Treatment options for COVID-19: The reality and challenges

Shio-Shin Jean, Ping-Ing Lee, Po-Ren Hsueh, Shio-Shin Jean, Ping-Ing Lee, Po-Ren Hsueh

Abstract

An outbreak related to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China in December 2019. An extremely high potential for dissemination resulted in the global coronavirus disease 2019 (COVID-19) pandemic in 2020. Despite the worsening trends of COVID-19, no drugs are validated to have significant efficacy in clinical treatment of COVID-19 patients in large-scale studies. Remdesivir is considered the most promising antiviral agent; it works by inhibiting the activity of RNA-dependent RNA polymerase (RdRp). A large-scale study investigating the clinical efficacy of remdesivir (200 mg on day 1, followed by 100 mg once daily) is on-going. The other excellent anti-influenza RdRp inhibitor favipiravir is also being clinically evaluated for its efficacy in COVID-19 patients. The protease inhibitor lopinavir/ritonavir (LPV/RTV) alone is not shown to provide better antiviral efficacy than standard care. However, the regimen of LPV/RTV plus ribavirin was shown to be effective against SARS-CoV in vitro. Another promising alternative is hydroxychloroquine (200 mg thrice daily) plus azithromycin (500 mg on day 1, followed by 250 mg once daily on day 2-5), which showed excellent clinical efficacy on Chinese COVID-19 patients and anti-SARS-CoV-2 potency in vitro. The roles of teicoplanin (which inhibits the viral genome exposure in cytoplasm) and monoclonal and polyclonal antibodies in the treatment of SARS-CoV-2 are under investigation. Avoiding the prescription of non-steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, or angiotensin II type I receptor blockers is advised for COVID-19 patients.

Keywords: Angiotensin converting enzyme inhibitors; Coronavirus disease 2019 (COVID-19); Hydroxychloroquine; Non-steroidal anti-inflammatory drugs; Remdesivir; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no conflicts of interest.

Copyright © 2020. Published by Elsevier B.V.

References

    1. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 11 doi: 10.1016/S0140-6736(20)30566-3. pii: S0140-6736(20)30566-3. [Epub ahead of print]
    1. Cheng Z.J., Shan J. 2019 Novel coronavirus: where we are and what we know. Infection. 2020 Feb 18 doi: 10.1007/s15010-020-01401-y. [Epub ahead of print]
    1. Wu Z., McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24 doi: 10.1001/jama.2020.2648. [Epub ahead of print]
    1. Holshue M.L., DeBolt C., Lindquist S., Lofy K.H., Wiesman J., Bruce H. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382:929–936. doi: 10.1056/NEJMoa2001191.
    1. Lee P.I., Hu Y.L., Chen P.Y., Huang Y.C., Hsueh P.R. Are children less susceptible to COVID-19? J Microbiol Immunol Infect. 2020 Feb 25 doi: 10.1016/j.jmii.2020.02.011. pii: S1684-1182(20)30039-6. [Epub ahead of print]
    1. Huang W.H., Teng L.C., Yeh T.K., Chen Y.J., Lo W.J., Wu M.J. 2019 Novel coronavirus disease (COVID-19) in Taiwan: reports of two cases from Wuhan, China. J Microbiol Immunol Infect. 2020;53:481–484. doi: 10.1016/j.jmii.2020.02.009.
    1. Burke R.M., Midgley C.M., Dratch A., Fenstersheib M., Haupt T., Holshue M. Active monitoring of persons exposed to patients with confirmed COVID-19 - United States, January-February 2020. MMWR Morb Mortal Wkly Rep. 2020;69:245–246.
    1. Liu J., Liu Y., Xiang P., Pu L., Xiong H., Li C. Neutrophil-to-lymphocyte ratio predicts severe illness patients with 2019 novel coronavirus in the early stage. medRxiv. 2020 doi: 10.1101/2020.02.10.20021584.
    1. Cao Q., Chen Y.C., Chen C.L., Chiu C.H. SARS-CoV-2 infection in children: transmission dynamics and clinical characteristics. J Formos Med Assoc. 2020;119:670–673.
    1. Peiris J.S., Chu C.M., Cheng V.C., Chan K.S., Hung I.F., Poon L.L. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003;361:1767–1772. doi: 10.1016/s0140-6736(03)13412-5.
    1. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–513.
    1. Hofmann H., Pyrc K., van der Hoek L., Geier M., Berkhout B., Pöhlmann S. Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. Proc Natl Acad Sci USA. 2005;102:7988–7993.
    1. Lee K.H., Yoo S.G., Cho Y., Kwon D.E., La Y., Han S.H. Characteristics of community-acquired respiratory viruses infections except seasonal influenza in transplant recipients and non-transplant critically ill patients. J Microbiol Immunol Infect. 2019 Jun 19 doi: 10.1016/j.jmii.2019.05.007. pii: S1684-1182(18)30233-0.
    1. Lee P.I., Hsueh P.R. Emerging threats from zoonotic coronaviruses-from SARS and MERS to 2019-nCoV. J Microbiol Immunol Infect. 2020;53:365–367. doi: 10.1016/j.jmii.2020.02.001.
    1. To K.W., Tsang T.Y., Leung W.S., Tam A.R., Wu T.C., Lung D.C. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 2020 Mar 23 doi: 10.1016/S1473-3099(20)30196-1.
    1. Li G., De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV) Nat Rev Drug Discov. 2020;19:149–150. doi: 10.1038/d41573-020-00016-0.
    1. Agostini M.L., Andres E.L., Sims A.C., Graham R.L., Sheahan T.P., Lu X. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) Is mediated by the viral polymerase and the proofreading exoribonuclease. mBio. 2018;9 doi: 10.1128/mBio.00221-18. pii: e00221-18.
    1. Sheahan T.P., Sims A.C., Graham R.L., Menachery V.D., Gralinski L.E., Case J.B. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9 doi: 10.1126/scitranslmed.aal3653. pii: eaal3653.
    1. Martinez M.A. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother. 2020 Mar 9 doi: 10.1128/AAC.00399-20. pii: AAC.00399-20.
    1. Warren T.K., Jordan R., Lo M.K., Ray A.S., Mackman R.L., Soloveva V. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531:381–385.
    1. Mulangu S., Dodd L.E., Davey R.T., Jr., Tshiani Mbaya O., Proschan M., Mukadi D. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med. 2019;381:2293–2303.
    1. Medrxiv News. from.
    1. Brown A.J., Won J.J., Graham R.L., Dinnon K.H., 3rd, Sims A.C., Feng J.Y. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antivir Res. 2019;169:104541.
    1. Ko W.C., Rolain J.M., Lee N.Y., Chen P.L., Huang C.T., Lee P.I. Arguments in favour of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents. 2020 Mar 6:105933. doi: 10.1016/j.ijantimicag.2020.105933.
    1. de Wit E., Feldmann F., Cronin J., Jordan R., Okumura A., Thomas T. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci USA. 2020 Feb 13 doi: 10.1073/pnas.1922083117. pii: 201922083.
    1. Wang Y., Fan G., Salam A., Horby P., Hayden F.G., Chen C. Comparative effectiveness of combined favipiravir and oseltamivir therapy versus oseltamivir monotherapy in critically ill patients with influenza virus infection. J Infect Dis. 2019 Dec 11 doi: 10.1093/infdis/jiz656. pii: jiz656.
    1. 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;93:449–463.
    1. XinhuaNet Favipiravir shows good clinical efficacy in treating COVID-19: official. From.
    1. Chan J.F.W., Yao Y., Yeung M.L., Deng W., Bao L., Jia L. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis. 2015;212:1904–1913.
    1. Zumla A., Chan J.F., Azhar E.I., Hui D.S., Yuen K.Y. Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15:327–347.
    1. Sheahan T.P., Sims A.C., Leist S.R., Schäfer A., Won J., Brown A.J. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11:222. doi: 10.1038/s41467-019-13940-6.
    1. Cao B., Wang Y., Wen D., Liu W., Wang J., Fan G. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020 Mar 18 doi: 10.1056/NEJMoa2001282.
    1. Baden L.R., Rubin E.J. COVID-19 - the search for effective therapy. N Engl J Med. 2020 Mar 18 doi: 10.1056/NEJMe2005477.
    1. News Abidol and darunavir can effectively inhibit coronavirus. [in Chinese]
    1. Falzarano D., de Wit E., Rasmussen A.L., Feldmann F., Okumura A., Scott D.P. Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med. 2013;19:1313–1317.
    1. Chu C.M., Cheng V.C., Hung I.F., Wong M.M., Chan K.H., Chan K.S. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59:252–256.
    1. Yan Y., Zou Z., Sun Y., Li X., Xu K.F., Wei Y. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res. 2013;23:300–302.
    1. Vincent M.J., Bergeron E., Benjannet S., Erickson B.R., Rollin P.E., Ksiazek T.G. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. doi: 10.1186/1743-422X-2-69.
    1. Wang M., Cao R., Zhang L., Yang X., Liu J., Xu M. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30:269–271.
    1. Cortegiani A., Ingoglia G., Ippolito M., Giarratano A., Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care. 2020 Mar 10 doi: 10.1016/j.jcrc.2020.03.005. pii: S0883-9441(20)30390-7.
    1. Yao X., Ye F., Zhang M., Cui C., Huang B., Niu P. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Clin Infect Dis. 2020 Mar 9 doi: 10.1093/cid/ciaa237. pii: S1684-1182.
    1. Gautret P., Lagier J., Parola P., Hoang V.T., Meddeb L., Mailhe M. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 17 doi: 10.1016/j.ijantimicag.2020.105949.
    1. Madrid P.B., Panchal R.G., Warren T.K., Shurtleff A.C., Endsley A.N., Green C.E. Evaluation of Ebola virus inhibitors for drug repurposing. ACS Infect Dis. 2015;1:317–326.
    1. Bacharier L.B., Guilbert T.W., Mauger D.T., Boehmer S., Beigelman A., Fitzpatrick A.M. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314:2034–2044.
    1. Wang Y., Cui R., Li G., Gao Q., Yuan S., Altmeyer R. Teicoplanin inhibits Ebola pseudovirus infection in cell culture. Antivir Res. 2016;125:1–7. doi: 10.1016/j.antiviral.2015.11.003.
    1. Zhou N., Pan T., Zhang J., Li Q., Zhang X., Bai C. Glycopeptide antibiotics potently inhibit cathepsin L in the late endosome/lysosome and block the entry of Ebola virus, Middle East respiratory syndrome coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) J Biol Chem. 2016;291:9218–9232.
    1. Baron S.A., Devaux C., Colson P., Raoult D., Rolain J.M. Teicoplanin: an alternative drug for the treatment of coronavirus COVID-19? Int J Antimicrob Agents. 2020 Mar 13:105944. doi: 10.1016/j.ijantimicag.2020.105944.
    1. Beigel J.H., Nam H.H., Adams P.L., Krafft A., Ince W.L., El-Kamary S.S. Advances in respiratory virus therapeutics - a meeting report from the 6th isirv Antiviral Group conference. Antivir Res. 2019;167:45–67. doi: 10.1016/j.antiviral.2019.04.006.
    1. Beigel J.H., Voell J., Kumar P., Raviprakash K., Wu H., Jiao J.A. Safety and tolerability of a novel, polyclonal human anti-MERS coronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind, single-dose-escalation study. Lancet Infect Dis. 2018;18:410–418.
    1. Cockrell A.S., Yount B.L., Scobey T., Jensen K., Douglas M., Beall A. A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nat Microbiol. 2016;2:16226.
    1. Glowacka I., Bertram S., Müller M.A., Allen P., Soilleux E., Pfefferle S. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J Virol. 2011;85:4122–4134.
    1. Kawase M., Shirato K., van der Hoek L., Taguchi F., Matsuyama S. Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. J Virol. 2012;86:6537–6545.
    1. Zhou Y., Vedantham P., Lu K., Agudelo J., Carrion R., Jr., Nunneley J.W. Protease inhibitors targeting coronavirus and filovirus entry. Antivir Res. 2015;116:76–84.
    1. News FDA approves COVACTA trial for RA drug Actemra in COVID-19 patients. From:
    1. Chen L., Xiong J., Bao L., Shi Y. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis. 2020 S1473–3099(20)30141-30149.
    1. Shen C., Wang Z., Zhao F., Yang Y., Li J., Yuan J. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020 Mar 27 doi: 10.1001/jama.2020.4783.
    1. Cunningham A.C., Goh H.P., Koh D. Treatment of COVID-19: old tricks for new challenges. Crit Care. 2020;24:91.
    1. Luo H., Tang Q.L., Shang Y.X., Liang S.B., Yang M., Robinson N. Can Chinese medicine be used for prevention of corona virus disease 2019 (COVID-19)? A review of historical classics, research evidence and current prevention programs. Chin J Integr Med. 2020 Feb 22 doi: 10.1007/s11655-020-3192-6.
    1. Lai CC, Wang CY, Hsueh -infection among patients with COVID-19.(manuscript submitted).
    1. Chou C.C., Shen C.F., Chen S.J., Chen H.M., Wang Y.C., Chang W.S. Recommendations and guidelines for the treatment of pneumonia in Taiwan. J Microbiol Immunol Infect. 2019;52:172–199. doi: 10.1016/j.jmii.2018.11.004.
    1. Jean S.S., Chang Y.C., Lin W.C., Lee W.S., Hsueh P.R., Hsu C.W. Epidemiology, treatment, and prevention of nosocomial bacterial pneumonia. J Clin Med. 2020;9:275. doi: 10.3390/jcm9010275.
    1. Yang X., Yu Y., Xu J., Shu H., Xia J., Liu H. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 Feb 24 doi: 10.1016/S2213-2600(20)30079-5.
    1. Guan W.J., Ni Z.Y., Hu Y., Liang W.H., Ou C.Q., He J.X. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020 Feb 28 doi: 10.1056/NEJMoa2002032.
    1. Fang L., Karakiulakis G., Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Mar 11 doi: 10.1016/S2213-2600(20)30116-8.
    1. FDA News No scientific evidence that NSAID use worsens COVID-19 symptoms. From:
    1. Day M. COVID-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ. 2020 Mar 17;368:m1086. doi: 10.1136/bmj.m1086.
    1. Society of Critical Care Medicine COVID-19 Guidelines. From:
    1. Wu C., Chen X., Cai Y., Xia J., Zhou X., Xu S. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020 Mar 13 doi: 10.1001/jamainternmed.2020.0994.
    1. Tang N., Bai H., Chen X., Gong J., Li D., Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 March 27 doi: 10.1111/jth.14817.
    1. Wösten-van Asperen R.M., Bos A.P., Bem R.A., Dierdorp B.S., Dekker T., van Goor H. Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome. Pediatr Crit Care Med. 2013;14:e438–e441. doi: 10.1097/PCC.0b013e3182a55735.
    1. Fedson D.S. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med. 2016;4:421. doi: 10.21037/atm.2016.11.03.
    1. Fedson D.S., Opal S.M., Rordam O.M. Hiding in plain sight: an approach to treating patients with severe COVID-19 infection. mBio. 2020;11 doi: 10.1128/mBio.00398-20.

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