Pulmonary inflammation and diffuse alveolar damage, the leading effects of SARS-CoV-2, appear to be driven by an autoimmune-mediated response stemming from the release of pro-inflammatory cytokines to the virus. Because the immune system and the inflammatory response are familiar in many disease settings for which a well-established index of drugs and immune modulating agents exists, these medications have become the focus of much attention as potential treatments for COVID-19.
Off-label Use of Medication for COVID-19
While the list of agents administered to COVID-19 patients increases daily, no single therapeutic agent has been evaluated in a complete, well-structured (randomized, controlled) clinical trial to date. Moreover, no agents have been reported under the scrutiny of peer review, and none have been confirmed in subsequent studies.
However, the pandemic has inspired a team of dedicated researchers at Penn Medicine and the Perelman School of Medicine to investigate, catalog and comment upon the existing armamentarium of medications. The effect of these considerations? Bringing therapies to the foreground that might otherwise have escaped notice, and benefit of scrutiny for therapies entering the popular media.
This article considers a few of these drugs currently of interest, including remdesivir, dexamethasone, and hydroxychloroquine.
A Systematic Review of Treatments Administered to COVID-19 Patients
In April 2020, David C. Fajgenbaum, MD, MBA, MSc, and colleagues from his laboratory at offered a consideration of the early treatments offered to the first 9152 COVID patients in reports published between December 1, 2019 and March 27, 2020.
The review, Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review (Infectious Diseases and Therapy) was intended to serve as an inventory of treatments administered to COVID-19 patients and to assist with prioritizing drugs for well-designed randomized controlled trials in the hope that agents with the potential to improve clinical outcomes would be identified, thus reducing the strain on inpatient care in the current pandemic.
Today, at roughly six months into the pandemic, the review is also notable for the agents that have since fallen by the wayside.
Given the pathophysiology of COVID-19, it's no surprise that the leading agents recorded in the report included antivirals, antibiotics and corticosteroids.
Of the 115 drugs reported, according to the authors, the most frequently administered was the antiviral combination lopinavir/ritonavir (~21.9%), followed by interferon a/b (19.3%), several lesser known antivirals and antibiotics and the corticosteroid methylprednisolone (4.6%) — although in total more than 20% of patients evaluated received other steroid drugs of some sort. Remdesivir and hydroxychloroquine use were not commonly reported (<2%).
Dr. Fajgenbaum is Director of the Penn Center for Cytokine Storm Treatment & Laboratory, and an Assistant Professor of Translational Medicine & Human Genetics at the Perelman School of Medicine at the University of Pennsylvania.
An Early Departure: Lopinavir/Ritonavir
Evaluated in HIV, SARS and Middle Eastern Respiratory Syndrome (MERS), the protease inhibitors lopinavir/ritonavir did not fare as well versus SAR-CoV-2.
Earlier this year, the World Health Organization (WHO) established the SOLIDARITY trial to find an effective COVID-19 treatment for hospitalized patients with four arms comparing various agents alone or in combination vs. standard of care: lopinavir/ritonavir, remdesivir, lorinavir/ritonavir with interferon b and hydroxychloroquine.
In July, the World Health Organization (WHO) chose to immediately discontinue the lopinavir/ritonavir and hydroxychloroquine arms in SOLIDARITY. Interim trial results show that both arms produced little or no reduction in the mortality of hospitalized COVID-19 patients when compared to standard of care. The lopinavir/ritonavir/ interferon and remdesivir arms continue.
A Resurgence for Remdesivir
Like lopinavir/ritonavir, the investigational broad-spectrum antiviral remdesivir was studied previously in Ebola and MERS, and has been evaluated for the treatment of COVID-19. The drug has received Emergency Use Authorization for the treatment of hospitalized patients with severe COVID-19, but to date, has not been approved by the FDA. Remdesivir does not cure COVID-19, and its safety and efficacy for the treatment of COVID-19 have not been established in well-designed clinical trials.
As reported by Gilead, the manufacturer of remdesivir, the Phase 3 SIMPLE-Severe trial of remdesivir noted a 62% reduction in mortality risk compared with standard of care for remdesivir and an improvement in clinical recovery.
Earlier, a preliminary report from a National Institute of Allergy and Infectious Disease randomized, double-blind, placebo-controlled study in hospitalized patients with COVID-19 had shown a shortened time to recovery for remdesivir by an average of four days as compared to placebo (11 vs. 15 days; p<0.001).
Is Dexamethasone the Answer to COVID-19?
With the recent news from the Randomized Evaluation of COVID-19 Therapy (RECOVERY) study, dexamethasone may yet achieve the vaunted goal of FDA approval subsequent to completion of a well-designed clinical trial.
RECOVERY involved 2,104 patients randomized to receive 6 mg of dexamethasone once daily compared to 4,321 patients randomized to a control group that received usual care. In a preliminary report from this study, the drug reduced deaths in patients receiving invasive mechanical ventilation by one-third, and by one-fifth in patients receiving oxygen without invasive mechanical ventilation.
The RECOVERY study was received with an acclaim described by one industry analyst as "irrational exuberance." The World Health Organization quickly began the process of updating treatment guidelines to include dexamethasone or other steroids, and the findings of RECOVERY, with those of earlier observational reports, found many advocates.
There are those, however, for whom dexamethasone and the RECOVERY trial, as reported, present a number of practical and clinical concerns.
Because dexamethasone is a steroid, its twin anti-inflammatory and immunosuppressant capacities constitute a potential two-edged sword for the treatment of COVID-19. A synthetic corticosteroid, dexamethasone would be expected to both suppress the cytokine drivers of inflammation and inhibit the body's immune response, including those T cell and B cell functions required to clear the virus from the body. Delayed clearance of viral RNA in the blood and respiratory tract with steroid therapy was among the findings of a recent large meta-analysis from China published in April involving 5249 subjects with MERS or SARS-CoV treated with steroids.
Corticosteroids have been available for a very long time (dexamethasone was FDA approved in 1958) and the weight of history may have a bearing on the present, as well. According to Carl June, MD, who was interviewed recently for the Cancer Research Institute, trials with corticosteroids have been conducted for 30 years at the Abramson Cancer Center and the Perelman School of Medicine without a positive result or a subsequent confirmation of previous findings.
Timing is Everything
Asked about dexamethasone and RECOVERY, Dr. June offered the view that the study investigators "may have just threaded the needle perfectly with a low dose at the right time in the infection."
This perspective is shared by the study investigators, who concluded that "the beneficial effect of corticosteroids in severe viral respiratory infections is dependent on using the right dose, at the right time, in the right patient. High doses may be more harmful than helpful, as may corticosteroid treatment given at a time when control of viral replication is paramount and inflammation is minimal."
Unanswered Questions
RECOVERY has not been completed, and its preliminary report leaves many questions unanswered. In the published report, the investigators do not distinguish between the forms of dexamethasone used (intravenous vs. oral), and did not define the dose or duration of use. The optimal time or phase at which to begin and cease dexamethasone use is also unclear, as were the virological measures for the patient population. Thus, long-term follow-up of the original cohort will be necessary to identify the further potential harms and benefits associated with dexamethasone in COVID-19.
A Hiatus for Hydroxychloroquine
A synthetic derivative of the drug quinine produced from the bark of the cinchona tree, hydroxychloroquine (HCQ), or quinine, is thought to have been used as an antimalarial drug by native South American populations and later Jesuit missionaries. The synthetic antimalarial form of quinine known as HCQ was developed in 1955.
In addition to its present-day use as an antimalarial, HCQ has numerous immunomodulatory effects. It has been used to treat bacterial and viral infections as well as a variety of rheumatic diseases such as rheumatoid arthritis. Some studies have indicated a potentially beneficial use of HCQ in reducing cardiovascular risk for conditions such as diabetes mellitus; others have shown that HCQ can prevent blood clotting in hip replacement patients.
The antiviral and anti-inflammatory properties of HCQ prompted clinical studies for use as a treatment for SARS-CoV-2 early in the COVID pandemic in China and in France, where the drug was combined with azithromycin. However, as noted by Dr. Fajgenbaum and his co-authors, later studies found discrepancies with studies reporting positive outcomes, null results, and safety for hydroxychloroquine, and as earlier indicated in this article, the drug has been removed from further consideration by the WHO International Steering Committee for the SOLIDARITY trial.
Sophie Roling, a Candidate for B.A. in Biology at the University of Pennsylvania, contributed to this article.