By: Jason Ifeanyi, PharmD Candidate c/o 2022

Severe acute respiratory syndrome 2 (Sars-Cov-2), the viral strain responsible for causing COVID-19, continues to have an undeniable impact both on a national level and a global level. As of June 20^th, 2020, there have been nearly 2.4 million reported cases in the United States, with nearly 122,000 deaths. In the State of New York, there have been over 400,000 confirmed cases, with a little over 31,000 reported deaths.⁶ As a brief overview of the nature of this pandemic, Sars-Cov-2 has an estimated incubation period of 14 days (median of 4-5 days). COVID-19 is characterized by a spectrum of illnesses that can range from asymptomatic infection to severe pneumonia with Acute Respiratory Distress Syndrome (ARDS) and eventual death. The most common symptoms, by percentage, seen in the US include cough (86), fever or chills (85), shortness of breath (80), diarrhea (27), and nausea (24). Other notable symptoms include sputum production, headache, dizziness, rhinorrhea, anosmia (partial or complete loss of the sense of smell), dysgeusia (distortion in the sense of taste), sore throat, anorexia, and vomiting. High risk populations include those over the age of 65, those living in a nursing home or a long-term care facility, and those with pre-existing conditions (hypertension, cardiovascular disease, obesity, renal disease, and chronic respiratory disease).¹

At this very moment, research studies are being conducted worldwide in order to find an effective treatment for this strain of Coronavirus in the form of randomized clinical trials (RCT’s), prospective and retrospective cohort studies, case-control studies, and case series/reports. In the last 3 months, an abundance of medical literature has been published discussing the results of completed studies. Systematic reviews of these medical literature findings have informed the National Institute of Health’s (NIH) understanding of the benefits/drawbacks of many drugs being investigated. Consequently, the NIH has since published their current treatment guidelines for COVID-19, which will be continuously updated as more trials and studies are completed and systematically reviewed. This article will highlight 4 drugs that are discussed at length within the treatment guidelines: remdesivir, chloroquine, hydroxychloroquine, and azithromycin. ³

It is important to note that, “recommendations in the guidelines are based on scientific evidence and expert opinion”. ¹ Each recommendation includes 2 rating scales: a letter and a roman numeral. The letter (A, B or C) indicates the strength of the recommendation, with “A” being a strong recommendation for the statement and “C” indicating an optional recommendation for the statement. The roman numeral represents the quality of evidence for each recommendation. Roman numeral “I” represents one or more randomized trials with clinical outcomes and/or validated laboratory endpoints. Roman numeral “III” indicates expert opinion. As mentioned prior, types of studies included in systematic analysis include case studies, prospective and retrospective cohorts, and RCT’s. The NIH panel includes members from health care and academic organizations, federal agencies, and professional societies. Majority vote was required by the panel for a recommendation to be included in the guidelines.¹

On the basis of preliminary clinical trial data, the COVID-19 Treatment Guidelines Panel recommends the investigational antiviral agent, remdesivir, for the treatment of COVID-19 in hospitalized patients with severe disease, “defined as SpO₂ (oxygen saturation) ≤ 94 percent on ambient air (at sea level), requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (BI)”.¹ So, why is there interest in remdesivir, a drug recently designated by the FDA as an orphan drug used for the treatment of Ebola virus? ⁵ This is because remdesivir has demonstrated in vitro activity against Sars-Cov-2, in addition to both in vitro and in vivo activity (based on animal studies) against Middle East Respiratory Syndrome (MERS) and Sars-CoV. Mechanism of action involves binding to the viral RNA-dependent RNA polymerase, inhibiting viral replication through premature termination of RNA transcription. ¹

The rationale for the NIH recommendation is largely based on preliminary data released on April 29th, 2020 for the Adaptive COVID-19 Treatment Trials (ACTT), which was NIH-sponsored. This was an international, randomized, double blind, placebo-controlled trial studying hospitalized adult patients (≥ 18 years of age) with confirmed COVID-19. The primary endpoint of the study was time to recovery. One thousand sixty-three participants were enrolled, and results indicate that those who received remdesivir had a 31 percent faster time to recovery than those who received placebo. Results also showed 8 percent mortality in the remdesivir cohort compared to 11.6 in the placebo group. This trial holds much significance because it is the first randomized, double blind, fully powered study to demonstrate the clinical benefit of a pharmacologic treatment for COVID-19.¹

Remdesivir is not FDA approved. It is available through Emergency Use Authorization (EUA) for the treatment of hospitalized adults and children with COVID-19 and is currently being investigated in clinical trials.² Remdesivir is also available through an emergency access program for children (< 18 years of age) and pregnant patients.  Adverse effects commonly reported include nausea and vomiting, with elevated transaminase levels and prothrombin time. Remdesivir is a substrate of CYP3A4, 2C8, and 2D6. Drug-drug interactions with co-administered CYP inducers and/or inhibitors must be monitored, although these interactions are expected to be clinically insignificant. The safety and effectiveness of remdesivir for COVID-19 treatment has not been evaluated in pregnant or pediatric patients, and remdesivir should only be used if the potential benefit justifies the potential risk for the mother and fetus. Remdesivir should not be withheld from pregnant patients if otherwise indicated. ¹

Chloroquine and hydroxychloroquine are two additional drugs that are being heavily studied during this time.  Chloroquine is an antimalarial drug that was developed in 1934. Hydroxychloroquine, an analog of chloroquine, was developed in 1946, and is used in the treatment of autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). As of June 15^th, the Panel recommends against the use of chloroquine or hydroxychloroquine for the treatment of COVID-19, except in a clinical trial (AII). The panel also recommends against the use of high-dose chloroquine for the treatment of COVID-19 (600 mg twice daily for 10 days) (AI). The rationale for this recommendation is that both drugs have been studied in small randomized trials and in some case series, producing conflicting study reports. Mechanism of action for both chloroquine and hydroxychloroquine involves increasing the endosomal pH, which inhibits the fusion of Sars-Cov-2 and the host cell membranes. Chloroquine inhibits glycosylation of the cellular angiotensin-converting enzyme 2 receptor, which may interfere with the binding of Sar-Cov-2 to the cell receptor. In vitro, both drugs may block the transport of Sars-Cov-2 from early endosomes, which may be required for release of the viral genome.¹

To compare the effects of high dose vs. low dose chloroquine, a randomized, double blind, phase 2b study analyzed hospitalized patients with suspected severe COVID-19. All patients received ceftriaxone + azithromycin, with 89.6 percent of patients receiving oseltamivir. The primary outcome measure was mortality at 13 days after treatment initiation. Originally, the study was supposed to have 440 participants, but the study was stopped by the data safety monitoring board (DSMB) after 81 patients were enrolled in the study. Forty-one patients were in the high dose group, with 40 patients in low dose. Low dose group had 15 percent mortality after 13 days, while the high dose group had 19 percent mortality. However, when the results were controlled for age, results were no longer statistically significant. QTc prolongation was more frequent in the high dose group (24.1 percent vs 3.6 percent). Limitations to this study included that more older patients with a history of heart disease were randomized to the high dose arm than to the low dose arm. ¹

Numerous studies have been done testing the effects of hydroxychloroquine. This includes the retrospective observational cohort from the United States Veterans Health Administration (US VHA). This study, which was not peer reviewed, studied patients who were hospitalized in the US VHA centers from March 9th – April 11^th, 2020 with confirmed COVID-19. Patients were categorized as either receiving hydroxychloroquine, hydroxychloroquine + azithromycin, or no hydroxychloroquine. Doses and duration of use were not specified, which limits researcher’s ability to confidently make definitive conclusions. All 368 patients were male, which is another limitation of this study, as it is hard to apply the results to a broader population. The primary endpoints studied were death and the need for mechanical ventilation. This study showed no beneficial effect of hydroxychloroquine + azithromycin for the treatment of COVID-19 and possible association of hydroxychloroquine with increased mortality. Another RCT studying the difference in effect between hydroxychloroquine and Standard of Care (i.e. empiric antimicrobial therapy, VTE prophylaxis for patients at risk of a thromboembolic event) was unable to detect a statistically significant difference in viral clearance between the 2 forms of therapy.¹ An observational retrospective cohort of hydroxychloroquine vs. no hydroxychloroquine was carried out at 4 French tertiary centers over a 2 week period (March 17 -March 31, 2020). Primary outcome studied was a composite of transfer to the ICU within 7 days of enrollment and/or death from any cause. Results showed no difference in clinically important outcomes between patients who received hydroxychloroquine within 48 hours of hospital admission and those who did not.

The results of these research studies had originally resulted in the FDA cautioning against the use of chloroquine and hydroxychloroquine for the treatment of COVID-19 outside the setting of a hospital or a clinical trial (AIII). Except in the context of a clinical trial, the panel recommends against the combination of hydroxychloroquine and azithromycin due to potential cardiac toxicity. ¹ As of June 15^th, the FDA has revoked its initial Emergency Use Authorization (EUA) for the use of chloroquine and hydroxychloroquine donated to the Strategic National Stockpile. The EUA authorized the use of these drugs for the treatment of hospitalized adolescent and adult patients with COVID-19 who weigh ≥50 kg and for whom a clinical trial is not available, or participation is not feasible. However, this recommendation is likely to change following an announcement made on June 22^nd that the NIH is putting a halt to a clinical trial on hydroxychloroquine.⁴ This trial was the Outcomes related to COVID-19 treated with hydroxychloroquine among In-patients with symptomatic Disease (ORCHID) study. This blind, randomized, placebo controlled RCT originally planned on enrolling 500 patients, and up until this point had enrolled 500. However, the data safety monitoring board (DSMB) has concluded that “while there was no harm, the study drug was very unlikely to be beneficial to hospitalized patients with COVID-19. The NIH joins Novartis and the World Health Organization (WHO) as 3 major clinical programs to end hydroxychloroquine studies in hospitalized patients.⁴

Chloroquine and hydroxychloroquine pose potential cardiac adverse effects, such as QTc prolongation, ventricular arrhythmias, and even cardiac death. These risks are higher in patients taking chloroquine. Consequently, baseline and follow up ECGs are recommended when there are potential drug interactions with concomitant medications or underlying cardiac diseases. Other adverse effects include hypoglycemia, rash, and nausea. Long term use may leave patients susceptible to retinopathy and/or bone marrow suppression. Glucose-6 phosphate deficiency (G6PD) leaves patients at greater risk of hemolysis, and G6PD testing must be done before initiating a patient on chloroquine. Both drugs are moderate inhibitors of CYP2D6 and P-glycoprotein. Use with caution when co-administering with medications metabolized by CYPD6 (beta blockers, antipsychotics, SSRIs, methadone) and drugs transported by P-glycoprotein: direct oral anticoagulants (DOACs) and digoxin. No dosage adjustments are needed in pregnant patients, and chloroquine has been routinely used in pediatric populations for the treatment and prevention of malaria and for autoimmune conditions (RA). ¹

In conclusion, there are currently no drugs FDA-approved for the treatment of COVID-19.  Despite the reports made in medical literature and lay press, definitive critical trial data is needed to identify safe and effective treatments for COVID-19. Presently, the NIH treatment panel recommends investigational antiviral agent remdesivir for the treatment of COVID-19 in hospitalized patients with severe disease. The Panel recommends against the use of chloroquine or hydroxychloroquine for the treatment of COVID-19, except in a clinical trial (AII). The panel also recommends against using high dose chloroquine (600 mg twice daily for 10 days), due to risk of cardiac toxicity. Furthermore, except in the context of a clinical trial, the Panel recommends against using a combination of hydroxychloroquine and azithromycin because of potential cardiac toxicities. As aspiring PharmD. graduates, and for those currently practicing as pharmacists, it is imperative that we understand that the recommendations made in the NIH treatment guidelines are not mandates, “The choice of what to do or not to do for an individual patient is ultimately decided by the patient together with the provider”.¹

Sources:

1. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://covid19treatmentguidelines.nih.gov/. Last Updated May 12, 2020. Accessed May 20, 2020.
2. Gershman, Jennifer. Investigational Drugs in the Pipeline for COVID-19. DrugTopics, https://www.drugtopics.com/latest/investigational-drugs-pipeline-covid-19. Published May 12, 2020, Acceded 05/15/20.
3. Lentile, Gabrielle. Coronavirus News Roundup: Drug Shortages, Clinical Trials, Testing Resources for Pharmacies. DrugTopics. https://www.drugtopics.com/coronavirus/coronavirus-news-roundup-drug-shortages-clinical-trials-testing-resources-pharmacies. , Published April 17, 2020, Acceded 05/15/20.
4. Liu, A. (2020, June 22). It’s the end of road for hydroxychloroquine in COVID-19 as Novartis, NIH and WHO pull out of trials. Retrieved June 22, 2020, from https://www.fiercepharma.com/pharma/end-road-for-hydroxychloroquine-covid-19-as-novartis-nih-and-who-pull-out-trials
5. U.S Food & Drug Administration. Search Orphan Drug Designations and Approvals. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=490515. Accessed 05/21/20.
6. Worldmeter. COVID-19 Coronavirus Pandemic. Worldmeter, https://www.worldometers.info/coronavirus/.Published June 22,2020. Accessed 06/22/20.

Published by Rho Chi Post