|Year : 2020 | Volume
| Issue : 1 | Page : 1-5
Therapeutic options for the treatment of 2019-novel coronavirus: An evidence-based approach
Phulen Sarma1, Manisha Prajapat1, Pramod Avti2, Hardeep Kaur1, Subodh Kumar1, Bikash Medhi1
1 Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||14-Feb-2020|
|Date of Decision||15-Feb-2020|
|Date of Acceptance||24-Feb-2020|
|Date of Web Publication||11-Mar-2020|
Dr. Bikash Medhi
Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sarma P, Prajapat M, Avti P, Kaur H, Kumar S, Medhi B. Therapeutic options for the treatment of 2019-novel coronavirus: An evidence-based approach. Indian J Pharmacol 2020;52:1-5
|How to cite this URL:|
Sarma P, Prajapat M, Avti P, Kaur H, Kumar S, Medhi B. Therapeutic options for the treatment of 2019-novel coronavirus: An evidence-based approach. Indian J Pharmacol [serial online] 2020 [cited 2021 Aug 5];52:1-5. Available from: https://www.ijp-online.com/text.asp?2020/52/1/1/280269
In the 21st century, three coronaviruses (CoVs) caused three major epidemic of respiratory distress syndrome, which include severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 with epicenter in Guangdong, China, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 in Saudi Arabia, and the third epidemic of respiratory coronavirus the 2019-novel coronavirus (2019-nCoV) or coronavirus disease (COVID-19) mainly centered in Wuhan province, China. The case fatalities vary from 2.5% (2019-nCoV), 10% (SARS), to 35% (MERS-CoV). Till now, there is no approved antiviral or vaccine for the management of infection by CoV. However, from earlier experience of the management of SERS-CoV and MERS-CoV, many agents are being used in the treatment of 2019-nCoV.
| » Antivirals|| |
Ribavirin, a nucleoside analog, shows antiviral activity against some animal CoVs, and in the SARS-CoV epidemic, many patients were treated with ribavirin along with corticosteroids and became a standard regimen for the treatment of SARS-CoV. However, lack of control group hindered the estimation of true effect size. Again,in vitro testing did not show efficacy of ribavirin against SARS-CoV. Ribavirin is known for its side effects (hemolytic anemia, hypocalcemia, and hypomagnesemia). Many subsequent studies questioned the efficacy of ribavirin. Many patients on ribavirin and corticosteroid combination even showed an increase in viral load following the treatment. Thus, its use declined over a period. Other important nucleoside analogs are favipiravir and galidesivir, but these are not evaluated till now in 2019-nCoV.
Neuraminidase inhibitors are indicated in the management of influenza. In a study on possible MERS-CoV cases in Paris from 2013 to 2016, a total of 35 patients received oseltamivir (37.6%). In patients positive for influenza virus (n = 25), 52% (n = 13) received oseltamivir and it was concluded that empirical oseltamivir can be started in suspected MERS-CoV cases. Many other studies also evaluated oseltamivir in MERS-CoV. Oseltamivir was also used in the management of 2019-nCoV; however, definite evidence of efficacy is inconclusive because of lack of suitable control group in the studies.
There are two types of protease present in SARS-CoV, the CL-like protease and the papain-like protease, which is important for cleaving the polyproteins and releasing the nonstructural proteins (NSP1–16), which carry out important functions in the CoV life cycle. Among protease inhibitors, lopinavir was the most inhibitor and saquinavir was the least powerful inhibitor of CoV protease. In molecular dynamic studies, flap closing was observed when these inhibitors bound to the SARS-CoV 3CL (pro). Hong Kong University researchers demonstrated anti-SARS-CoV action of lopinavir at concentration of 4 μg/mlin vitro against the HKU-39849 isolate. Ritonavir boosting along with lopinavir is used in the management of HIV. A clinical study at the same Hong Kong University suggests that even after adjustment for LDH level (possible confounder), a significant association was seen between lopinavir/ritonavir use and better outcome. As per the current guidelines, lopinavir + ritonavir is the recommended protease inhibitor for the treatment of 2019-nCoV (weak recommendation).
| » Immunomodulators|| |
Corticosteroids were widely used for the treatment of SERS-CoV and MERS-CoV and are also used in the management of the current epidemic of 2019-nCoV. However, the interim guidelines by the WHO prohibit the use of routine corticosteroids unless indicated for other clinical ground. Use of corticosteroid is reported to be associated with delayed clearance of viral RNA (both in case of SERS-CoV and MERS-CoV) and other steroid-related complications such as psychosis.
Interferons (IFNs) are broad-spectrum antivirals, primarily used in the treatment of hepatitis B. In SARS-CoV patients, compared to ribavirin or interferon (IFN) alone, the benefit was seen on IFN-α + high-dose corticosteroid group. Other observational studies also support these findings and the combined use of IFN-α and corticosteroid (corticosteroid arm n = 13; corticosteroid + IFN-α arm n = 9) showed less disease-associated oxygen saturation impairment. For the treatment of 2019-nCoV (7), IFN-α (5 million U bid inh) is recommended along with lopinavir + ritonavir combination.
In case of critically ill SARS, who show signs of deterioration, further escalation of immunomodulation is indicated and intravenous (i.v.) immunoglobulin may be considered. Patients who show poor response to initial empirical therapy may get benefit from i.v. immunoglobulin.
| » Host-Directed Therapies|| |
Host-directed therapies basically target improvement of the status of the host, improvement of host immune response, or handling of host-related factors associated with viral replication. Apart from immunomodulators, metformin, atorvastatin, fibrates, as well as nutritional supplements may help in treating acute respiratory distress syndrome (ARDS) by boosting immunity. However, evidence of efficacy in SARS-CoV or MERS-CoV is poorly reported.
Zinc is reported to have antiviral effect, and it inhibits CoV RNA polymerase activity and thus hampers replication in cell culture experiments. As cytokine storm is a pathognomonic feature of COVID-19, inhibition of these pro-inflammatory cytokines may theoretically prove useful (e.g., inhibition of IL-6 by tocilizumab).
| » Other Therapies|| |
Other treatment options, which are either used rarely or in experimental state, are SiRNA, tumor necrosis factor-alpha inhibitors, neutralizing antibodies, pentoxifylline, etc., However, the level of evidence is quite poor and hence not recommended for routine care.
| » Management of 2019-Novel Coronavirus (Coronavirus Disease-19)|| |
Clinical care of suspected patients with 2019-nCoV should focus on recognition of the disease condition at the earliest, isolation and adoption of proper infection control measures, and delivery of optimized supportive care toward the suspected/confirmed cases. For preventive measure, the WHO guideline “Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected” mainly focuses on avoiding close contact with persons suffering from acute respiratory infections, frequent hand wash, and avoidance of unwanted contact with wild animals. In case of patients with respiratory distress, the patient is to be evaluated for the presence of shock. Empirical antimicrobial coverage is to be given (to cover up the likely causative organisms, which may be responsible for severe acute respiratory infection). Special concern is to be given for other comorbid conditions. In case of hypoxemic respiratory failure, it needs to be managed aggressively with high-flow nasal oxygen or noninvasive ventilation or by endotracheal intubation and positive pressure ventilation as required. Special concern is to be taken for the identification and management of septic shock.
| » Treatment of 2019-Novel Coronavirus: Evidence from China|| |
The details of treatment reported in case of 2019-nCoV are presented in [Table 1]. The antiviral agents which are used in the management of 2019-nCoV episodes are lopinavir, ritonavir, arbidol, oseltamivir, i.v. ganciclovir. Among immunomodulators, the commonly used agents are systematic corticosteroids,, and i.v. immunoglobulin was used in more serious cases who were refractory to initial therapy. Among herbal medicines, Chinese herbal medicinal products Tanreqing i.v. gtt, shufeng jiedu capsule (a traditional Chinese medicine) was used. The WHO has specified that at this present time there is no high level evidence is available, which favous use of a single specific antiviral agent for the treatment of patients with suspected or confirmed 2019nCoV infection. Although many of the death cases were in higher age group and many were smokers and had bilateral disease, lack of appropriate control group is the main hindrance in interpreting these prognostic factors.
|Table 1: Details of reported therapeutic strategies to counter 2019-nCoV infection|
Click here to view
| » Recent Advances in the Treatment of 2019-Novel Coronavirus|| |
Remdesivir and chloroquine
Using clinical isolates of 2019-nCoV, Wang et al., 2020 evaluated the efficacy of seven agents (ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine, remdesivir [GS5734], and favipiravir (T-705)) inin vitro conditions. Cytotoxicity was evaluated in vero E6 cells, which was followed by infection of the cells with 2019-nCoV clinical isolates, and the test drug was evaluated at different doses. Reverse transcription polymerase chain reaction-based quantification was done to get the viral yield, which was later confirmed by immunofluorescence microscopy (nucleocapsid protein visualization). Both chloroquine and remdesivir inhibited virus infection at micromolar level (0.77–1.13 μM) and with high selectivity.
Being an adenosine analog, remdesivir gets incorporated into viral RNA and causes premature chain termination. The importance of chloroquine as an antiviral agent is coming up. Chloroquine even showed efficacy as a potent antiviral against SARS-CoV infection and spread. Pretreatment with chloroquine renders vero E6 cells refractory to SARS CoV infection. Moreover, in the postinfection period, treatment with chloroquine prevents the spread of SARS-CoV infection. Chloroquine increases endosomal pH and thus makes the environment unfavorable for the virus/cell fusion. Chloroquine also affects the glycosylation process of angiotensin-converting enzyme 2 (ACE-2, receptor for binding of viral spike protein, which is essential for interaction with the host). Being nonexpensive and easily available agent, chloroquine may prove as a promising candidate.
The SARSCoV and the 2019nCoV both enters host cells through ACE2 receptormediated entry, especially through AT2 cells present in lungs. Downstream signaling of this receptor mediates the endocytosis process, and AP2-associated protein kinase 1 (AAK1) plays a major role in this process. Thus, AAK1 represents an important target. Richardson et al., 2020 evaluated 378 ligands, of which 47 were already approved for use in other conditions. Among these ligands, six inhibited AAK1 with high affinity. Considering the side effect profile, they found janus kinase inhibitor baricitinib to be the most important agent. In addition to AAK1, baricitinib also binds to another endocytosis regulator protein (cyclin G-associated kinase). Thus, the authors suggest that baricitinib can be evaluated in thein vitro conditions as well as in the clinical trial settings for 2019-nCoV.
Limitations of current research
Lack of high-quality evidence (especially randomized controlled trails [RCTs]) is the most important limitation of the current CoV research. As most of the CoV strains are genetically different and the outbreaks occur extremely randomly, conducting an RCT is extremely difficult, and we have to rely on observational studies (most of which do not have proper control group), which hamper the estimation of proper treatment effect.
| » References|| |
Graham RL, Donaldson EF, Baric RS. A decade after SARS: Strategies for controlling emerging coronaviruses. Nat Rev Microbiol 2013;11:836-48.
Battegay M, Kuehl R, Tschudin-Sutter S, Hirsch HH, Widmer AF, Neher RA. 2019-novel coronavirus (2019-nCoV): Estimating the case fatality rate – A word of caution. Swiss Med Wkly 2020;150:w20203.
Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses-drug discovery and therapeutic options. Nat Rev Drug Discov 2016;15:327-47.
Li G, Clercq ED. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov 2020;19:149-50.
Tai DY. Pharmacologic treatment of SARS: Current knowledge and recommendations. Ann Acad Med Singapore 2007;36:438-43.
Neuraminidase inhibitors for treatment of influenza A and B infections. MMWR Recomm Rep 1999;48:1-9.
Bleibtreu A, Jaureguiberry S, Houhou N, Boutolleau D, Guillot H, Vallois D, et al
. Clinical management of respiratory syndrome in patients hospitalized for suspected Middle East respiratory syndrome coronavirus infection in the Paris area from 2013 to 2016. BMC Infect Dis 2018;18:331.
Al-Abdely HM, Midgley CM, Alkhamis AM, Abedi GR, Lu X, Binder AM, et al
. Middle East respiratory syndrome coronavirus infection dynamics and antibody responses among clinically diverse patients, Saudi Arabia. Emerg Infect Dis 2019;25:753-66.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al
. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
Dayer MR, Taleb-Gassabi S, Dayer MS. Lopinavir; a potent drug against coronavirus infection: Insight from molecular docking study. Arch Clin Infect Dis 2017;12:e13823. Available from: http://archcid.com/en/articles/13823.html
. [Last accessed on 2020 Feb 12].
Nukoolkarn V, Lee VS, Malaisree M, Aruksakulwong O, Hannongbua S. Molecular dynamic simulations analysis of ritonavir and lopinavir as SARS-CoV 3CL (pro) inhibitors. J Theor Biol 2008;254:861-7.
Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al
. Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings. Thorax 2004;59:252-6.
Oldfield V, Plosker GL. Lopinavir/ritonavir: A review of its use in the management of HIV infection. Drugs 2006;66:1275-99.
Jin YH, Cai L, Cheng ZS, Cheng H, Deng T, Fan YP, et al
. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res 2020;7:4.
Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020;395:473-5.
Zhao Z, Zhang F, Xu M, Huang K, Zhong W, Cai W, et al
. Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China. J Med Microbiol 2003;52:715-20.
Loutfy MR, Blatt LM, Siminovitch KA, Ward S, Wolff B, Lho H, et al
. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: A preliminary study. JAMA 2003;290:3222-8.
Lau AC, Yam LY, So LK. Management of critically Ill patients with severe acute respiratory syndrome (SARS). Int J Med Sci 2004;1:1-10.
Tsang K, Zhong NS. SARS: Pharmacotherapy. Respirology 2003; 8 Suppl 1:S25-30. doi: 10.1046/j.1440-1843.2003.00525.x.
Zumla A, Hui DS, Azhar EI, Memish ZA, Maeurer M. Reducing mortality from 2019-nCoV: Host-directed therapies should be an option. Lancet 2020;395:e35-6.
te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activityin vitro
and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog 2010;6:e1001176.
Wang Z, Chen X, Lu Y, Chen F, Zhang W. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment [published online ahead of print, 2020 Feb 9]. Biosci Trends 2020;10.5582/bst.2020.01030. doi:10.5582/bst.2020.01030.
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al
. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020;395:507-13.
Zhang Z, Li X, Zhang W, Shi ZL, Zheng Z, Wang T. Clinical features and treatment of 2019-nCov pneumonia patients in Wuhan: Report of a couple cases. Virol Sin 2020. doi: 10.1007/s12250-020-00203-8.
Kui L, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, et al
. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province [published online ahead of print, 2020 Feb 7]. Chin Med J (Engl) 2020;10.1097/CM9.0000000000000744. doi:10.1097/CM9.0000000000000744.
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al
. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro
. Cell Res 2020;30:269-71. doi: 10.1038/s41422-020-0282-0.
Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al
. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016;531:381-5.
Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al
. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005;2:69.
Hoffmann M, Kleine-Weber H, Krüger N, Müller M, Drosten C, Pöhlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells [Internet]. Molecular Biology; 2020. Available from: http://biorxiv.org/lookup/doi/10.1101/2020.01.31.929042
. [Last cited on 2020 Mar 04].
Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, et al
. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020;395:e30-1.