REVIEW ARTICLE

Novel Coronavirus - Novel Treatments: A Review

Harshini Suresh, Mansoor Ahmed

Department of Community Medicine, Mysore Medical College and Research Institute, Mysuru, Karnataka, India

ABSTRACT

The pandemic of coronavirus disease (COVID 19) caused by novel coronavirus (nCoV) emerged in Wuhan-China in late 2019 and it causes severe respiratory infection in humans. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Countries across the globe have adopted various prevention and control measures to minimize negative health impacts. At present, there is no approved treatment for COVID 19. Several drugs and vaccines are being tested for their potential activity and their side effects. The drug which is currently showing the most promising results is remdesivir though it is not yet approved by FDA. Regarding the use of hydroxychloroquine, there are many controversies. Another emerging treatment is the use of neutralizing antibodies. This review article was designed to evaluate the various treatment modalities followed in different countries where they successfully treated the patients.

Key words: Pandemic, COVID-19, Treatment, Review

INTRODUCTION COVID 19 patients, 80% do not need hospitalization, 20% require hospitalization, and among these, only 5% need iruses continue to emerge and pose a challenge to Public ventilators.[4] As of June 1, 2020, there have been more than Health. Human health, animal health, and the state of 6 million reported cases and 379,044 deaths in more than ecosystems are inextricably linked. About 70–80% of 216 countries. The world is carrying out two concurrent V [1] emerging and re-emerging infections are of zoonotic origin. wars against coronavirus: On the one hand, it is trying to Population growth, climate change, increasing urbanization, slow down or stop the spread of the disease and, on the other and international travel have increased the emergence of hand, is trying to find out effective treatments. At present, respiratory pathogens.[1] On December 31, 2019, many more than 300 active trials are underway. The majority of the pneumonia cases of unknown etiology were reported in the trials aim to repurpose the commonly used medications such city of Wuhan in China. Novel coronavirus (2019-nCoV) was as anti-malarial, anti-influenza, anti-HIV combinations, and identified as the agent causing this pneumonia on January 7, antibacterial, immunomodulators.[5] In this article, we discuss 2020. The outbreak was declared a Public Health Emergency some of the drugs that showed promising results based on of International Concern on January 30, 2020. The WHO their compassionate use against COVID 19. has now characterized the outbreak as a global pandemic. A nCoV is a new strain that has not been previously identified in MATERIALS AND METHODS humans. The main route of transmission is through respiratory droplets or close contact with an infected person, including A literature search was performed using PubMed and Google through fomites. Contact transmission includes contact with scholar websites, and we accessed published literature, oral, nasal, and mucous membranes of the eye.[2] Highest newspaper articles, and other internet resources. Our study viral loads were detected within 3 days after symptom onset, included articles published between February 1, 2020 (1st case with higher viral loads detected in the nose than in the throat, in India was reported on January 30) and June 1, 2020. especially in the early stage of illness. Viral loads peaked between 6 and 12 days after symptom onset and were highest in those most severely ill.[3] The most common symptoms of Various Treatments under Trial for COVID-19 COVID-19 are fever, tiredness, and dry cough. Some patients Mycobacterium w may have aches and pains, nasal congestion, runny nose, sore throat, or diarrhea. Some people become infected but do not Mycobacterium w was developed as an immunomodulator develop any symptoms and do not feel unwell. Among the for leprosy which acts through the toll-like receptor pathway

Correspondence: Dr. Mansoor Ahmed, Department of Community Medicine, Mysore Medical College and Research Institute, Mysuru, Karnataka, India. E-mail: [email protected]

103 Annals of Community Health • Jul-Sep 2020 • Vol 8 • Issue 3 Suresh and Ahmed: Coronavirus treatments and enhances T cell responses. Indian Pharmaceutical have not been published in a peer-reviewed journal to date.[10] major Cadila at Ahmedabad in Gujarat, along with Council Now a Mumbai based company in India is conducting phase for Scientific and Industrial Research (CSIR) in India, three trials and expecting trial results by July or August. has successfully tested Mycobacterium w (heat-killed Favipiravir is being tested in many countries against COVID- Mycobacterium Indicus Pranii). The safety trial of this drug 19 and results are awaited. was completed in the 1st week of May 2020, but its actual trial is ongoing among 40 patients in PGIMER, AIIMS Delhi, Remdesivir and AIIMS Bhopal in India to analyze the use of Mw as an adjunct to the treatment of critically ill COVID 19 patients. Remdesivir (GS-5734) was developed to treat Ebola In the multi-center trial conducted in PGIMER, it was found disease during the outbreak caused by RNA virus. It is a that Mw reduces the mortality in ICU patients with severe broad-spectrum antiviral that is being currently tested in sepsis and reduces the cytokine storm seen in COVID 19 various countries as a potential treatment for COVID-19. patients.[6] It has shown promising results in animal models for treating SARS-CoV-2 that causes COVID-19 infection. It was observed that the drug has antiviral activity in vitro Ivermectin + Doxycycline against pathogens that cause MERS and SARS, which are Dr Tarek Alam from Bangladesh conducted a trial using coronaviruses and structurally similar to SARS-CoV-2 that ivermectin (anti-parasitic drug) + Doxycycline (antibiotic), causes COVID-19, an RNA virus.[11] It is an experimental among 60 COVID 19 patients in Bangladesh Medical College drug and is not yet licensed or approved anywhere for the and found an astounding success with this combination. use of any condition. It was found in a study that remdesivir All of them recovered within 4 days.[7] A study conducted targets polymerase, making the virus difficult to spread. The in the University of Melbourne and Monash University by trial, known as Adaptive COVID-19 treatment trial or ACTT, Caly et al. which was published in the Journal “Antiviral demonstrated that remdesivir accelerates the recovery from Research” in March 2020 suggested that a single treatment patients with advanced COVID-19 with lung involvement. of ivermectin was able to effect a 5000-fold reduction in National Institute of Allergy and Infectious Disease in the the viral RNA in ivermectin-treated patients compared to USA stated that patients who took remdesivir had 30% fast control subjects, indicating that ivermectin treatment resulted time to recovery than those who received placebo.[12] Gilead in the effective loss of essentially all viral material by 48 h Sciences a US-based company has released the results of the in cell culture.[8] Sodhi et al. from the University of British phase three trial of this drug on June 1, 2020. They conducted Columbia in Canada observed that the nCoV depends on the an open-label study and evaluated 5-day and 10-day courses matrix metalloproteinases for survival, cell infiltration, and of the investigational antiviral remdesivir plus standard of replication. Tetracyclines, which are highly lipophilic drugs, care versus standard of care alone. In this study, hospitalized inhibit matrix metalloproteinases, which reduces the viral patients with confirmed COVID-19 infection and evidence of load.[9] pneumonia without reduced oxygen levels were randomized (1:1:1) to receive open-label remdesivir for 5 or 10 days or standard care alone. They assessed the clinical status by a Favipiravir seven-point ordinal score on day 11, ranging from hospital Favipiravir is an anti-viral agent that selectively inhibits RNA- discharge to increasing levels of oxygen and ventilatory dependent RNA polymerase of RNA viruses. The new strain support to death. The study stated that patients in the 5-day of severe acute respiratory syndrome coronavirus 2 (SARS- treatment group were 65% more likely to have clinical CoV-2) is also a positive sense single-stranded RNA virus. improvement on day 11 compared with those in the standard Favipiravir has shown anti-viral activities against several RNA of care group, which was statistically significant. The viruses such as Arenaviruses, Bunyaviruses, and Filoviruses. improvement in clinical status within the 10-day treatment Hence, these unique anti-viral profiles will make favipiravir a course of remdesivir versus standard care was also favorable, potential drug for specifically untreatable RNA viral infections, but it was not statistically significant. Remdesivir is currently including COVID-19. Favipiravir was first approved for the approved in Japan as a treatment for patients infected with treatment of influenza in Japan in 2014. Favipiravir is under SARS-CoV-2. Outside Japan, this drug is an investigational trial in many countries to treat COVID-19. The CSIR in India drug. It is authorized for use under an Emergency Use has received approval from the Drug Controller General of Authorization only for the treatment of patients with suspected India for clinical trials of favipiravir – an antiviral drug that or laboratory-confirmed SARS-CoV-2 infection. In clinical can stop the viral replication in infected cells.[10] In a non- studies with this drug, infusion-related reactions and liver randomized study in China by in March 2020, a comparison transaminase elevations have been observed. They also stated of two treatment regimens was done. It was found that those that it is possible that Gilead may make a strategic decision to who took favipiravir along with inhaled interferon cleared the discontinue the development of remdesivir or that FDA and virus in an average of 4 days compared with 11 days in the other regulatory agencies may not approve remdesivir, which control group (lopinavir/ritonavir). The results of this study may have significant limitations on its use.[11] However, in a

Annals of Community Health • Jul-Sep 2020 • Vol 8 • Issue 3 104 Suresh and Ahmed: Coronavirus treatments study published in the Journal “Lancet” done by Wang et al. Indian Pharmacopoeia Commission, results of all people in China in March 2020 showed that remdesivir was not taking HCQ are being monitored.[16] associated with statistically significant clinical benefits.[13] Lopinavir–Ritonavir Chloroquine and Hydroxychloroquine Lopinavir–Ritonavir an anti-HIV drug combination is also Hydroxychloroquine or chloroquine, often in combination under trial in many countries for COVID-19. The Indian with a second-generation macrolide, is being widely used for Council of Medical Research has suggested lopinavir/ the treatment of COVID-19, despite no conclusive evidence ritonavir combination therapy for laboratory-confirmed of their benefit. Although, generally safe when used for COVID-19 patients based on the observational studies of approved indications such as autoimmune disease or clinical benefit among patients with SARS-CoV and MERS- malaria, the safety, and benefit of these treatment regimens CoV, as well as the docking studies conducted by the National are poorly evaluated in COVID-19. Hydroxychloroquine Institute of Virology, Pune in India. The Indian Regulatory and chloroquine (used with or without a macrolide) are Authority, Central Drugs Standard Control Organization, has widely advocated for the treatment of COVID-19 based on accorded approval for restricted public health emergency in vitro evidence of an antiviral effect against SARS-CoV-2. use of this treatment protocol. The initial treatment protocol Their use is based on small uncontrolled studies and in the was for administering the combination treatment to all absence of evidence from randomized controlled trials. laboratory-confirmed patients. However, the first three On March 28, 2020, the FDA issued an emergency use laboratory-confirmed patients from Kerala (in India) had authorization for these drugs in patients if clinical trial mild symptoms of diagnosis and had a stable course of illness. access was unavailable. Other countries, such as China, Hence, lopinavir/ritonavir treatment was not administered in have issued guidelines allowing for the use of chloroquine these patients. It is, however, crucial to initiate the treatment in COVID-19. Several countries have been stockpiling before the patient develops features of severe illness. In the drugs, and shortages of them for approved indications, view of this, the treatment protocol was subsequently such as for autoimmune disease and rheumatoid arthritis, amended to include additional criteria of severity as well have been encountered. In a study published in the Journal as organ damage for initiating the combination treatment. “Lancet” by Mehra et al. in May 2020, which was based on The inclusion criteria also include high-risk group patients hospital registry data (96,000 hospital registries) it was found associated with a higher risk of mortality (age >60 years, that the use of a regimen containing hydroxychloroquine or hypertension, diabetes mellitus, renal failure, chronic lung chloroquine (with or without a macrolide) was associated disease, and immunocompromised persons) for initiating the with no evidence of benefit, but instead was associated combination therapy. This treatment protocol has a limitation. with an increase in the risk of ventricular arrhythmias and The combination treatment is approved for emergency public a greater hazard for in-hospital death with COVID-19. health use, only among laboratory-confirmed patients with a These findings suggest that these drug regimens should not moderate degree of severity and not designed as a controlled be used outside of clinical trials, and urgent confirmation clinical trial. However, the treatment outcomes among the first from randomized clinical trials is needed. In this study, it few cases would be useful in providing guidance about the was given that the use of the drug increased the risk of death clinical management of COVID-19 cases in the future.[17] If by 34% and increased the risk of serious heart disease by found useful in managing initial COVID-19 infected patients, 137%.[14] However, this Lancet study was based on hospital further evaluation using a randomized control trial design is registry data, not a randomized controlled trial. Based on this warranted to guide future therapeutic use of this combination. study, the WHO announced a temporary suspension of the A study published by Hung et al. in the Journal “Lancet” in clinical trial of hydroxychloroquine, which has been used May 2020 stated that a treatment involving a combination for the treatment of COVID-19 patients.[15] However, Indian of the drugs interferon beta-1b, plus antiviral combination Council of Medical Research (ICMR) announced on May 27 lopinavir-ritonavir, and ribavirin is better at reducing the viral that it will be continuing the use of hydroxychloroquine as load than lopinavir-ritonavir alone.[18] prophylaxis for COVID-19 disease. The council found that the drug is very effective, and it is having less side effects Interferon for prophylaxis consumption. Taking into consideration the biological plausibility, in vitro data, and safety level of the Interferons are a group of signaling proteins made and drug, the ICMR had recommended it for empiric use under released by the host cells in response to the presence of strict medical supervision.[16] Case–control and observational several viruses. Commercially available interferons are studies were conducted in AIIMS, ICMR, and also in three human interferons manufactured using recombinant DNA public hospitals in Delhi in India. Although randomized technology. A Researcher Dr Eleanor Fish quoted that trials of the drug were not conducted, the ICMR observed “Rather than developing virus-specific anti-viral for each new that it may be working and without major side effects except virus outbreak, we should consider interferons as the “first nausea, vomiting, and palpitations occasionally. As per the responders” in terms of treatment.”[19] Interferon provided

105 Annals of Community Health • Jul-Sep 2020 • Vol 8 • Issue 3 Suresh and Ahmed: Coronavirus treatments therapeutic benefit during the SARS outbreak of 2002 and category of mammals as camels, produces antibodies that 2003. Researchers have found that interferon-alpha2b can bind to the key protein on the nCoV.[24] Clinical trials need to help speed up the recovery of COVID-19 patients. A study be done to prove this. Another research team from University published in the Journal “Frontiers of Immunology” by Zhou of Washington in US found that a combination of antibodies, et al. in China stated that treatment with interferon a2b may including the patient who recovered from the 2002 to 2003 significantly accelerate virus clearance and reduce levels SARS pandemic virus infection, can effectively block the of inflammatory proteins in COVID-19 patients. Treatment nCoV. One of the molecules S309 showed strong neutralizing with this drug has been used clinically for many years, activity against SARS-CoV-2. They also stated that adding and it has significantly reduced the duration of detectable an S309 antibody in combination with another less potent virus in the upper respiratory tract on an average by about antibody targets different site on the virus.[25] These results 7 days. It also reduced blood levels of interleukin (IL)-6, are yet to be validated in human trials. C-reactive protein (CRP), and inflammatory proteins found in COVID-19 patients. Randomized clinical trial is the next Plasma Therapy important step for evaluating this drug.[20] Now ICMR has approved interferon for clinical trials against COVID-19 Convalescent plasma therapy has been around for more than patients, which is being tried in the state of Kerala in India. 100 years and was used during the flu pandemic in 1918. The use of convalescent plasma is not a new concept. The therapeutic potential of convalescent sera has been well Neutralizing Antibodies recognized and was used to stem outbreaks of viral diseases The neutralizing antibody is an antibody that defends a cell such as poliomyelitis, measles, and mumps.[26-28] Based on the from a pathogen or infectious particle by neutralizing any prior experience and existing evidence in treating other viral effect it has biologically and makes the pathogen no longer infections, the early administration of convalescent plasma infectious. The Council of Scientific and Industrial Research or hyper-immune immunoglobulin from patients containing (CSIR) in India has approved a multinational project on significant antibody titers is likely to reduce the viral load and May 9, 2020, to develop human monoclonal antibodies disease mortality. Over the past two decades, this therapy was (hmAbs) that can neutralize coronavirus in patients. This successfully used in the treatment of SARS-CoV-1, H5N1 project was to generate hmAbs to SARS-CoV-2 from the avian influenza, and H1N1 influenza wherein the transfusion convalescent phase of COVID-19 patients and select high of convalescent plasma was found to be both effective and affinity and neutralizing antibodies. The project also aimed safe.[29] In 2014, the use of convalescent plasma collected to understand the future adaptation of the virus and generate from patients who had recovered from Ebola virus disease hmAbs clones that can neutralize the mutated virus so that was recommended by the WHO as an empirical treatment it could be readily used for combating future SARS-CoV during the outbreaks.[30] COVID-19 convalescent plasma is infections.[21] Chinese scientist Sunney Xie who is the director currently being studied as a therapy for COVID-19 patients. of Beijing Advanced Innovation Centre for Genomics said Preliminary data from China and other countries suggest some that when they injected neutralizing antibodies into infected potential promise and further study is needed to determine its mice, after 5 days, the viral load reduced by a factor of 2500. efficacy. The US FDA is accepting emergency Investigational The drug uses neutralizing antibodies produced by the human New Drug Applications for the use of plasma from recovered immune system to prevent the virus from infecting cells for patients to treat people who are critically ill with COVID-19.[31] which they isolated the blood of 60 recovered patients.[22] One of the effective passive therapeutic approaches during These neutralized antibodies can become a specialized drug an outbreak of any infectious disease is the passive antibody that would stop the pandemic. therapy from convalescent patients sera who have recovered from the infection.[29] This can be used for the treatment of Another study done in China by Dai et al., who published patients who contract the infection in future. This type of his study in the Journal “Science” in April 2020, stated the passive therapy is simple but potentially a very effective tool probable effectiveness of two small molecule drug candidates for developing immediate immune responses under critical named 11a and 11b which could block the SARS-CoV-2 M conditions. In case of the current COVID-19 pandemic protease enzyme (which the virus uses to make copies of (SARS-CoV-2), the patients with resolved SARS-CoV-2 viral itself). The molecules could stop the virus from replicating infection will develop significant serum antibody response in monkey cells and it was found safe for administration in (IgG) to different viral epitopes of the SARS-CoV-2 virus rats and beagles.[23] For both drugs, further studies must be and some of these developed antibody responses in the host conducted. Scientists have also tested the effectiveness of system will be likely to have the potential to neutralize the therapies involving the use of antibodies that can bind to virus.[29] The high level of antibody titers produced by the host- some parts of the virus and block their entry into host cells. immune system against the SARS-CoV-2 virus significantly Furthermore, in a study published in the Journal “Cell” stated reduces the chances of getting reinfected.[29] A case series that antibodies derived from the immune system of the South described administration of plasma from donors who had American mammal called Ilamas which belong to the same completely recovered from COVID-19 to five patients with

Annals of Community Health • Jul-Sep 2020 • Vol 8 • Issue 3 106 Suresh and Ahmed: Coronavirus treatments severe COVID-19 on mechanical ventilation and persistently Itolizumab high viral titers despite investigational antiviral treatment. The Drug used for Biocon’s psoriasis is now being tested in patients had decreased nasopharyngeal viral load, decreased India in the cities Mumbai and Delhi for moderate cases of disease severity score, and improved oxygenation by 12 days COVID 19.[37] after transfusion, but these findings do not establish a causal effect. Finding appropriate donors and establishing testing to confirm neutralizing activity of plasma may be logistical Disulfiram challenges. It is used to treat alcoholism. It was used in SARS and MERS outbreaks and helps to produce an immune response. It is yet WHO’s “Solidarity Trial” to be studied if the drug is effective against COVID-19.[37] The WHO is conducting an International Clinical trial to find an effective treatment for COVID-19. This trial will Sarilumab (Kevzara) compare four treatment options against the standard of care, A monoclonal antibody does not attack the nCoV but instead to assess the effectiveness against COVID-19. Remdesivir, inhibits an abnormal immune response called “cytokine lopinavir/ritonavir, lopinavir/ritonavir with interferon storm.” However, a small study was conducted in china beta-1a, and hydroxychloroquine had been initially selected which showed no benefit to the patients.[37] as treatment options. Following new evidence on the safety and efficacy of hydroxychloroquine as a treatment for hospitalized COVID-19 patients, enrollment for this drug CONCLUSION was temporarily suspended on May 24, 2020. Over 100 countries have expressed an interest in participating in the A plethora of treatment modalities are being conceptualized, trial and the WHO is actively supporting more than 60 of but we found that the most promising results were observed them. To date, over 400 hospitals in 35 countries are actively with remdesivir, followed by triple combination of lopinavir- recruiting patients and nearly 3500 patients have been ritonavir, interferon beta-1b, and ribavirin and then with enrolled from 17 countries.[32] hydroxychloroquine but there are many unanswered questions. Neutralizing antibodies are also a promising option. Although many trials are ongoing for COVID-19, MISCELLANEOUS at present the best strategy to overcome this pandemic is by the time tested concept of prevention: By maintaining Social Oseltamivir Distancing, Proper hand hygiene, Cough Etiquette and the A neuraminidase inhibitor used for the treatment of influenza use of masks. has no documented effect against SARS-CoV-2. COVID- 19 outbreak occurred during the influenza season, so the REFERENCES patients were empirically given oseltamivir until they found the cause of COVID-19 as SARS-CoV-2.[33] Many clinical 1. World Health Organization. Coronavirus. Geneva: World trials included oseltamivir in the comparison group but not as Health Organization; 2020. Available from: https://www. [34] therapeutic option. who.int/emergencies/diseases/novel-coronavirus-2019. [Last accessed on 2020 May 27]. Umifenovir 2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in An antiviral agent which effectively inhibits the fusion of Wuhan, China. Lancet 2020;395:497-506. virus with host cells. This drug is used in Russia and China 3. Rajgopal T. COVID-19: Epidemiology and public health for the treatment of influenza and based on the in vitro data, aspects. Indian J Community Med 2020;45:111. now this drug is under trial for COVID-19. A study by 4. Q and A on Coronaviruses (COVID-19). Available from: Wang et al. published in the Journal of “Clinical Infectious https://www. who.int/news-room/q-a-detail/q-a-coronaviruses. Disease” stated that a non-randomized study was conducted [Last accessed on 2020 June 01]. on 67 patients with COVID-19 and it showed that the 5. Aljofan M, Gaipov A. COVID-19 treatment: The race against treatment with Umifenovir for 9 days lowered the mortality time. Electron J Gen Med 2020;17:em227. 6. Mycobacterial w (Mw) Drug Trial to be Conducted on rates and ensured high discharge rates compared with those [35] 40 Patients at Three Hospitals: PGIMER Director; 2020. who did not receive the drug. In India, phase three trial Available from: https://www.timesnownews.com/health/ has been started in Mumbai by a company named Glenmark article/mycobacterial-w-mw-drug-trial-to-be-conducted-on- Pharmaceuticals for the combination of two antiviral drugs 40-patients-at-three-hospitals-pgimer-director/586472?utm_ favipiravir and Umifenovir in COVID-19 patients. The study source=relatedarticles&utm_medium=widget&utm_campaign will involve 156 hospitalized patients who have moderate =related. [Last accessed on 2020 May 23]. symptoms of COVID – 19.[36] 7. Bangladeshi Doctors Tout COVID-19 “cure”: Could a

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