It is important to note that there are currently no FDA-approved or even recommended agents for the treatment of the novel coronavirus (COVID-19), for which the World Health Organization (WHO) declared as pandemic on Wednesday. Any agent being used at this time is being administered in an experimental setting under controlled conditions. However, one of the fears of this virus is that there is no currently known treatment for it, and often it is the pharmacist that people look to first for information about medication developments.

In February 2020, the WHO published an overview of the potential therapeutic candidates for the treatment of COVID-19.1,2 The 36-page document outlines 76 regimens that have been proposed (as of February 17, 2020) for the treatment of patients infected with the virus. Thirty-eight of these candidates are in the preclinical state with minimal information available on their proposed mechanism, uses, doses routes, or planned trials. Sixteen of the remaining regimens contain an interferon-based product. The rest include a variety of antimicrobials, corticosteroids, convalescent plasma, and biologics.

Clinical trials of several other products not listed in the WHO document have been posted to ClinicalTrials.gov, and the Chinese government has released several versions of guidelines for the prevention, diagnosis, and treatment of the virus that includes specific medication recommendations.2 Some of the candidates are approved by the FDA for other indications, but the majority of the agents are not currently commercially available in the United States for therapeutic use.

Remdesivir
The agent that has received the most attention in the media is remdesivir, a nucleoside inhibitor also known as GS-5734. The monophosphoramidate prodrug has potent activity against several families of RNA viruses.1,3-4 Originally under development for Ebola, remdesivir incorporates into nascent viral RNA chains, and causes premature termination.3 Animal studies revealed that it reduces the viral load of lung tissue in Middle East respiratory syndrome (MERS).2

A recently published in vitro study showed that remdesivir had potent antiviral activity against COVID-19 in a human cell line.3 One case reported encouraging results from its use in a patient with COVID-19 in the US.4 A phase 2, multicenter, placebo controlled, international study is currently recruiting adult patients.5 Four of the study sites are located within the United States. Patients randomized to remdesivir will receive 200 mg IV on day 1, and then 100 mg IV once daily for the duration of their hospitalization, up to 10 days total. The study is not scheduled to conclude until 2023; unless the independent data and safety monitoring board identifies a significant difference in clinical outcomes, a full evaluation of the data may not be available for several years.

Two phase 3 studies intended to begin in March are set to conclude in May 2020.2,6-7  Both studies have similar designs and will compare remdesivir 200 mg IV loading dose followed by 100 mg IV daily to standard of care therapy. Both studies have 5-day and 10-day treatment durations that are being evaluated. Additionally, the U.S. Army Medical Research and Development Command is operating an expanded access program.8

It is hoped that from these studies, the health care community will have evidence on the safety and efficacy of remdesivir within months rather than years. At this time, evaluation of an oral version of remdesivir has not been proposed and it is unknown if this antiviral would be useful for patients whose symptoms are not severe enough to warrant hospitalization.

Hydroxychloroquine
Another agent that appears to have gained traction in evaluation for COVID-19 is hydroxychloroquine, or chloroquine. The heme polymerase inhibitor that is currently used to treat a variety of conditions that include malaria, lupus, and rheumatoid arthritis is being evaluated to determine if its use in COVID-19 leads to improved virological clearance and mortality. The same in vitro study that stated remdesivir’s antiviral activity also showed chloroquine potent activity versus COVID-19 in human cells.3 It appears to block viral infection by increasing endosomal pH needed for virus/cell fusion, and interferes with the glycosylation of virus cellular receptors. The drug also has immune-modulating activity which is proposed to enhance its antiviral effect in vivo.3

A Chinese clinical study evaluating 5 daily doses of 400 mg in adults who developed pneumonia from the viral infection is scheduled to conclude in the latter half of 2020. The study is sponsored by the Shanghai Public Health Clinical Center, and it is unknown how long after study conclusion the information may be shared with other stakeholders.

A large ongoing study is comparing hydroxychloroquine’s clinical outcomes to carrimycin, lopinavir/ritonavir, and umifenovir, but the study is not anticipated to conclude before February 2021. The most recent Chinese guidelines on COVID-19 recommend chloroquine phosphate 500 mg twice a day for up to 10 days.2

Given that hydroxychloroquine is already available in the US, comes in oral dosage forms, has a known safety profile, and is relatively inexpensive (compared to newer agents), it would not be as difficult to utilize this product as some of the other candidates, should the results of any studies confirm the findings of the in vitro study in a patient care setting. However, it is precisely because it is so readily available that it is important to note that until official recommendations are made, any use of hydroxychloroquine for COVID-19 should only occur in the investigational setting. 

Umifenovir
Among several other antivirals being investigated, umifenovir is approved in Russia and China for influenza treatment and prophylaxis.1 It is a non-nucleoside broad-spectrum agent with immune-enhancing effects that possesses antiviral activity against several other coronaviruses.9-10 The current Chinese COVID-19 guidelines recommend a dose of 200 mg 3 times a day for up to 10 days.2 All of the studies of umifenovir are being conducted in China, and there are is not current indication on whether it may or may not be submitted to the FDA for approval if the outcomes of those studies are positive.10-11

Baloxavir
The WHO identifies baloxavir, a newer medication approved for influenza in the US as a possible candidate.1 The proposed regimen is 80 mg given 3 times over a 7-day period.1 No other details of a potential clinical trial for baloxavir are available, and the WHO is the only institution identifying it as a potential therapeutic candidate.

Favipiravir
Another antiviral, favipiravir, which is approved for influenza in some countries outside of the US, is under investigation for COVID-19.1-2 A trial enrolling 80 patients in China suggested that favipiravir had more potent antiviral action than lopinavir/ritonavir against COVID-19, while maintaining a good safety profile.2 Another phase 2 study evaluating its efficacy is set to begin in March in Thailand.12

Lopinavir and Ritonavir
One of the regimens included in the most studies currently is the combination of the antiretrovirals lopinavir and ritonavir, which is currently used to treat human immunodeficiency virus (HIV).1,12-15 It was shown to be effective against severe acute respiratory syndrome (SARS) in vitro, and in some clinical trials.2 Like umifenovir, lopinavir/ritonavir is included in the latest Chinese guidelines using a 200 mg/50 mg capsule at a dose of 2 capsules twice a day for up to 10 days.2 The medication is being studied alone and in combination with other agents including ribavirin and interferon.1

Two published cases detail lopinavir/ritonavir’s use in COVID-19, thus far. One case involved a male in China aged 47 years with a 7 day history of symptoms, who was diagnosed with COVID-19 in January 2020.16 He was treated with lopinavir/ritonavir (800/200 mg) in combination with methylprednisolone, interferon, and moxifloxacin. By day 2 of treatment, his symptoms had started to improve, and he was able to be discharged home on day 10. The second case involved a Korean man, aged 54 years. This man traveled from Wuhan, China to Korea in January 2020, and was diagnosed with COVID-19 a few days after his arrival.17 Lopinavir/ritonavir (2 tablets of 200 mg/50 mg twice daily) was started on hospital day 8, which was day 10 of the patient’s illness. On day 2 of therapy, the patient’s viral load began to decrease and were continuously undetectable by day 8 of treatment. The clinical studies underway will provide more guidance on the role of lopinavir/ritonavir, but the above case reports are encouraging.

Corticosteroids
Corticosteroids are being investigated in multiple trials for the novel virus.1,18-19  Steroids were and are used in the treatment of other severe coronavirus infections including SARS and MERS.20 Several concerns arose from those studies including delayed clearance of viral RNA from the respiratory tract, drug-induced diabetes, and psychosis.20  Interim guidance from the WHO recommends against using corticosteroids in patients with COVID-19 unless they have another indication.20

Two studies evaluating methylprednisolone are schedule to complete in April and May of 2020.18-19 The studies are only evaluating hospitalized patients with COVID-19, with 1 only enrolling critically ill patients. No planned studies for steroid administration to patients stable enough for home care could be identified and their use in outpatients cannot be recommended until more information is available.

While infections are not overall a new situation that we deal with, many patients in the US cannot recall a time when antimicrobials were not available. When novel pathogens emerge, the fear of not having a therapeutic method for combating the infection is aroused.

The worldwide medical community has worked at quick pace to try to identify potentially effective and safe treatments for COVID-19. There still needs to be substantially more data before specific agents and regimens can be recommended, but the influx of clinical data that is emerging on a day-to-day basis is encouraging that COVID-19 will not be a virus without a known treatment for long.



REFERENCES
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  3. Wang M, Cao R, Zhang L et al. Remdesivir and chloroquinine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res.2020;30:267-271
  4. Holshue ML, DBolt C, Lindquis S. et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382:929-936
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