Antiviral therapy for COVID-2019

Hanik Badriyah Hidayati 1, Evi Octavia 2, Cempaka Thursina Srisetyaningrum 3
Author affiliations:
  1. Neurology Department, Faculty of Medicine, Universitas Airlangga/ Dr. Soetomo General Hospital, Surabaya - Indonesia.
  2. Hospital Pharmacy Installation of Dr. Soetomo General Hospital, Surabaya, East Java, Indonesia.
  3. Neurology Department, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta - Indonesia.
*Correspondence: Hanik Badriyah Hidayati; E-mail: hanikhidayati@fk.unair.ac.id.
Abstract

The whole world is experiencing a global pandemic caused by Coronavirus disease 2019. As the pandemic progresses, there has been much research on antiviral drugs, such as hydroxychloroquin, chloroquine, remdesivir, lopinavir-ritonavir, favipiravir, oseltamivir, and umifenovir.  Specific antiviral drugs proven to be effective against SARS-CoV-2 have not been found and approved for the medication of COVID-19. Currently, case detection, infection control, monitoring, prevention, and supportive care are the means focused on the treatment of COVID-19. A large scale research is currently underway to analyze safety and efficacy of antiviral drugs, while trials of the SAR-CoV-2 vaccine are rapidly expanding. This mini review briefly introduces the current antiviral therapy for COVID-19.
Key word: Antiviral therapy; Drugs; COVID-19
Citation: Hidayati HB, Octavia E, Srisetyaningrum CT. Antiviral therapy for COVID-2019. Anaesth. pain intensive care 2021;25(3):387–390. DOI: 10.35975/apic.v25i3.1522
Received: January 8, 2021; Reviewed: March 11, 2021; Accepted: March 11, 2021
Introduction

The whole world is experiencing a global pandemic caused by Coronavirus disease - 2019.1 Based on data according to the World Health Organization, Globally, as of 18 May 2021, there have been 163,312,429 confirmed cases of COVID-19, including 3,386,825 deaths, reported to WHO. As of 18 May 2021, a total of 1,407,945,776 vaccine doses have been administered.1,2 COVID-19 infection rates continue to increase sharply.3 As of 18 May, 2021 there have been  880,362 confirmed cases and 19,617deaths in Pakistan.1
Compared to COVID-19, Severe Acute Respiratory Syndrome (SARS–CoV) had the incidence of 8,422 cases with a case fatality rate (CFR) of 11%, and the Middle East Respiratory Syndrome (MERS) 2574 laboratory-confirmed cases, including 886 associated deaths (case-fatality ratio 34.4%). While the diagnostic ctiteria of COVID-19 is still being periodically reviewed, it might take years for the actual number of cases to be known.4 As the pandemic progresses, there has been extensive research on antiviral drugs, namely hydroxychloroquin, chloroquine, remdesivir, lopinavir-ritonavir, favipiravir, oseltamivir, and umifenovir.5 We present here an overview of the current anti-viral drugs being used.

Antiviral therapy

Due to the clinical manifestations of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, antiviral therapy that can treat COVID-19 is being investigated. Mechanism of action of antiviral drugs is by inhibiting the entry of the virus (by transmembrane serine protease 2 (TMPRSS2) and the angiotensin-converting enzyme 2 (ACE2) receptor; fusion inhibitors inhibit the fusion process and endocytosis or the action of the RNA-dependent RNA polymerase and the SARS-CoV-2 3-chymotrypsin-like protease (3CLpro).3,6,7 Antivirals may have the biggest impact because viral replication is probably very active initially in the progression of COVID-19 before the disease moves to the high inflammation syndrome state that can lead towards the next step of disease inclusive of hypercritical stage. Therefore, the role of antiviral drugs needs to be understood in curing minor, moderate, major and critical disease, so that the treating physicians may optimize medication for the COVID-19 patients.3,6
In clinical trials antiviral therapy was investigated to find the efficacy of SARS-CoV-2 treatment. It is reported that single therapy or combinations therapy for the COVID-19 patients differs in different countries of the world. These methods of therapy usually depend on the number of deaths and the frequency of mechanical ventilation the patients use. In addition, there is no specific medication for the COVID-19. Currently, various countries around the world have been investigating different antiviral therapies for the COVID-19 (Table 1).8 Specific antiviral drugs proven to be effective against SARS-CoV-2 have not been found and approved for the medication of COVID-19. Therefore, rapid assessment of the antiviral drugs currently available for use in COVID-19 patients is critical at this time of crisis, as well as for finding newer drugs.9
Antimalarial
Hydroxychloroquine and Chloroquine
Hydroxychloroquine and chloroquine are antimalarial drug. Hydroxychloroquine is a chloroquine analogue. June 15, 2020, the FDA withdrew the emergency use authorization for hydroxychloroquine, throwing out that it is unlikely to be effective in medicating COVID-19. In Addition, given the processing of that viral fusion does not occur, and cytokine release converting enzyme 2 (ACE2) cellular receptor, acidification of the cell membrane at the surface, so immunomodulation.10 Neither drugs are approved by FDA for the medication of COVID-19 patients. Have serious cardiac adverse events and other serious side effects (methemoglobinemia) of hydroxychloroquine do not justify its continued use.10,11 Chloroquine was introduced in 1934, while hydroxychloroquine was introduced in 1946.6 Hydroxychloroquine used to medicate systemic lupus erythematosus (SLE), rheumatoid arthritis, and also malaria. Normally, hydroxychloroquine has less and lower toxicity (including a small tendency to interval QTc prolongation) and minor drug-drug interactions than chloroquine (Table 1).6 Mechanisms may include inhibiting viral enzymes or processes such as DNA.
HIV Protease inhibitor
Lopinavir/Ritonavir
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication relies on the splitting of a helicase, and polyproteins become an RNA-dependent RNA polymerase. In the splitting, protease, which is responsible, namely: 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro).6 Ritonavir acts to increase plasma level of lopinovir by inhibiting the CYP3A-mediated metabolism of lopinavir.11 The combined use of these drugs can increase the bioavailability of lopinavir significantly, and the effect of antiviral is improved in vivo.12 Lopinavir and ritonavir have mechanism of action may bind to primary enzyme, it called Mpro, supressing the repilicationof  the coronavirus so that it does not occur. This can suppress activity of the corona virus.13 Lopinovir and ritonavir have been researched in patients with COVID-19. The clinical trials on lopinavir/ritonavir have not established their efficacy for the treatment of COVID-19.6,13 The common adverse events of lopinavir/ritonavir observed are diarrhea, nausea and vomiting, while severe adverse event include interval QTc prolongation and hepatotoxicity (Table 1).3,6
Nucleotide reverse transcriptase inhibitor

pyrazinecarboxamide derivative prodrug of a nucleoside analogue that can be triphosphorylated in and RNA polymerase of the virus, protein glycosylation, assembly of the virus, new virus
Remdesivir and Favipiravir
Remdesivir is a nucleotide prodrug of an adenosine analog, and is infised intravenously. Favipiravir is a cells and acts as the virus RNA-dependent RNA polymerase (RdRp) substrate.12
Remdesivir and favipiravir inhibit viral replication through premature termination of RNA transcription.6,12 Food and Drug Administration (FDA) hs approved remdesivir for the medication of COVID-19 in hospitalized pediatric patients of at least 40 kg and 12 years or older and the adults.11 Remdesivir should be administered in a hospital or a healthcare setting that can provide the same level of care to an inpatient hospital.6 Remdesivir is administered as a loading dose 200 mg on day 1, followed by once daily 100 mg IV dose for a total of 10 days, similar to the doses used in the clinical trials to medicate Ebola for adults (Table 1).3,11 Remdesivir can lead to gastrointestinal symptoms such as nausea, raised levels of transaminase, an elevated time of prothrombin, and hypersensitivity reactions.6
Favipiravir was developed in Japan in 2014. Initial clinical trial outcome indicate that favipiravir produces much greater improvement in chest imaging in COVID-19 patients compared to lopinavir. Faster viral clearance and fewer adverse events were also viewed in patients taking favipiravir compared to those taking lopinavir-ritonavir.3 The most serious adverse events of favipiravir is teratogenicity. Common adverse events were gastrointestinal symptoms, liver enzyme abnormalities, raised serum uric acid, and psychiatric issues.12
Several clinical trials analyzing remdesivir and favipiravir for the medication of COVID-19 are currently underway or in development.6
Neuraminidase inhibitor (Virus release inhibitor)
Oseltamivir
Oseltamivir is inhibitor of a neuraminidase and is used to treat influenza A and B. It is also being researched for the medication of COVID-19. It has been reported potentially inhibiting the SARS-CoV-2. Case reports suggest a better prognosis in COVID-19 patients taking oseltamivir. However, oseltamivir efficacy for the medication of COVID-19 needs long term clinical trials.5
Fusion Inhibitor 
Uminefovir
Umifenovir, also called as arbidol, is another antiviral agent whish acts by inhibiting spike protein /ACE2 binding and fusion of viral envelopes providing antiviral effects. Initial studies showed that arbidol medication was likely to raise the discharge rate and reduce the mortality rate for patients with COVID-19. Currently, arbidol effectiveness still has no clear evidence and needs further research.5
Conclusion

COVID-19 infection rates continue to increase sharply, as well as the number of antiviral drugs that work as a treatment for COVID-19. Currently, case detection, infection control, monitoring, prevention, and supportive care are the mean focus in the treatment of COVID-19. No specific antiviral therapy has been confirmed to be effective in curing COVID-19. Studies are currently underway to analyze the safety and efficacy of antiviral drugs, while trials of the SAR-CoV-2 vaccines are rapidly expanding. 
Conflict of Interest

The authors declare no conflict of interest.

Acknowledgement

The authors are thankful to Hanik Badriyah Hidayati for Checking plagiarism and Celine Anindytha for helping hyperlinking the references.

References
  1. Wungu CDK, Khaerunnisa S, Putri EAC, Hidayati HB, Qurnianingsih E, Lukitasari L, et al. Meta-analysis of cardiac markers for predictive factors on severity and mortality of COVID-19. Int J Infect Dis. 2021;105:551–9. [PubMed] DOI: 1016/j.ijid.2021.03.008
  2. Organization W. Coronavirus disease (COVID-19) Situation Report. 2021. (Cited: March 20, 2021) Available from: https://covid19.who.int/
  3. Lam S, Lombardi A, Ouanounou A. COVID-19: A review of the proposed pharmacological treatments. Eur J Pharmacol. 2020;886(May):173451. [PubMed] DOI: 1016/j.ejphar.2020.173451
  4. Rochmawati N, Hidayati HB, Yamasari Y, Yustanti W, Rakhmawati L, Tjahyaningtijas HPA, et al. Covid Symptom Severity Using Decision Tree. Proceeding - 2020 3rd Int Conf Vocat Educ Electr Eng Strength Framew Soc 50 through Innov Educ Electr Eng Informatics Eng ICVEE 2020. 2020; (Cited: March 20, 2021) Available from: https://ieeexplore.ieee.org/abstract/document/9243246
  5. Zhao M, Zhang J, Li H, Luo Z, Ye J, Xu Y, et al. Recent progress of antiviral therapy for coronavirus disease 2019. Eur J Pharmacol. 2021;890. [PubMed] DOI: 1016/j.ejphar.2020.173646
  6. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines.Disponible en: https://covid19treatmentguidelines.nih.gov/. NIH. 2020;2019:130.
  7. Nugraha D, Kloping NA, Yudhawati R, Purwandhono A, Hidayati HB. A current update in COVID-19 associated acute respiratory distress syndrome: Focus on mesenchymal stem cell therapy. Anaesth Pain Intensive Care. 2020;24(6):671–81. DOI: 35975/apic.v24i6.1404
  8. Kivrak A, Ulaş B, Kivrak H. A comparative analysis for antiviral drugs: Their efficiency against SARS-CoV-2. Int Immunopharmacol. 2021 Jan;90:107232. [PubMed] DOI: 1016/j.intimp.2020.107232
  9. Frediansyah A, Tiwari R, Sharun K, Dhama K, Harapan H. Antivirals for COVID-19: A critical review. Clin Epidemiol Glob Heal . 2021 Jan-Mar;9:90-98. [PubMed] DOI: 1016/j.cegh.2020.07.006
  10. Smith T, Bushek J, Leclaire A, Prosser T. COVID-19 Drug Therapy What' s been updated : Highlights : 2020; IBM Micromedex. DynaMed [cited 2012 Mar 15]. Available from: https://www.dynamed.com/drugsbrowse
  11. Wang D, Li Z, Liu Y. An overview of the saety, clinical application and antiviral research of the COVID-19 therapeutics. J Infect Public Health. 2020;13(10):1405–14. [PubMed] DOI: 1016/j.jiph.2020.07.004
  12. ASHP COVID-19 Resource Center. Assessment of Evidence for COVID-19-Related Treatments : Updated 4 / 10 / 2020 TABLE OF CONTENTS; 2020. p.1–138. Available from: https://www.ashp.org/COVID-19?loginreturnUrl=SSOCheckOnly
  13. Jolanda van Zuuren MD, Lacoviello Vito MD F. DynaMed. [cited 2021 Mar 15]. Available from: https://www.dynamed.com/condition/covid-19-novel-coronavirus


    Table 1. Review of antiviral therapy to treat COVID-19(3,8,11,13)
Drug Mechanism of action Trial or Clinical Experiance  Dosage Approved indication(s) Adverse drug reaction Drug interaction country that use drugs
Remdesivir inhibitor of RNA-dependent RNA polymerase administration; 200 mg day 1 loading dose one times daily followed by 100 mg one times  daily for a total of 10 days (IV) None Common: Gastrointestinal:nausea (3-7%)

Serious: cardiac arrest, Transaminase level raised, hepatotoxicity, anaphylaxis, hypersensitivity reaction ( less than 2%), infusion reaction		 ·          CYP3A4 inducers decrease effectiveness

·          Major Interaction; Chloroquine , Hydroxychloroquine		 Italy, spain, germany
Lopinavir-ritonavir

( kaletra)		 inhibitor of 3CL protease 400mg/100 mg twice daily for maximum to 14 days ( oral) HIV Gastrointestinal disturbances (nausea 10.3% vomiting 6.8% adult ,pediatric 12%, diarrhea adult 19.5%, pediatric 12%), raised transaminase,raised  bleeding, insulin resistance , hyperlipidemia, hyperglycemia, , prolong of QT interval, possible renal dysfunction risk, steven-Johnson syndrom, central nervous depression, respiratory depression ·          inhibitor of CYP3A4 and substrate - substrate of CYP2D6

·          Contraindicated Interaction: Amiodaron, fluconazole, simvastatin, phenytoin, rifampin, ketoconazole		 Italy, pain, South Korea, USA, China
Favipiravir inhibitor of RNA-dependent RNA polymerase 1600-1800 mg daily on day1, then 600 mg two times daily for 7-14 days ( oral) Ebola virus, Influenza A and B, Norovirus Gastrointestinal disturbances (nausea, vomiting diarrhea), hyperuricemia, elevated transaminases, decreased neutrophil count ·          Mainly mediated by aldehyde oxidase, not substrat CYPs Turkey
Chloroquine

Aralen)		 inhibitor of Viral entry 500 mg orally one or two times daily for 5–10 days  ( oral)  

Autoimmune disease:

rheumatoid arthritis (RA),

Systemic lupus erythematosus (SLE).

malaria		 Gastrointestinal disturbances (e,g, vomiting diarrhea, nausea), headache, delirium, QT prolongation, Torsades de Pointes, arrhythmia, agranulocytosis, extrapyramidal disease, seizures, retina disorder rare renal toxicity, anorexia, bitter taste ·          CYP3A4/5, 2D6, and 2C8 substrat

·          increased risk of  prolonging  QT interval with other QT prolongation agents ( antibiotikquinolon, macrolide)

·          raised  digoxin levels

·          raised risk of hypoglycemia with blood glucose-lowering agents

·          major interaction: Azitromycin

·          Metabolized by CYP3A4; monitor closely CYP3A4 strong inducers/inhibitors

·          Antacids		 Italy, spain, South Korea, USA, Brazil, China
HidroxychloroquinePlaquenil) inhibitor of Viral entry Day 1 400 mg two times daily, followed by 200 mg two times daily for 5–10 days Alternative: 200 mg Three times daily for 10 days or 400 mg one daily for 5 days  ( oral) Gastrointestinal disturbances (nausea), QT prolongation, hypoglycemia, neuropsychiatric effects, agranulocytosis, extrapyramidal disease, disorder muscle,  hearing loss, angiodema Italy, Spain, Turkey, Russia, South Korea, Brazil
Oseltamivir Neuraminidase inhibitor 75 mg every 12 hours ( oral) Influenza A and B Gastrointestinal disturbances (nausea 8-10%, vomiting 2-8% adult 8-16% pediatric), headache, cardiac dyrhythmia, hepatitis, seizure, , anaphylaxis Major interaction: warfarin Italy,USA, China,
Umifenovir Spike protein/ACE2 membrane fusion inhibitor 200 mg 3 times daily for duration of 7-10 days/longer  ( oral) Influenza A and B Gastrointestinal disturbances ( nausea,vomitting),  allergic reaction, elevated transaminases Metabolized by CYP3A4; monitor strong inducers/inhibitors of CYP3A4 Russia
.