinical, and pharmaceutical companies
exploring the disease biology and potential drug targets and vaccines; disease epidemiologists
defining the appropriate strategies for the containment of the virus; regulatory bodies
clearing clinical trials and scientific studies at a neck-breaking speed; police and
authorities enforcing social distancing; scientific societies imparting knowledge
about this disease and creating specific guidelines; the publishing houses disseminating
relevant knowledge by very fast track online publication(s); and the countrymen cheering
the COVID warriors in innovative ways and staying at home. This pandemic is also marked
by exposure of weak side of humanity such as game of blames, rumors, stockpiling and
hoarding, and assaults on health care professionals and policemen. While this pandemic
brought great challenges, it however also brought the whole world together.
Health care professionals worldwide are trying to beat this pandemic by exploring
novel ideas and innovations to explore and establish appropriate management strategies
for COVID-19. There is flurry of new knowledge almost every day and it is hard to
keep a track of all that is new, especially in the therapeutics of COVID-19. That
being said, the review by Kant Kumar et al published in this journal is a welcome
manuscript which adequately summarizes the available therapeutic options as of now
and briefly touches upon the status of vaccine development.[2]
It is very reassuring that majority of patients with COVID-19 disease have a mild
course and only approximately 10 to 15% of them require substantial health care facility
and specific treatment.[3] Therefore, the mainstay of treatment of COVID-19 is supportive for all the stages
of the disease and use of lung protective ventilation, Surviving Sepsis Guidelines
for COVID, and investigational agents only in a few selected patients.[4]
[5]
Talking about the extraordinary efforts to explore appropriate treatment of SARS-CoV-2
infection, 745 studies are registered on ClinicalTrials.gov as of April 22, 2020.
Of them, 342 are clinical trials.[6]
The investigational drugs which are being explored to target different steps of SARS-CoV-2
lifecycle in humans including inhibition of entry of virus into the target cell by
inhibition of angiotensin-converting enzyme-2 receptor and transmembrane protease
serine-2 (TMPRSS2) by Olumiant (baricitinib)[7] and camostat mesylate,[8] respectively; inhibition of the viral entry by inhibition of the membrane fusion
and endocytosis by chloroquine or hydroxychloroquine[9] and umifenovir (arbidol)[10]; inhibition of viral replication by protease inhibitors such as lopinavir[11] and darunavir; and blockade of viral ribonucleic acid (RNA) synthesis by remdesivir,[12] ribavirin,[13] and favipravir.[14] The other class of drugs control the hyperinflammatory phase such as corticosteroids,
immunomodulators, and anti-cytokines such as interleukin (IL)-6 inhibitor tocilizumab.[15]
Hydroxychloroquine has been the most hyped drug in the recent times and this drug
has been approved by the U.S. Food and Drug Administration, European Medical Association,
and Indian Council for Medical Research for its use in the treatment of COVID-19 patients
as a desperate measure even in the absence of strong supportive evidence of its efficacy.
Hydroxychloroquine has also been approved for use as a prophylaxis in asymptomatic
health care workers involved in the care of suspected or confirmed patients with COVID-19
and asymptomatic household contacts of laboratory-confirmed COVID-19 patients.[16] One must remember that use of these drugs is known to prolong QT interval and fatal
arrhythmia. Nevertheless, as of now at least 10 clinical trials are underway and the
results of at least some of them should be available over a few weeks to months which
will enable us to make more evidence-based decisions.
Antiviral drugs have been considered to be one of the front-runner drugs; however,
lopinavir/ritonavir combination in comparison to standard of care was neither associated
with a clinical improvement, nor mortality at 28 days in a randomized controlled trial
including 199 patients with COVID-19.[11] Remdesivir is another major drug which has already been approved for Ebola virus
infection. While remdesivir has shown its efficacy in a small nonrandomized study,[12] provisional report of a phase 3 clinical trial, currently being done in Chicago,
United States, has also confirmed its efficacy in moderate and severe COVID-19 patients.[17] Based on these early clinical results, remdesivir has been approved for its use
on a compassionate ground in appropriate patients awaiting confirmation of its efficacy
at the completion of the ongoing study. Other antiretroviral drugs such as darunavir/cobicistat
are also being evaluated for its efficacy in COVID-19 patients.[15]
Although in the review by Kant Kumar et al, they have comprehensively covered most
of the main pipeline drugs, a few more, we believe, are worthy of a mention here.[2] As we said earlier, in this unprecedented time, authors are relaying on the results
of their studies through prepublication portal till the paper is peer-reviewed. One
of such drug is favipravir which is a RNA polymerase inhibitor drug and it has shown
its efficacy against influenza virus and Ebola virus infection. In a multicenter study
including 240 patients with moderate and severe COVID-19, favipravir has shown good
results in comparison to another drug umifenovir (arbidol).[14]
The SARS-CoV2 viral infection may have three phases, including early viral phase,
pulmonary phase, and it may pass on the to the most fatal hyperinflammation phase
in a small subset of patients.[18] The hyperinflammation phase is critical and it is characterized by cytokine storm
and thus attracting therapies such as corticosteroids, immunomodulators, and anti-cytokines
therapy. The hyperinflammatory phase is uniquely characterized by high level of IL-6
and hence early result of tocilizumab (400 mg single dose), an IL-6 receptor antagonist,
in 21 patients of an ongoing clinical trial in China has demonstrated an improvement
in clinical condition in 75% and radiological resolution in 90.5% of patients.[19]
[20]
Another adjunctive therapy showing promise in COVID-19 is immunoglobulin administration
from convalescent plasma of recovered individuals thus providing passive immunization.[15] It has been successfully used earlier in the treatment of SARS, MERS, and 2009 H1N1
pandemic with good efficacy and safety. A meta-analysis of 32 studies reporting outcome
of use of convalescent plasma in patients with influenza and SARS has shown a consistent
reduction in mortality, especially if administered early after symptom onset.[11] Convalescent plasma is one of the most promising options as a rescue treatment for
severe cases of COVID-19 and it is being explored at least in 17 ongoing trials worldwide,
including some Indian centers.[6]
Prevention of infection by augmenting immunity against SARS-CoV-2 virus using vaccine
is the ultimate long-term goal. As highlighted by Kant Kumar et al, several vaccine
are being explored with some starting early clinical trials, the availability of an
effective vaccine is not close and it may take 9 to 12 months for mass production
and mass use.[2] We will have to wait for results of ongoing trials before specific treatment and
preventive strategies are established as a standard of care, and till then, prevention
of the spread of the disease remains at the center stage.
In conclusion, an extraordinary effort is being made by the governments, scientists,
and health care professionals to unravel a magic drug or a target to protect human
kind from this viral pandemic. While we wait for the brighter side, we in the meanwhile
should rise to our best in discharging our duties as responsible health care professionals.
While we are learning and adapting to the new ways of treating our patients in the
COVID and post-COVID era, we surely have learnt three buzz words, namely social distancing,
PPE, and flattening of the curve.
Humanity at its best and cheers!
