IJCRR

IJCRR - 12(9), May, 2020

Pages: 26-35

Date of Publication: 04-May-2020

Current Consensus on Drugs and Biologics against nCOVID-19 \- \? A Systematic Review

Author: Rashmi Jain, Ajay SS, Talagavadi Channaiah Anudeep, Dharma U Shetty, Madhan Jeyaraman, Aditi Chawla, Shivam Mahajan, Trisha Tarunita

Category: Healthcare

Abstract:The deadly pandemic caused by the novel coronavirus continues to jeopardize humanity. The current situation report published by the World Health Organization (on1st May, 2020) confirms32,49,022 nCOVID-19 cases with 2,30,804 toll of human lives. This global statistical data reflects the contagiosity of SARS-CoV-2 across the world. This newly emerged strain has presented an unequalled challenge for identifying effective drugs & biologics. Till date, no proven effective therapy exists for SARS-CoV-2 infection. The past experience of managing viral aetiological outbreaks renders background for extrapolation to nCOVID-19, yet effectivity remains uncertain. This dire scenario has been addressed with an escalation in the number of clinical trials in order to comeup with specific treatment. Repurposed drugs, Antibodies and Vaccines are under various stages of clinical trials currently. In the interim, supportive care, infection prevention measures and extended psychological assistance concords the core strategy to battle against this virus.

Keywords: Pandemic, World Health Organization, nCOVID-19, SARS-CoV-2, Effectivity

Full Text:

Introduction

Humanity is being jeopardized under the grip of the newly emerged strain of coronavirus (SARS-CoV-2).It was declared as a pandemic by the World Health Organization on 11^th March 2020. Since its inception, nCOVID-19 is spreading like a global wildfire. The ongoing pandemic has challenged the solidarity of rapidly progressing medical sciences and technologies. The genomic studies render natural selection process as the plausible explanation of the emergence of SARS-CoV-2 and rules out the view of it as a product of laboratory manipulation¹. The epidemiological studies have described bats as the reservoir host and Malayan pangolins as intermediate host². The transmission occurs either by direct contact or indirect contact. Understanding of the pathogenesis has rendered insight into the potential target sitesfor therapeutics; however those identified are in trial and not specifically approved. The global statistical data confirms 32,49,022 nCOVID-19 cases with 2,30,804 toll of human lives (on 1^st May2020)(3). The incidence and mortality reported are subject to geographic variation³.

The past experience of managing outbreaks of viral aetiology (SARS-CoV-1, Influenza, MERS-CoV and EBOV) paves the ground for extrapolation to SARS-CoV-2 pandemic.  Yet no proven therapies to vanquish the virus are rationally validated. The data as on 15^th April 2020 at ClinicalTrials.gov with the searched terms- nCOVID-19, SARS-CoV-2, 2019-nCoV, 2019 novel coronavirus, severe acute respiratory distress syndrome, coronavirus-2 shows 833 enrolled studies and of all 541 are interventionalstudies⁴. This shows the glimpse of the global pace in the quest to find specific therapy with proven efficacy and rationality. Numerous authorities have collaborated for active clinical trials and these are underway. One such multinational megatrial launched by the WHO is ‘Solidarity’ which is directed to find the effectiveness of four subsets of drugs- Remdesivir;  Lopinavir/Ritonavir; Lopinavir/Ritonavir with Interferon β-1a and Chloroquine or Hydroxychloroquine (selection based on evidence from laboratory, animal and clinical studies)⁵. In addition, few therapies which emerged as a result of divergent thought processincludes vitamin-D supplementation, the role of mesenchymal stem cells, monoclonal antibodies and convalescent plasma are also under clinical evaluation.

As of now, supportive care, strict implementation of infection control measures and extended psychological assistance are the concordant principles to deterrence. This review article adduces current consensus regarding proposed treatment, repurposed or experimental drugs and biologicsfor nCOVID-19 with a brief outline of preventive strategies advocated currently.

Figure 1: Simplified Representation ofMolecular Pathogenesis of SARS-CoV-2 with Potential Target Site of Selected Repurposed and Investigational Drugs & Biologics¹

[(1)Binding of spike protein to ACE-2 and TMPRSS-2 facilitates virion entry; (2) Release of RNA by virion; (3) Translation of RNA into proteins by protein making machinery; (4)Formation of Replication Complex to produce more RNA; (5) Assembling of protein & RNA in golgi apparatus; (6)Virion Released]

SARS-CoV-2 is a single-stranded positive sensed, RNA enveloped virus belonging to the beta subfamily of Coronaviridae family¹. The virus glycoprotein- (S) spike protein targets angiotensin converting enzyme 2 (ACE-2) receptors, which are widely distributed over the alveolar type II (AT2) cells and endothelium and bind to it⁶. Another host type 2 transmembrane serine protease (TMPRSS-2) facilitates the entry mechanism via S protein⁷. The complex procedure of the replication of SARS-CoV-2 following a series of steps has been depicted in figure¹. The understanding of viral life-cycle renders selection of a potential site for optimizing drug targets. Remdesivir is the most promising drug currently. However, the FDA has categorised it as an Investigational Agent (IND)⁸.

The Pipeline of Drugs & Biologics for nCOVID-19

Antiviral Drugs

A. REMDESIVIR (formally GS-5734)

Remdesivir is an investigational nucleoside analogue of Remdesivir triphosphate (RDV-TP) discovered amidst a screening procedure against RNA viruses such as Flaviviridae and Coronaviridae. During the outbreak of EBOV, this was found to be a ‘promising agent’ due to its low EC₅₀ with host polymerase selectivity against EBOV⁹. It acts as an inhibitor of RNA-dependent RNA polymerase (RdRps). Remdesivir was found to prevent haemorrhage in the lungs with a reduction in viral lung titres more than comparator agents in a murine lung infection model with MERS-CoV¹⁰. It is currently a promising potential drug due to its broad-spectrum effect with potent in-vitro activity against several coronaviruses including SARS-CoV-2 with EC₅₀ and EC₉₀ values found to be 0.77µM and 1.76µM respectively^{11 12}. Single and multiple-dose phase-1 clinical trials evaluated the safety and pharmacokinetics of this drug where intravenous infusions ranging 3-225mg demonstrated to be well-tolerated without any substantiation of hepatic and renal toxicity. However, multiple dosing showed a rise in reversible aspartate aminotransferase and alanine transaminase levels ¹³.

Notably, it is not approved by the FDA at present and can be obtained via expanded access, enrolling in a clinical trial or for compassionate use only for children who are <18 years and pregnant women. Currently clinical trials are going on for evaluating the safety and antiviral efficacy in patients of nCOVID-19 (NCT04292899, NCT04292730, NCT04321616, NCT04280705, NCT04315948, NCT04335123) (14). The results of the randomized control trials are anticipatory for incorporating Remdesivir as considerable drug against SARS-CoV-2.

B. LOPINAVIR/RITONAVIR

Oral combination agent approved by the US-FDA for treating HIV infection has been repurposed for nCOVID-19 treatment. In-vitro and animal model studies have outlined its potential activity against SARS-CoV-1 and MERS-CoV respectively^15,16. Recently, the in-vitro activity of lopinavir against SARS-CoV-2 has been adduced¹⁷. These are HIV protease inhibitors which act by binding to M^Pro enzyme which is regarded as the key enzyme of replication; thereby suppresses coronavirus activity¹⁸. Clinical outcomes from SARS-CoV-1 and MERS-CoV-1 confer no effect with delayed lopinavir/ritonavir therapy and put forth to have considerable importance when administered during the early phase of viral replication (early 7-10 days)^16,19.

In a recent rapid review on the efficacy of lopinavir/ ritonavir in nCOVID-19 by Jienchi Dorward and Kome Gbinigie concluded that there is insufficient evidence to recommend the use of this combination of drugs for nCOVID-19 outside the research studies. The identified clinical trials are subjected to methodological flaws. These conclusions are based on the final review of 2 clinical trials [Cao et al. ²⁰and ELACOI²¹] and 4 cohort studies selected as per full-text screening by the authors (article yet to be peer-reviewed)²². It emphasises its consideration on the basis of several ongoing clinical trials. The drug combination with and without interferon beta is included as subsets in the large megatrial launched by the World Health Organization⁵. Yet its role in nCOVID-19 treatment is limited.

The most studied lopinavir/ritonavir dose regime for nCOVID-19 treatment is 400mg/100mg BD (twice daily) for 14days^20,23. A randomized control trial by Cao et al. revealed that 50% of the enrolled patients experienced an adverse effect and 14% discontinued this combination therapy because of gastrointestinal adverse effect. In nCOVID-19 patients, drug-induced transaminitis may exacerbates and may result in fatal liver injury. Several investigational clinical trials regarded an increase in alanine transaminase levels as the exclusion criteria.

Another protease inhibitor, Darunavir demonstrated activity against SARS-CoV-2 as per in-vitro cell study models. Currently, a randomized control trial is underway from China assessing the efficacy and safety of Darunavir and Cobicistat for nCOVID-19 (NCT04252274) ¹⁴.

C. FAVIPIRAVIR (formerly T-705)

It’s a prodrug of a purine nucleotide.Its active form inhibits the RNA polymerase which in turn halts the viral replication. It is an IND (Investigational New Drug) mainly studied with respect to Influenza and Ebola virus infection. But in a study by Furuta Y et al., it demonstrated broad-spectrum activity against other RNA viruses as well²⁴. The in-vitro study reported EC₅₀ against SARS-CoV-2 to be 61.88μM/L in Vero-E6cells (25). The drug dose regime recommended for this includes a loading dose of (2400 mg to 3000 mg every 12 hours× 2 doses) and thereafter maintenance dose of (1200 mg to 1800 mg every 12 hours) respectively²⁶. Overall this drug is well-tolerated with mild adverse effect profile. Still, there is a limited adverse event profile for higher dose regime²⁷.

Chang Chen et al. conducted a prospective, randomized, controlled, open-label multicentre trial wherein 240 patients were randomized for assessment of Favipiravir v/s Umifenovir. These patients were randomly assigned in a ratio of 1:1 and were administered Favipiravir in dose of (1600mgx 2/first day followed by 600mgx2/day) and Umifenovir (200mgx3/day) for the duration of 10 days.  The clinical recovery rate on day-7 did not significantly differ between both the group (P=0.1396, difference of recovery rate; 95% CI: 0.0305 to 0.2213) ²⁸. Another interventional study (randomized; open label) is underway from China with an enrolment of 150 patients belonging to age group 18-65 years. The primary purpose of this intervention is to study the combined effects of Favipiravir and Tocilizumab in the treatment for nCOVID-19 (NCT04310228) (14). RCTs are the need of the hour in order to rationalise the use for nCOVID-19.

D. RIBAVIRIN

It is a guanine analogue inhibiting the viral RNA-dependent RNA polymerase. In-vitro evidence and the potency enhancing strategies developed during the SARS-CoV-1 and MERS-CoV outbreaks, this drug can be extrapolated for treating nCOVID-19. In-vitro studies on SARS-CoV-1 demonstrated inhibition of viral replication at higher doses (1.2 g – 2.4 g orally every 8 hours) singly and in combination therapy²⁹. Moreover,the clinical studies in connotation to these mentioned prior outbreaks outline its associated dose-dependent haematological toxicity and elevations of transaminases causing liver injury^29,30. Ribavirin is contraindicated in pregnancy due to its known teratogenicity³¹. The wide availability, low-cost accessibility and substantial evidence from the past rendered it as an option to be used during the inception of the outbreak in China³².                       

A randomized control, phase 2 study from Hong Kong evaluated the combination therapy with Lopinavir/Ritonavir, Ribavirin and Interferon-beta enrolling 127 patients. The study has been completed, yet results are awaited (NCT04276688)¹⁴. As of now, the data on the efficacy of ribavirin therapy is inconclusive and if used then combination therapy holds scope for a beneficial role in nCOVID-19 treatment.

E. UMIFENOVIR (ARBIDOL)

This drug is unique in its mechanism of action; targeting the S protein/ACE2 and inhibits the membrane fusion of the envelope of virus ³³. Currently, this drug is available in Russia and China as prophylaxis and therapeutics for Influenza. Here also it is seemingly of great interest due to its in-vitro activity against SARS-CoV-2³⁴. The dosingregimen used in Influenza (200 mg orally every 8 hours) will be evaluated for nCOVID-19 therapy (NCT04260594)¹⁴. In addition to this, two large phase -4 combination studies involving intervention with Arbidol or Lopinavir/ritonavir or Oseltamivir (NCT04255017) and Arbidol or Lopinavir/Ritonavir (NCT04252885) from China is underway¹⁴.

F. OSELTAMIVIR

Neuraminidase inhibitor is a specific drug for treating Influenza. No corroborative findings are available in context to its in-vitro activity against SARS-CoV-2. Notably, the influenza season in China masked the plausibility of the emergence of a new aetiological agent; thereby oseltamivir was administered as empirical therapy during initial the phase of the outbreak ³⁵. The role in nCOVID-19 is ill-defined once the influenza has been ruled out. On-going clinical trials have placed it as comparator rather as a therapeutic agent.

Antimalarial Drugs

A. CHLOROQUINE & HYDROXYCHLOROQUINE

The long-standing record of therapeutic efficacy can be traced back to approval for treating vector-borne disease like malaria and systemic inflammatory diseases³⁶. The mechanism of action is by blocking the entry of the virus via inhibition of glycosylation of host receptors, proteolytic processing and acidification of endosomes. In addition to this, they impart an immuno-modulatory effect by attenuating the production of cytokines and inhibiting autophagy and lysosomal activity into host cells. The antiviral activity against SARS-CoV-2 has been noted in-vitro wherein hydroxychloroquine reported lower EC₅₀ than chloroquine (hydroxychloroquine: EC₅₀ =6.14μM < chloroquine: EC₅₀ =23.90μM) respectively^37,38. The dosing regimen for SARS-CoV-2 has been variable among the clinical trials and further delineation to be done on the basis of randomized control trials. This is presently tagged as repurposed drug and being used as off-label across countries; briefly discussed in Table-1. Studies have reported hydroxychloroquine to be more potent than chloroquine. These agents are known to cause rare and serious adverse effects like the prolongation of QT_c interval, hypoglycaemia, neuropsychiatric effects and retinopathy³⁹. Chloroquine and hydroxychloroquine usage is considered safe in pregnancy. Further Osadchy A et al. in his literature review of 12 studies enrolled 588 patients receiving hydroxychloroquine or chloroquine found no overt ocular toxicity in infants⁴⁰.

An open-labelnon-randomized clinical trial from France enrolling a small sample size (36 patients) noted that the treatment with hydroxychloroquine was significantly associated with a reduction in the viral load on day-6 in nCOVID-19 patients and further the effect was reinforced by the Azithromycin⁴¹. Interestingly, a recent study by Mahevas M. et al concluded that the use of hydroxychloroquine in patients hospitalised for documented nCOVID-19 positive hypoxic pneumonia was not found to be effective⁴². This study was based on the data collected from 4 French-based hospitals.

This repurposed drug is one of the subsets to be studied under the WHO launched megatrial ⁵.

Several clinical trials are underway either assessing the efficacy of hydroxychloroquine as post-exposure prophylaxis or as a therapeutic agent for nCOVID-19 (NCT04322396, NCT04341727, NCT04341727, NCT04342221, NCT04321278, NCT04344951, NCT04316377, NCT04325893, NCT04304053, NCT04350684, NCT04351724) (14). Among these clinical trials, NCT04304053 is a phase-3, open-label, randomized clinical trial for the treatment of nCOVID-19 cases and chemoprophylaxis of contacts as prevention which will be primarily completed by 15^th June 2020. Small studies have reported it with positive effect however results are awaited for further substantiation of its efficacy and safety concerns.

Antiparasitic Drug

A. IVERMECTIN

Ivermectin is a FDA approved drug for treatment of parasitic infections.It has recently reported to have broad-spectrum anti-viral activity in-vitro against SARS-CoV-2 wherein it has shown about 5000 fold reduction in viral RNA at 48 hr with addition of single dose to vero-h SLAM cells after 2 hours of post infection⁴³. It acts via inhibition of nuclear transport. However there is lack of evidence on safety measures especially during pregnancy

B. NITAZOXANIDE

This anti-helminthic drug has a broad spectrum of antiviral activity with favourably relative safety perspective. Antiviral activity in-vitro against MERS and SARS-CoV-2 has been demonstrated ⁴⁴.  But the lack of evidence warrants further detail study.

Adjunctive Drugs

A. CORTICOSTEROIDS

The rational use of corticosteroids is for downregulation of the inflammatory process in the lungs and thereby preventing the onset of acute respiratory distress syndrome (ARDS). On the contrary, these benefits can be outweighed by its adverse effect wherein associated with delayed viral load clearance and additionally paving the ground for secondary infections. The later can be substantiated from a randomized control trial by Wong et al. in SARS-CoV patients, noted higher concentrations of viral RNA in 2/3^rd week of infection upon measuring at regular intervals in non-intubated patients treated with corticosteroids when compared to placebo⁴⁵. On the other hand, another Chinese Study on SARS-CoV separated patients into 4 treatment groups and it was identified that early high dose steroids administered in combination with a quinolone yielded the most favourable outcome⁴⁶. In a recent retrospective study from China, reported decrease risk of death in patients with ARDS when treated with methylprednisolone in comparison to without steroids intervention(23/50 [46%] with steroids vs 21/34 [62%] without; HR, 0.38 [95%CI, 0.20-0.72])⁴⁷. Due to the lack of proven data, the cautious use of corticosteroids is justifiable rather routinely used in nCOVID-19 patients.

B. AZITHROMYCIN

This macrolide antibiotic is reported to curb pulmonary inflammation due to its immunomodulatory effect. In addition, it prevents bacterial superinfection. In a clinical study from France; notable was its enforced effect on the decrease in viral load when administered as adjunctive with HCQ (41).It is to be used cautiously as it is associated with QT- interval prolongation. The documentation of its role as an adjunct in severe cases is limited. These medications may be effective as individual or adjunct, but its widespread adoption calls for more number of randomized control trials for the same.

C. MONOCLONAL ANTIBODIES

These represent another potential class of adjunctive drugs which targetthe specific inflammatory cytokine or innate immune response resulting in an immunomodulatory effect. Cytokine storm phenomenon is the cause behind mortality seen in nCOVID-19 patients as it triggers the uncontrolled release of pro-inflammatory cytokines (IFN-α, IFN-γ, IL-1β, IL-6, IL-12, IL-8, IL-33, TNF-α, TGF-β) and chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL-10 etc)^6,48.

Early case series from China identified IL-6 as the driving factor behind such dysregulation ⁴⁹. So, theoretically, monoclonal antibodies against IL-6 lessen and improvise clinical outcome. Tocilizumab, Sarilumab and Siltuximab are IL-6 receptor antagonists approved by FDA for the treatment of Chronic Inflammatory disorders. Among all, Tocilizumab has been studied in clinical trials and viewed to have a favourable clinical outcome. China reported a beneficial outcome of Tocilizumab asa single dose in a study, but it lacked comparator group warranting further studies for its efficacy. In a recent retrospective study on 15 patients, Pan Luo et al. noted that Tocilizumab is beneficial in relieving inflammation in nCOVID-19 patients; however, repeated dosing is recommended for critically ill-patients and stated the need to study more number of cases in order to verify the same⁵⁰. Currently, several randomized control trials are underway in China assessing it as single or combination therapy (NCT04310228, ChiCTR200002976)¹⁴. Sarilumab is also included in clinical trials and one such study including it is an adaptive phase 2/3, randomized, double-blind, placebo controlled study with 300 participants to assess its efficacy and safety for hospitalized nCOVID-19 patients (NCT04327388)¹⁴.

Currently, clinical trials in China or as expanded access in the U.S, other monoclonal antibodies like Eculizumab (inhibition of terminal complement; NCT04288713); fingolimod (immunomodulator approved for treatingmultiple sclerosis; NCT04280588) and bevacizumab (anti–VEGF medication; NCT04275414) are afoot.

D. ACEINHIBITORS & ARBs

ACE2 is an enzyme which is physiologically involved in the activation of RAAS mechanism. Upon recognising that the SARS-CoV-2 viral infectivity is mediated by ACE2 receptors led to preclinical trials which suggested that RAAS inhibitors may further increase the expression. However, the insufficient data impels to ponder upon whether this translates to humans or not. The abrupt withdrawal in high-risk individuals may result in instability clinically with adverse outcome. Muthiah et al. recommend the continuation of RAAS inhibitors in otherwise stable patients with underlying co-morbidities until further substantiation is done from clinical trials⁵¹. Currently, two randomized control studies from Ireland (NCT04330300), France (NCT0439195) and one cross-sectional study from Italy (NCT04331574) are advancing for understanding the role of ACE inhibitors and ARBs in nCOVID-19 respectively¹⁴.

E. INTERFERON-α and β

These have been studied in the prior outbreaks and interferon β notably demonstrated antiviral activity against MERS-CoV²⁹. Current guidelines by Chinese authorities have enlisted it as an alternative treatment²³. These have been studied as a combination therapy with lopinavir/ritonavir or ribavirin so far.  Sallard E et.al. conclude that interferon-β may  be regarded as safe and easy for upscaling treatment against nCOVID-19 in early stages of the infection⁵².Currently, included in WHO launched megatrial in combination with lopinavir/ritonavir for evaluation of efficacy and safety⁵. Clinical trials have been registered to evaluate this potential therapy includes (ChiCTR2000029387) and (NCT04276688).

F. VITAMIN- D                                               

Its imperative role has been demonstrated in prior for preventing respiratory infections which renders for consideration as an adjunct in boosting up immunity. Three mechanisms have been reported wherein it strengthens physical barrier, channelizes cellular innate immunity for antimicrobial activity and adaptive immunity suppresses and further inhibits inflammatory response and attenuates cytokine storm respectively^53,54. An observational study (case-control; prospective) enrolling 80 participants is afoot for assessing prophylaxis for healthcare professionals with hydroxychloroquine adjunct with vitamin C &D and zinc during nCOVID-19 pandemic (NCT04326725)¹⁴.

Cell & Plasma based Biologics

A. MESENCHYMAL STEM CELLS

Novel therapeutics stemmed out from the core principles of regenerative medicine to be optimised for nCOVID-19. Mesenchymal Stem Cells are specialized cells which lack key entry points (ACE-2 & TMPRSS-2) for nCOVID-19 and hence they are immune to it, wherein imparting the immunomodulatory effect by attenuating the cytokine storm and repair of damaged tissue⁵⁵. Zikaun Leng et al. reported that mesenchymal stem cells transplantation in 7 enrolled nCOVID-19 patients at Beijing Youan Hospital had improved clinical outcomes ⁶. The evidence cited put forth for considering as treating modality in severely- ill patients after proven efficacy and safety in large cohorts.Currently, 9 studies are afoot to optimise mesenchymal stem cells for nCOVID-19¹⁴.

B. CONVALESCENT PLASMA

The beneficial experience in managing prior viral aetiological outbreaks of SARS-CoV-1, MERS-CoV and EBOV renders it as a potential therapy to be optimised for SARS-CoV-2.  The management of SARS-CoV-1 with Convalescent plasma therapy is the best way to reduce viral load in a short span of time. The principle strategy is passive immune therapy involving retrieval of plasma (rich in viral neutralising antibodies) from the recovered patients and transfusing the same to exposed individuals or positive cases. Currently, the US FDA has approved the emergent use of convalescent plasma as an investigational drug for critically ill patientsand has also instructed the doctors to follow the usual system for an investigational new drug (IND) application in case if they want to study^56,63. However, the randomized control trials may be undertaken to rationalise the titres for utility and establish safety measures.

Figure 2: Schematic Representation of Rationalised Use of Drugs & Biologics

(As per current clinical studies in relation to clinical spectrum) for nCOVID-19

(Modified from Siddiqu et.al ⁶⁵)

Preventive strategies

In the interim of lack of definitive licensed drugs, biologics and vaccines, implementation of infection control measures is the key strategy to deterrence. Re-allocation of resources and global solidarity can gear-up the fight against nCOVID-19. The front liners are at the highest risk and should undertake all the indicated biosafety level measures. The need of the hour calls for the practice of quarantine, isolation, social distancing, hand hygiene and respiratory etiquettes wisely. Amidst all, it has fuelled up anxiety, stress, panic, apprehension, phobia, depression, disturbed sleep etc. People are experiencing varied emotions such as anger outburst, aggression, loneliness, irritation, fatigue, frustration, guilt, emotional dissatisfaction which in turn is responsible for triggering depression, self-harm and suicide. People have bottled up feelings of helplessness and hopelessness which in turn challenge their psychological resilience. At present, the practice of tele-medicine and the concerned protocols are made available. Counselling sessions in person or as tele-medicine practice focus on the relaxation techniques like breathing exercises and JPMR (Jacobson Progressive Muscle Relaxation) in order to deal with issues of anxiety, stress, psycho-somatic symptoms etc. Various countries have devised help-line numbers to provide information to its residents regarding nCOVID-19.

The dire need is to address the scenario holistically and collaboratively in order to relegate SARS-CoV-2.

Discussion

The recent guidelines unrolled by the World Health Organization explicably mentions that currently there is no evidence favouring recommendation of any drug as specific nCOVID-19 treatment for patients with nCOVID-19 conformational status. These guidelines direct to provide supportive care in relation to severity of the presenting nCOVID-19 illness and don’t support routine use of systemic corticosteroids for treating pneumonia of viral aetiology outside clinical trials. Further to add on; IND’s for nCOVID-19 treatment to be used in an approved randomized controlled clinical trial only⁶⁶. Similarly the guidelines issued by the Centre for Disease Control and Prevention outlines the unavailability of specific drug as nCOVID-19 treatment at present. These direct for prompt implementation of infection prevention and control measures along with supportive management of associated complications. Systemic corticosteroids should not be used unless indicated otherwise. In context to IND; the CDC recommends its utilization either via compassionate use or through clinical trials⁶⁷.

Evidences are emerging on prevention and divergent plausible therapeutics for nCOVID-19. In recent, BCG vaccine has been linked to reduce morbidity and mortality due to nCOVID-19. However, the WHO stated that due to lack of evidence at present it is inconclusive and doesn’t substantiates enough for amending prevailing policies across various countries⁶⁸. Apart from this; the role of herd immunity for nCOVID-19 has emerged as a debatable issue with one of the prime reason as lack of vaccination against SARS-CoV-2. Amidst, tele-medicine is popularising as the key practicing and due guidelines have been issued for the same.

Currently lockdown measures have been adopted as a public health measure to curb down SARS-CoV-2 contagiosity by one-third of the countries across the globe.The linchpin for addressing prevailing scenariocalls for strategical steps to break the chain of transmission. This in turn rests on escalating procedural for testing and tracing contacts respectively. In addition to these; there is an urgent need to scale up clinical trials for repurposed drugs, other plausible therapeutics (Stem Cells; Convalescent Plasma; Plasma Lysate therapy; NK cell therapy & SVF) and importantly vaccines so as to sooner come-up with specifically proven treatment for nCOVID-19. Notably, many prospective randomized controlled trials are underway for the same with a beacon of hope to find specific agent pulverizing SARS-CoV-2.

Conclusion

The world is battling nCOVID-19 pandemic wherein this generation is confronting the global health crisis. No proven therapies to vanquish SARS-CoV-2 exist currently. A holistic outlook should be considered whilst this period. The global rush of clinical trials launched for investigating the potential drugs, biologics and vaccines outlines the need and potential to provide high-quality substantiation amidst the pandemic. It is critical for clinicians to continually monitor, rapidly adapt tothe emerging evidence-based literature and report their experience in managing and treating nCOVID-19 to the medical fraternity for further optimisation of the treatment recommendations and protocols.

Acknowledgements: Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors / editors / publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed. We thank Dr.PavanIdhole, Resident, North DMC Medical College & Hindu Rao Hospital, Delhi, India, Dr. Shirodkar Jaswandi Dilip, Medical Officer, ESIS hospital (Worli), Mumbai, Maharashtra, India and Ms. Bhavya Saluja, Department of Clinical Psychology, RML Hospital, Atal Bihari Vajpayee Institute of Medical Sciences, New Delhi, India for literature search regarding COVID-19.

Conflict of Interest: None

Funding Sources: None

Abbreviations

ACE2 – Angiotensin-Converting Enzyme 2; ARDS – Acute Respiratory Distress Syndrome; AT2 – Alveolar Type 2; nCOVID-19 – Novel Corona Virus Disease-2019; EBOV – Ebola Virus Disease; FDA – Food and Drug Administration; HCQ – Hydroxychloroquine;  ICMR – Indian Council of Medical Research;  IND – Investigational New Drug; JPMR – Jacobson Progressive Muscle Relaxation;  MERS – Middle East Respiratory Syndrome; RAAS – Renin-Angiotensin-Aldosterone-System; RDV-TP – Remdesivir Triphosphate; SARS – Severe Acute Respiratory Syndrome; TMPRSS2 – Transmembrane Protease Serine 2 ; WHO – World Health Organization.

References:

1. Andersen, K.G., Rambaut, A.,Lipkin,W.I. et al. The proximal origin of SARS-CoV-2. Nat Med. 2020;26:450–452.

2. Lam, T.T, Shum, M.H., Zhu, H. et al. Identifying SARS-CoV-2 related coronaviruses in Malayan pangolins. Nature. 2020.

3. Coronavirus disease 2019 (COVID-19). 2020. Situation Report-82.https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200411-sitrep-82-covid-19.pdf?sfvrsn=74a5d15_2 [Cited: 1^st May, 2020].

4. Search result for a keyword ‘COVID-19’ on ClinicalTrials.govhttps://www.clinicaltrials.gov/ct2/results/details?=Intr&Covid-19.[Cited: 1^st May, 2020].

5. WorldHealth Organization. 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments.[Cited: 1^st May, 2020].

6. ZikuanLeng, Rongjia Zhu, Wei Hou, Yingmei Feng, Yanlei Yang, Qin Han et al. Transplantation of ACE2- mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging and Disease. 2020;11(2):216-228.

7. Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection. J Virol. 2019;93(6): e01815-18.

8. Remdesivir Approval Status. https://www.drugs.com/history/remdesivir.html. [Cited: 15^th April, 2020].

9. Siegel D, Hui HC, Doerffler E, et al. Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses. J Med Chem. 2017;60(5):1648-1661.

10. 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.

11. Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med Infect Dis.2020: 101615.

12. 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.

13. WHO R&D blueprint: ad-hoc expert consultation on clinical trials for Ebola therapeutics. Organization, World Health. October 2018.https://www.who.int/ebola/drc-2018/treatments-approved-for-compassionate-use-update/en/ [Cited: 1^st May, 2020].

14. Search result for a keyword ‘Remdesevir’ on https://www.clinicaltrials.gov.https://clinicaltrials.gov/ct2/results?cond=remdesivir[Cited: 15^th April, 2020]

15. Chen F, Chan KH, Jiang Y et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J ClinVirol. 2004;(1):69-75.

16. Yao TT, Qian JD, Zhu WY et al. A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus- A possible reference for coronavirus disease-19 treatment option. J Med Virol. 2020. (In press)

17. Choy KT, Yin-Lam Wong A, Kaewpreedee P, et al. Remdesivir, Lopinavir, Ementine and homoharringtonine inhibit SARS-CoV-2 replication in-vitro. Antiviral Res. 2020. (In press)

18. Liu X, Wang XJ. Potential inhibitors for 2019-nCoV coronavirus M protease from clinically proven medicines.J Genet Genomics. 2020. (In press)

19. Chan KS, Lai ST, Chu CM, et al. Treatment of severe acute respiratory syndrome with Lopinavir/Ritonavir: A multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9(6):399-406.

20. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.N Engl J Med. 20 (In press)

21. Li Y, Xie Z, Lin W, et al. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). medRxiv. 2020. (In press)

22. JienchiDorwardand KomeGbinigie. CEBM. 2020. https://www.cebm.net/covid-19/lopinavir-ritonavir-a-rapid-review-of-the-evidence-for-effectiveness-in-treating-covid/. [Cited: 16^th April, 2020]

23. National Health Commission and State Administration of Traditional Chinese Medicine. Diagnosis and treatment protocol for novel coronavirus pneumonia.https://www.chinalawtranslate.com/wp-content/uploads/2020/03/Who-translation.pdf. [Cited: 15^thApril, 2020]

24. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci.2017;93(7):449-463.

25. Tim Smith et al. COVID-19 Drug Therapy. Elsevier. 2020. (In press)

26. Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther. 2020; 107512 (In press)

27. Kumagi Y, Murakawa Y, Hasunuma T, et al. Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults. Int J Clin Pharmacol Ther. 2015:53(10);866-874.

28. Chang Chen, Yi Zhang et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv. 2020. (In press)

29. Stockman LJ et al. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343.

30. Arabi YM, Shalhoub S, Mandourah Y et al. Ribavirin and interferon therapy for critically ill patients with Middle East Respiratory Syndrome: A multicenter observational study. Clin Infect Dis. 2020:5;70(9):1837-1844.

31. Altinbas S, Holmes JA. Altinbas A. Hepatitis C virus infection in pregnancy: an update. GastroenterolNurs. 2020;43(1):12-21.

32. Khalili JS, Zhu H, Mak NSA, Yan Y, Zhu Y. Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19. J Med Virol. 2020. (In press)

33. Kadam RU, Wilson IA. Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc Natl AcadSciUSA. 2017;114(2):206-214.

34. Khamitov RA, Loginova Sla et al. Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndromein the cell cultures. VoprVirusol. 2008;53(4):9-13.

35. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020. (In press)

36. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of Chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3(11):722-7.

37. Al-Bari MAA. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol Res Perspect. 2017;5(1):e00293.

38. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus. Clin Infect Dis. 2020. (In press).

39. AC Kalil. Treating COVID-19 - off label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA. 2020. (In press)

40. Osadchy A, Ratnapallan T, Koren G. Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature, J Rheumatol. 2011;38(12):2504-8.

41. Gautret P, Lagier J, Parola P, et al. Hydroxychloroquine and Azithryomycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int. J Antimicrob Agents. 2020. (In press)

42. Matthieu Mahevas, VietThi Tran, Mathilde Roumier, Amelie Chabrol, Romain Paul Constance Guillaud et al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial. medRxiv. 2020. (In press).

43. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA - approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. J Antiviral. 2020; 104787.

44. Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health. 2016;9(3):227-30.

45. Wong SSY, Yuen K-Y. The management of coronavirus with particular reference to SARS. J Antimicrob Chemother. 2008;62(3):437-41.

46. Zhao Z, Zhang F, Xu M, et al. Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China. J Med Microbiol. 2003;52(Pt 8):715-720.

47. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020. (In press)

48. Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal. 2020. (In press)

49. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective study. Lancet. 2020;395(10229):1054-1062. 

50. Pan Luo, Yi Liu, Lin Qiu, Xiulan Liu, Dong Liu, Juan Li. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol. 2020. (In press)

51. Muthiah Vaduganathan et al. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020. (In press)

52. Sallard E, Lescure FX, Yazdanpanah Y, Mentre F, Peiffer-Smadja N. Type 1 interferons as a potential treatment against COVID-19. Antiviral Res. 2020;178:104791.

53. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;15(356):i6583.

54. William B Grant, Henry Lahore, Sharon L. McDonell, Carole A. Bggerly, Christine B. French, Jennifer L. Aliano and Harjit P. Bhattoa. Evidence that Vitamin D Supllementation Could Reduce Risk of Influenza and COVID-19Infections and Deaths. Nutrients. 2020.

55. Jeyaraman M, Somasundaram R, Anudeep TC, Ajay SS, Vinodh KV, Jain R and Khanna M. Mesenchymal Stem Cells (MSC's) as a Novel Therapeutic Option for nCOVID-19- A Review. Open Journal of Regenerative Medicine. 2020;9:20-35.

56. Tanne., Janice Hopkins. Covid-19: FDA approves use of convalescent plasma to treat critically ill patients. BMJ. 2020. (In press)

57. Zhonghua Jie He He Hu Xi ZaZhi. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia.2020;43(3):185-188. 

58. Physicians work out treatment guidelines for coronavirus. Korea Biomedical Review. 2020.http://www.koreabiomed.com/news/articleView.html?idxno=7428[Cited: 25^th April 2020]

59. Treatment of confirmed COVID-19 case by CD MICC team. 2020. https://www.medcampus.io/mnotes/protocol-for-treatment-of-confirmed-covid-19-5e5e2781e86c5d0001f77303[Cited: 25^th April 2020]

60. Vademecum for the treatment of people with COVI-19 disease. Italian Society of Infectious and Tropical Diseases. Lombardy Region Section. 2^nd Ed., 2020. https://www.simit.org/medias/1555-covid19-linee-guida-trattamento-01mar.pdf. [Cited: 25^th April, 2020]

61. Mount Sinai Health System Treatment Guidelines for SARS-CoV-2 Infection (COVID-19).https://www.mountsinai.org/health-library/diseases-conditions/2019-novel-coronavirus-2019-ncov.[Cited: 25^th April,2020].

62. Revised Guidelines on Clinical Management of COVID – 19. Ministry of Health & Family Welfare; Government of India. 2020.https://www.mohfw.gov.in/pdf/RevisedNationalClinicalManagementGuidelineforCOVID1931032020.pdf. [Cited: 1^st May, 2020].

63. Recommendations for Investigational COVID-19 Convalescent Plasma. 2020.https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma. [Cited: 1^st May, 2020].

64. Containment Plan for Large Outbreaks Novel Coronavirus Disease 2019 (COVID-19). Ministry of Health and Family Welfare, Government of India. 2020.https:/www.mohfw.gov.in/pdf/3ContainmentPlanforLargeOutbreaksofCOVID19Final.pdf. [Cited: 1^st May, 2020].

65. Siddiqu HK, Mehra MR. COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal. Journal of Heart and Lung Transplantation. 2020. (In press)

66. World Health Organization. Clinical management of severe acute respiratory infection when COVID-19 is suspected. Updated March 13, 2020. https://www.who.int/publications-detail/clinical-management-ofsevere-acute-respiratory-infection-when-novelcoronavirus-(ncov)-infection-is-suspected. [Cited: 25^th April, 2020].

67. Centers for Disease Control and Prevention. Corona virus disease 2019 (COVID-19) clinical care. Updated March 30, 2020. https://www.cdc.gov/coronavirus/2019ncov/hcp/clinical-guidance-management-patients. Html [Cited: 25^th April, 2020].

68. Bacille Calmette-Guérin (BCG) vaccination and COVID-19. Scientific brief.https://www.who.int/news-room/commentaries/detail/bacille-calmette-gu%C3%A9rin-(bcg)-vaccination-and-covid-19[Cited: 25^th April, 2020].