Potential Drugs for COVID-19 Treatment

Introduction

As the name implies, COVID-19 is a new disease, born in the year 2019. But the virus causing the condition is nothing new. In fact, coronavirus was first detected in the1930’s. This new virus is officially known as SARS-CoV-2. However, until now, no drug has been proven effective against viruses. On the same note, to date, there is no vaccine available as well.

Evidently, there are a lot of aspects of the virus that are not yet understood. We are still learning the course of the disease, its infectivity and ability to inflict harm and fatality. From all over the world, different figures in term of the number of people affected and the number of deaths is emerging, from some countries, it is trickling, but from some other corners of the world, it looks like the dam has cracked. The development and progression of the disease are unpredictable, thus deciding on the best drug to target this virus is not easy.

Previous experiences in two other outbreaks of coronavirus, in the form of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), have helped us in many ways in managing critical COVID-19 patients. Numerous drugs have been trialled during the previous two outbreaks, as well as during this short period of dealing with the current pandemic. Not surprisingly, many of these drugs are not the traditional antivirals that we recognized. Even though the use of some drugs are not providing much hope, but some drugs have shown promising results. At the time of writing, there is no antiviral drug that has been proven effective to treat COVID-19.

There are no drugs or other therapeutics presently approved by the U.S Food and Drug Administration (FDA) to prevent or treat COVID-19. Thus, experts have tried to use existing drugs to prevent or treat the disease based on hypotheses and the limited available evidence. These include remdesivir, lopinovir / ritonavir and chloroquine/hydroxychloroquine.

Remdesivir

Among several potential drugs tested for efficacy in the treatment of COVID-19, remdesivir is one of the most promising antivirals. Remdesivir was initially produced by an American biotech company, Gilead Sciences Inc. (GS-5734; Gilead Sciences Inc., Foster City, CA, USA) to treat Ebola¹.

Remdesivir is an adenosine analogue inhibitor of RNA-dependent RNA polymerases. It works by targeting viral RNA-dependent RNA polymerase and evading proofreading by viral exoribonuclease, resulting in premature termination of viral RNA transcription². Remdesivir has broad-spectrum antiviral activities against RNA viruses, including filoviruses (e.g., Ebola) ^2,3 arenaviruses and coronaviruses (e.g., SARS-CoV and MERS-CoV) ^4,5.

Previous research in cell cultures and animal models including mice and nonhuman primate (NHP) has shown that remdesivir can block replication of a variety of these coronaviruses and filoviruses. It is active in vitro and animal models against SARS, MERS, and other coronaviruses ^2-6.

The effectiveness of remdesivir as a treatment for COVID-19 is currently being studied in controlled trials all around the world, including in China and the US. In the compassionate-use remdesivir cohort, patients hospitalized for severe COVID-19 who were treated with remdesivir, clinical improvement was observed in 36 out of 53 patients (68%). The 53 patients came from the United States (22), Europe or Canada (22) and Japan (9)⁷.

Remdesivir has also been used to treat COVID-19 patients in Malaysia. Malaysia is the first country in Southeast Asia that has been chosen by the World Health  Organization (WHO) to be involved in clinical trials of this drug. One hundred patients will be recruited from nine hospitals throughout Malaysia⁸.

Lopinovir / Ritonavir

Lopinovir-Ritonavir (Kaletra®) is a fixed-dose combination drug used to treat human immunodeficiency virus (HIV) infection. Lopinavir is an HIV aspartate protease inhibitor while ritonavir helps to stabilize lopinavir. Ritonavir boosts lopinavir level, and this will help lopinavir work better. They are used with other HIV medications to help control HIV infection. The use of lopinovir-ritonavir is based on the previous experience with the drug, which has shown promising results in treating SARS patients in 2003.

Cao et al.⁹ carried out a randomized, controlled, open-label trial for lopinavir-ritonavir in 199 hospitalized patients with severe COVID-19, of whom 99 were assigned to the treatment group, and 100 received the standard of care. They found that the addition of lopinavir-ritonavir treatment did not reduce viral RNA loads or the duration of viral RNA detectability compared to standard supportive care alone. SARS-CoV-2 RNA was still detected in 40.7% of the patients in the lopinavir-ritonavir group at the end of the trial (day 28). The treatment was not associated with clinical improvement or mortality in severely ill patients with COVID-19 or different from those receiving standard care alone. From their study, it can be concluded that in hospitalized adult patients with severe COVID-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care⁹.

Chloroquine / hydroxychloroquine

Chloroquine and its less toxic derivative hydroxychloroquine are typically used as antimalarials and as disease-modifying antirheumatic drugs (DMARD) for the treatment of systemic lupus erythematosus, rheumatoid arthritis and other rheumatological conditions^{10, 11}.

Hydroxychloroquine is currently recommended as empirical treatment under the Malaysian Ministry of Health’s interim guidelines for severe acute respiratory infection

(SARI)/pneumonia with features suggestive of viral origin which may include specific chest X-Ray changes and normal or low white cell count, particularly the lymphocyte count.

The mechanism of action of these drugs against Plasmodium parasites is generally believed to be through inhibition of the polymerization of heme to non-toxic hemozoin. The increased pH and the accumulation of heme will result in oxidative damage to the membrane, and this will cause the lysis of the parasites.

At the time of the SARS epidemic, chloroquine was suggested as a drug that could be used to treat this infection^12,13. Therefore, some clinicians have suggested that the medications may be helpful to treat COVID-19.

Recent in vitro studies have shown that both hydroxychloroquine and chloroquine have antiviral properties against SARS-CoV-2.¹² However, the mechanism of action of hydroxychloroquine/chloroquine against SARS-CoV-2 is not entirely understood. According to Vincent et al¹², it is believed that like SARS-CoV, SARS- CoV-2 enters cells by binding to the angiotensin-converting enzyme 2 (ACE-2) receptor, and chloroquine may prevent the virus from binding to this receptor by inhibiting terminal glycosylation¹². However, another research reported that the mechanism of action of these drugs involves the disruption of viral replication, propagation, endocytosis/exocytosis by increasing the pH of endosomes/lysosomes¹³.

As with many other antiviral drugs, the clinical evidence or response is less clear and more difficult to interpret compared to in vitro data. Several studies have been done to examine the effectiveness of the drugs towards SARS- CoV-2^14,15,16. Some reported positive results for hydroxychloroquine and chloroquine in COVID-19 treatment. But some concluded that chloroquine and hydroxychloroquine are less likely to be effective against this novel coronavirus. On the other hand, FDA has warned that using hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting may put people at risk of serious heart rhythm problems, especially QT prolongation¹⁷. Current data is still minimal. More research is required in order to determine the best effective dose, when to give it and for how long, and how the risks and benefits of these drugs measure up in the fight against COVID-19.

Conclusion

From the limited information and experience in using drugs to treat COVID-19, it is still not possible to draw a firm conclusion. However, some drugs are useful and cannot simply be disregarded. More trials and work need to be done to develop the treatment that is effective and safe.

References

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2. Tchesnokov EP, Feng JY, Porter DP, Götte M. Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir. Viruses 2019 Apr 4; 11(4): pii: E326.

3. Warren T, Jordan R, Lo M, Soloveva V, Ray A, Bannister R, et al. Nucleotide prodrug GS-5734 is a broad-spectrum filovirus inhibitor that provides complete therapeutic protection against the development of Ebola virus disease (EVD) in infected nonhuman primates. Open Forum Infect Dis 2015; 2.

4. Emmie de-W, Friederike F, Jacqueline Cr, Robert J, Atsushi O, Tina T et Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. PNAS March 24 2020; 117 (12): 6771-6776.

5. Julie D, Robin G, Jason K, Reed FJ, Gene GO, Lisa EH et al. Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies. Drugs 2017; 77(18): 1935–1966.

6. Manli W, Ruiyuan C, Leike Z, Xinglou Y, Jia L, Mingyue X et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30: 269–271.

7. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A et al., Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med April,

8. SungaI Buloh Hospital patient first in Asean to be given Remdesivir, New Straits Times, May 5, 2020; Malaysia.

9. Cao B, Yeming W, Danning W, Wen L, Jingli W, Guohui F, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med March 18, 2020.

10. Tönnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy - a review of the literature. Immunopharmacol Immunotoxicol 2013; 35:434–42.

11. Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol 2012; 42:145–53.

12. Vincent MJ, Bergeron E, Benjannet S et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005; 2:69.

13. Al-Bari MA. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicrob Chemother 2015; 70:1608–1621.

14. Jianjun G, Zhenxue T, Xu Y. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. BioScience Trends. 2020; 14(1):72-73.

15. Philippe G, Jean-Christophe L, Philippe P, Van TH, Line M et Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of anopen-label non-randomized clinical trial.  Int J Antimicrob Agents 2020.

16. Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, de Castro N. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect 2020.

17. S Food and Drug Administration [Internet].  FDA cautions against the use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems [cited 2020 May 2]. Available: https://www.fda.gov/drugs/drug-safety-and-availability