Coronavirus disease 2019 (COVID-19) infection, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in the most serious public health crisis of the 21st century. As of March 23, 2020, there have been 339,259 global confirmed cases and 14,704 deaths, according to John’s Hopkins University. COVID-19 infection has spread throughout the world and the impact on population health and world economies has been substantial. 

Since early January 2020, many case reports of treatment for COVID-19 have been published. However, as of today, there is no high quality, randomized control trial or meta-analysis data reported. The World Health Organization (WHO), FDA, and the Centers for Disease Control and Prevention (CDC) all agree that there is no approved treatment for COVID-19 infection (Cortegiani, 2020).

In light of this, many front-line clinicians have been investigating existing medications and repurposing them for COVID-19 treatment. This has resulted in case reports for repurposed medications that suggest some treatments helped or may have cured some patients. Although promising, these reports do not take the place of well-designed, double blind, and randomized control trials. Although these case reports can serve as a guidepost, they cannot be used to exclusively to establish treatment protocols.    

One of the goals of this article is to summarize currently reported pharmaceutical treatments and existing clinical trials, and organize them in a manner that is easy for readers to follow. A second goal is to summarize the most common medication dosages being studied and/or reported. 

A third goal is to note major medical safety concerns associated with investigational treatments. The final goal is to help health care professionals make sense of the large volume of information regarding COVID-19 treatment that is being published, reviewed and revised on a daily basis.

There have been numerous reports from various sources regarding the use of Eastern medicine, natural herbs, vitamins, and other alternative medicines to treat COVID-19 symptoms or boost the immune system. This information is not included in this article.

On March 21, 2020, the CDC updated its “Information for Clinicians on Therapeutic Options for COVID-19 Patients.” In this document, the CDC listed remdesivir, hydroxychloroquine and chloroquine as investigational treatments. Lopinavir-ritonavir was mentioned as well, but the existing data did not seem promising, according to the CDC.

Since all reported COVID-19 treatments are considered investigational by the WHO and FDA, at this time and their efficacy and safety are not fully tested. Also, all medications mentioned have potential adverse effects on patients. 

It is crucial that all treatment must be evaluated on a case-by-case basis by the treatment team. The WHO stated, “Use of investigational anti-COVID-19 therapeutics should be done under ethically approved, randomized, controlled trials.” 

This disease is fast-spreading and new evidence is emerging every day, so regular review and update of evidence is crucial for patient safety and critical for public health. The following are the findings for each investigational treatment option for COVID-19. 
           
Chloroquine and hydroxychloroquine were FDA-approved for Lupus erythematosus, malaria, and rheumatoid arthritis. Chloroquine has broad spectrum activities against both RNA and DNA viruses in vitro. It increases endosomal pH of the phagolysosome, thus interfering with the virus and cell fusion. It also interferes with ACE2 glycosylation of the CARS-Cov cellular receptors (Colson et al, 2020). Hydroxychloroquine is the prodrug of chloroquine, so for the purpose of this article, they will be evaluated together. 

The General Office of National Health Commission and State Administration of Traditional Chinese Medicine of China released the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) on March 3, 2020. This is an update from a rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version), which was published in early February (Jin et al, 2020). 

They suggested giving patients with COVID-19 chloroquine phosphate 500 mg bid 7 days for adults (aged 18 to 56 years) with weight >50 kg; and 500 mg bid for days 1 and 2, then 500 mg QD for days 3 to 7 for adults with weight < 50 kg. 

The majority of the significant toxicities of chloroquine are associated with long-term use. However, QT prolongation has been reported for short-term use, with fatality. The risk is dose-dependent and will also increase with concomitant use of other QT prolongation medications (Powell, 1967).

Chloroquine and hydroxychloroquine have received the most attention among antiviral treatments for COVID-19. Gao, Tian and Yang (2020) reported on 15 clinical trials conducted in the People’s Republic of China, which involved 10 hospitals in several major Chinese cities with more than 100 patients enrolled. The preliminary reports stated that chloroquine and hydroxychloroquine were superior compared with the control treatment of COVID-19 infection.

No major adverse effects were reported and no safety concerns were raised. Yao et al (2020) reported that hydroxychloroquine is more effective in vitro than chloroquine in inhibiting SARS-CoV-2 growth. 

However, like all other reported treatments for COVID-19 infection, there is no FDA-approved indications for COVID-19. High quality evidence from randomized controlled trials is lacking. 

Cortegiani et al performed a review of 6 published articles and 23 ongoing clinical trials. They cautioned that clinical use must be guided by the principles of Monitored Emergency Use of Unregistered Interventions (MEURI). 
           
There are 3 ongoing clinical trials reported by the US National Library of Medicine, which are investigating the efficacy and safety of chloroquine in the treatment of SARS-CoV-2 infection, 1 of which is actively recruiting enrollees. Chloroquine is given, 500 mg QD, in combination with 3 other antiviral medications—darunavir, ritonavir and oseltamivir. Two more new studies are underway, but have not started recruiting yet (ClinicalTrials.gov, 2020). 

Remdesivir is a broad-spectrum antiviral medication developed against RNA viruses for the treatment of Ebola infection. It is designed to prematurely terminate the viral RNA transcription. 

Animal models indicated that remdesivir can reduce clinical signs of COVID-19 infection, as well as decrease viral replication and lung lesions (el Wit et al, 2020). Remdesivir is a prodrug which needs CYP3A4 to convert it to its active form. Thus, if the patient is on a CYP3A4 inhibitor or inducer, drug interactions can be an issue. 

Elevated aminotransferase levels were reported in 3 hospitalized patients with laboratory confirmed COVID-19 (Jin, 2020). Patients’ hepatic functions must be monitored closely, especially for patients who are on other hepatically cleared medications, acetaminophen for example, which is commonly used for fever. 
           
Remdesivir has been investigated for the treatment of COVID-19 infection in humans in multiple ongoing studies in China. Chih et al (2020) reported on a case of COVID-19 pneumonia that responded very well to remdesivir treatment. Baron et al (2020) reported that remdesivir, as well as chloroquine, lopinavir, ribavirin and ritonavir, all showed efficacy against coronavirus in vitro. 
           
Multiple studies are underway to evaluate the efficacy and safety of remdesivir in the treatment of COVID-19 infection. Currently, there are 4 clinical trials evaluating the role of remdesivir in the treatment of COVID-19 infection.

The commonly used adult dose in these studies is 200 mg intravenously (IV) once on day 1, then 100 mg IV daily, duration of therapy are 10 days for 2 studies. The other 2 studies are parallel assignment studies with 5 days in one treatment arm, and 10 days in the other. No results were reported at this time. The earliest preliminary completion dates are May of 2020 (ClinicalTrials.gov, 2020).  

Lopinavir/ritonavir (Kelatra), is a combination of 2 antiretroviral medications indicated for HIV infection. Lopinavir is a protease inhibitor, which prevents HIV from reaching its mature state, thus preventing HIV infection. It is metabolized by CYP 3A enzymes in the liver. 

Thus, a CYP 3A inhibitor, ritonavir, is added to this combination drug to decrease metabolism and increase drug bioavailability for lopinavir (Sham et al, 1998). Since this combo is so involved with the CYP 3A enzyme system, drug-drug interaction is expected. 

It is necessary to closely monitor patients who are on other CYP 3A4 substrates to prevent unintended toxicity. Lopinavir/ritonavir were reported to exhibit anti-SARS-Cov activities in 2004 (Chu et al), so this combination drug has been studied for the treatment of SARS-Cov2. 

The New England Journal of Medicine published a randomized, controlled, open-label trial on March 20, 2020. The researchers (Cao et al, 2020) investigated the effect of lopinavir-ritonavir (400 mg/100 mg twice a day for 14 days, N=199). Ninety-nine patients were assigned to the treatment arm and 100 received standard care. 

At baseline, there were no differences between the treatment and control groups in demographics and major lab results. However, the standard care group had a higher percentage of diabetes (13% vs 10%) and cardiovascular disease (8% vs 5%) compared with the treatment group. 

The researchers found no benefit from lopinavir/ritonavir treatment compared with standard care in reducing viral RNA load, time to clinical improvement, and mortality. However, they reported shorter intensive care stays in the treatment group. 

Study limitations included that it was not a double blind study and the treatment group had higher throat viral load at the beginning of the study. The researchers recommended further investigation of this and other medications in the treatment of COVID-19 infection. 

Twelve more clinical trials are actively investigating the anti-COVID-19 activities of lopinavir/ritonavir, 3 of which are phase 3 trials and 3 of which are phase 4 trials. The earliest primary completion date is expected to be May 14, 2020. The most common dosage studied is lopinavir/ritonavir 400 mg/100 mg by mouth, every 12 hours for 7 to 10 days.

The interleukin (IL)-6 receptor blocker tocilizumab was mentioned under immunotherapy in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (trial version), but a PubMed search with search words “tocilizumab, COVID-19 and Coronavirus” yielded no articles. 

There is 1 randomized, parallel assignment, open label study investigating the efficacy and safety of tocilizumab in the treatment of COVID-19 in combination with favipiravir, which had a primary completion date of May 20, 2020. Another phase 2/3 trial will evaluate the monoclonal antibody sarilumab’s role in COVID-19 treatment (ClinicalTrial.gov, 2020). Fudan University in Shanghai reported that the human monoclonal antibody can bind potently to the COVID-19 receptor-binding domain, so it may have the potential to prevent infection (Tian, 2020).

Many other treatment options have been reported, such as darunavir, ritonavir and oseltamivir, favipiravir and multiple Chinese medicine products. IFN-α inhalation of 5 million units twice daily were reported to be effective in treating SARS-Cov in vitro in 2006. It is listed as a treatment option in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) (Jin et al, 2020). 

Conclusion
Overall, there is still no sufficient high quality evidence to establish the safety and efficacy of any investigational medication for the treatment for COVID-19. However, there are more positive reports for the efficacy of hydroxychloroquine and chloroquine. Remdesivir and the lopinavir/ritonavir combination need further investigation. 

Many researchers and clinicians are working day and night to find a cure for COVID-19 and new evidence is fast emerging, so a regular review and update of evidence is crucial for patient safety and critical for public health. This article will be updated regularly as new evidence becomes available and results of current clinical trials are published.

Author Affiliations 
  1. Providence St. Joseph Health, System Pharmacy, Renton Washington
  2. University of Washington, School of Pharmacy, Seattle, Washington

Appendix
Summary of currently reported investigational treatments for COVID-19
Drug w/special notes                              COVID-19
Investigational Dosage
Duration of treatment Commons
Remdesivir
 
200 mg IV once on day 1, then 100 mg IV daily.  No more than 10 days CYP3A4 dependent, watch for D-D interactions. Elevated aminotransferase levels were reported in 3 hospitalized patients with laboratory confirmed COVID-19.
Lopinavir/ritonavir (strong CYP3A4 inhibitor, watch for D-D interactions) 400 mg/100 mg Q12H
 
7 to 10 days Multiple D-D interactions.
Example: amiodarone, anticoagulants, chemotherapeutic agents, cyclosporine, tacrolimus, sirolimus, anticonvulsants, rifampin, antifungals…
Chloroquine phosphate
 
500 mg bid for 7 days for adults aged 18-65 weigh > 50 kg;
500 mg bid for days 1 and 2 and 500 mg qd
for days 3-7 for adults weigh < 50 kg
 
No more than 7 days QT prolongation, with fatalities, has been reported
Hydroxychloroquine 400 mg twice daily X 1 day, followed by 200 mg given twice daily for 4 days
 
5 days QT prolongation, do not give with other meds which causes QT prolongation

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