Treating SARS-CoV-2 coronavirus & COVID-19
Updated: August 13, 2022
Introduction
Despite 2 years having passed since the start of the COVID-19 pandemic, there is still intense debate about the best therapeutic strategy for patients with COVID-19. Multiple randomized studies have evaluated the efficacy of different antiviral, anti-inflammatory, and antithrombotic treatments. However, results have been disparate and difficult to interpret at times due to conflicting results; some trials have reported that treatments reduce mortality and other trials, reporting on the same treatment, have shown mortality to be unaffected.
Part of the uncertainty is due to the complexity of COVID-19 disease, manifesting in those severely affected as different and overlapping pathophysiological phenotypes among different people—mainly viral pneumonia, hyperinflammatory response, thrombotic events, organizing pneumonia, heart failure, or co-infections (such as bacterial or fungal infections). Indeed, presentations of the range of physiological conditions are clinically similar: fever, dyspnea or respiratory failure (or both) with the need for oxygen therapy, thus requiring hospital admission. Therefore, treatment or combination treatments considered most appropriate can vary among patients. However, most randomized studies assessing response to specific treatments have, to date, included all patients with COVID-19, irrespective of phenotype assessment.
A serious warning
Before proceeding to a discussion of the proposed medications for treatment of the SARS-CoV-2 coronavirus infection and the COVID-19 disease, anyone considering taking any of these medications should consider the following warning and proceed with extreme caution since few, if any of the medications proposed as treatment for the coronavirus infection and/or the COVID-19 disease have been studied in any considerable detail in the laboratory or clinical trials.
Warning! Exercise caution before using any medication
Every effective medication is physiologically active. That means it causes some biochemical or biophysical process in your body to modify its normal activity or activate in response to some stimulus, usually an attack from a virus, a bacterium, or some toxic substance.
Before taking any medication whether it has been prescribed for you or you are choosing to self-medicate with an “over-the-counter” product based on the advertising and promotion you have been watching on television or seeing in print, there are some basic facts you should thoroughly understand and seriously consider.
Although the biochemical and biophysical physiology of most human beings, just as their general anatomy, is similar it is not identical. Your personal physiological response to any medication will vary from the responses of other individuals, even parents, siblings, and close relatives. We are not clones. The DNA of every individual is not identical to that of any other individual, except perhaps an identical twin, and the genetic results of those differences are often manifest at the most fundamental level of biochemical and biophysical physiology.
That is the why those taking medications often report “side effects.” A “side effect” is nothing more than the reaction by your body to the presence of a physiologically active foreign substance which triggered some kind of “defense.” If the side effects are tolerable and pass quickly and a medication successfully addresses the disease or other attack on your body then the side effects are considered an acceptable risk.
Benefit/risk analysis
Before taking any medication, you should conduct a thorough benefit/risk analysis. Without a thorough benefit/risk analysis, you cannot reach an informed opinion about taking any medication.
The usual cautionary admonition, “consult your physician” is not always sufficient. In the years prior to World War II most neighborhoods had family doctors or small medical practices where the patients and their medical history as well as the community environment in which they lived were well-known to the physician.
Today, the practice of medicine is largely directed by insurance companies and the bureaucrats which manage government medical payment programs such as Medicare and Medicaid, so there is very little direct knowledge of family history by a physician or even the long-term history of a single patient in the files.
Every individual patient should conduct their own research into any prescribed medication and then insist on explanations from their healthcare provider as to how the medication is expected to act during the course of treatment and after the treatment is terminated based on the side effects reported in the medical and scientific literature at that time.
Many of the reports on side effects following treatment with certain medications are to be found only in scientific and medical journals which are difficult access and require access to other materials in order to be understood.
The important questions
If you are planning on taking any prescribed medication, make sure you ask your prescribing healthcare provider a number of relatively simple questions. The questions may in some cases require complex answers but nevertheless you should insist on answers in language you can understand.
The most obvious questions are:
What is this medication supposed to do?
How does it work?
What systems of the body does it affect?
How can I expect my body to react if I take the medication as prescribed?
How long has the medication been used for this condition or these symptoms?
What has been the clinical experience with this medication used as prescribed?
Where can I find reliable information about this medication and the effects of its use?
If I declined to take this medication, what can I expect to occur with respect to my symptoms?
If I declined to take this medication, what can I expect to happen with respect to whatever is causing my symptoms?
Am I in danger of death or serious debilitating disability if I do not take this medication?
Is there a stage in my condition where it will become critically necessary to take this medication?
If your healthcare provider cannot or will not answer these questions to your satisfaction, find another healthcare provider as soon as possible and tell them quite frankly that you were prescribed a medication but your former healthcare provider refused to answer a simple series of questions about my condition and the prescribed medication.
There are many medications, such as aspirin and quinine which have been used throughout the world for generations and even hundreds of years without significant ill effects and with substantial empirical evidence of successfully treating particular conditions and reducing the effects of symptoms associated with those conditions. Recently, however, with the aid of machine learning and high-speed computer support as well as advances in genetic engineering and molecular modification, pharmaceutical researchers have created a great many new physiologically active products which are being marketed using all of the techniques of modern advertising to encourage the use of these products.
When these new products are advertised on television, there is usually a sotto voce disclaimer listing side effects and adverse results which may be associated with use of the product. Those disclaimers also indicate that one of the risks associated with use of the product is death. Another is, “lessening of resistance to infection” which simply means the medication attacks some element of your natural immune system which normally protects you against infections.
How the government protects you
The American people have been led to believe that a federal agency, The Food and Drug Administration evaluates prescription medications as well as many over-the-counter drugs for both their safety and effectiveness. To some extent that is true, however, the criteria used to determine safety and effectiveness by the Food and Drug Administration may not be sufficient to protect all individuals for whom the medication may be prescribed.
Basically, Food and Drug Administration Approval means that the medication has not killed or made seriously ill a statistically significant number of patients enrolled in one or more clinical trials. It also means that the medication seems to have improved the condition of a statistically significant number of those patients.
With respect to assurances from the Food And Drug Administration, the devil is in the details. Without reading the actual clinical studies, the consumer cannot be sure that the clinical sampling included representatives from the population who will be treated with the new medication who are substantially similar to you in terms of age, genetic background, and overall physical health. Clinical studies often include only small numbers of patients.
The British database
Fortunately, with respect to the SARS-CoV-2 coronavirus and the COVID-19 disease, there is a very large population of individuals in the United Kingdom for whom there are extensive medical records including radiographic studies such as CT scans and MRIs who are being followed by researchers exploring the effects of the coronavirus infection and the COVID-19 disease. The results of those studies which have been published in the open literature on the Internet are generally reliable with respect to the information they provide. They are also regularly updated.
Although the public health officials at the Centers for Disease Control and the Food and Drug Administration in the United States and their equivalents in other developed countries provide regular information about treatment of SARS-CoV-2 coronavirus and COVID-19 to physicians and elected officials. Unfortunately, there is generally little of the scientific evidence to support those treatment protocols presented in an easily accessible fashion. This page will be updated as reliable scientific evidence becomes available and therefore will lag somewhat behind the public pronouncements by government agencies, elected officials, bureaucrats, and the pundits of the popular media.
Evusheld (Astra Zeneca
In 2020, researchers at Vanderbilt University Medical Center discovered particularly potent monoclonal antibodies, isolated from COVID-19 patients infected with a SARS-CoV-2 coronavirus circulating at that time. Antibody engineering was used to transfer their SARS-CoV-2 binding specificity to IgG scaffolds that would last longer in the body).]
Evusheld includes two monoclonal antibodies, tixagevimab and cilgavimab. The medication is given as two consecutive intramuscular injections during a single visit to a doctor’s office, infusion center, or other healthcare facility. The antibodies bind to the SARS-CoV-2 spike protein and prevent the virus from getting into human cells and infecting them. It’s authorized for use in children and adults aged 12 years and older who weigh at least 88 pounds.
Evusheld monoclonal antibodies binding to CoV-2 spike
Remdesivir (Veklury)
Remdesivir, sold under the brand name Veklury, is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences. It is administered via injection into a vein. Remdesivir is an FDA-approved drug for the treatment of COVID-19 patients.
Remdesivir was originally created and developed by Gilead Sciences in 2009, to treat hepatitis C and respiratory syncytial virus (RSV)but was ineffective. It was then repurposed and studied as a potential treatment for Ebola virus disease and Marburg virus infections and a collaboration of researchers from the Centers for Disease Control and Prevention (CDC) and Gilead Sciences subsequently discovered that remdesivir had antiviral activity in vitro against multiple filoviruses, pneumoviruses, paramyxoviruses, and coronaviruses. Preclinical and clinical research and development was done in collaboration between Gilead Sciences and various US government agencies and academic institutions and the United States Patent and Trademark Office (USPTO) granted two patents on remdesivir to Gilead Sciences on 9 April 2019: one for filoviruses, and one which covered both arenaviruses and coronaviruses.
The most common side effect in healthy volunteers is raised blood levels of liver enzymes. The most common side effect in people with COVID‑19 is nausea. Side effects may include liver inflammation and an infusion-related reaction with nausea, low blood pressure, and sweating.
Remdesivir: The Solidarity study
In The Lancet, the WHO Solidarity Trial Consortium report their assessment of the prognostic impact of remdesivir and three other drugs (lopinavir, hydroxychloroquine, interferon-β1a) in an unmasked, open-label trial that included, across 35 countries, 14 221 adults hospitalised with COVID-19. No placebos were given. All patients received the local standard of care. Each drug was compared only against its own control group. The cohort was 38% women; 45% of participants were aged 50–69 years and 54% came from Asia and Africa. All analyses were done in the modified intention-to-treat population (ie, according to the assigned treatment), excluding patients with a refuted COVID-19 diagnosis or consent not encrypted into the database.
Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948.
The latest published update of this study reports both a decrease in mortality among non-ventilated adults with oxygen and a lower progression to mechanical ventilation or death in patients receiving remdesivir.
Carolina Garcia-Vidal, Maurizio Sanguinetti, WHO Solidarity Trial Consortium, Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet. 2022; (published online May 2, 2022) https://doi.org/10.1016/S0140-6736(22)00519-0. The lead author has received honoraria for talks on COVID-19 from Gilead.
Duration of hospital stay was not the main objective of the study because that outcome could be biased by the choices made by treating physicians or the need for intravenous treatment, or both. The results showed that remdesivir use did not improve mortality risk in ventilated patients. A potential explanation is that hyperinflammation, thrombosis, or co-infection are frequent causes of patient deterioration that result in admission to an intensive care unit and the need for mechanical ventilation—often several days after symptom onset. The new findings are consistent with other publications that show improved outcomes in patients with COVID-19 receiving remdesivir.
The common denominator across this research is the reporting of better outcomes during the initial disease stage when the viral component is high.
Nonetheless, other studies have not shown a positive effect of remdesivir for COVID-19. The most likely explanation for the conflicting findings might be that clinical phenotypes differ among patients. For example, in one of the negative studies, a randomised, double-blind, multicentre trial of remdesivir versus placebo in China, the median time between symptom onset and remdesivir administration was 11 days and 19% of the patients included had undetectable viral RNA on the nasopharyngeal and oropharyngeal swab taken at baseline, despite being PCR-positive at enrolment.
The COVID-19 pandemic has presented various turning points in epidemiology, which are not entirely reflected over the course of the Solidarity trial —for example, the emergence of multiple viral variants causing disease with varying severity and ability for replication.
Due to the inclusion periods established for Solidarity, patients with the delta or omicron (B.1.1.529) variants were not considered for inclusion in the study. In addition, it is unclear what effect remdesivir or any other antiviral treatment has irrespective of vaccination status. Most patients included in Solidarity are unvaccinated.
Remdesivir mode of action
Remdesivir is a prodrug.
Remdesivir structure
Remdesivir structure (ball&stick molecular model)
Ball-and-stick model of a remdesivir molecule, C27H35N6O8P as found in the crystal structure of remdesivir dichloromethane solvate monohydrate, reported in J. Med. Chem. (2017) 60, 1648-1661 (CSD Entry: ZARNAK). Similar image to File:Remdesivir-from-xtal-Mercury-3D-balls.png, but with bond orders shown: a CN triple bond in the nitrile group, C=O and P=O double bonds, the benzene ring’s aromaticity indicated with a circle, and the pyrrolo[2,1-f][1,2,4]triazine π-system represented by single and double bonds. Colour code: Carbon, C: grey Hydrogen, H: white Nitrogen, N: blue Oxygen, O: red Phosphorus, P: orange Model manipulated and image generated in CCDC Mercury 3.8.
After intake, remdesivir is intended to allow intracellular delivery of GS-441524 monophosphate which is then metabolized and converted within the body into pharmacologically active GS-441524 triphosphate, a ribonucleotide analogue inhibitor of viral RNA polymerase.
Remdesivir activation
The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling.
Using synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling researchers at the Max Plank Institute in Germany found that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RNA-dependent RNA polymerase (RdRp) and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease.
Remdesivir is a phosphoramidate prodrug that is metabolized in cells to yield an active NTP analog that we refer to as remdesivir triphosphate (RTP). Biochemical studies show that the RdRp can use RTP as a substrate, leading to the incorporation of remdesivir monophosphate (RMP) into the growing RNA product. After RMP incorporation, the RdRp extends RNA by three more nucleotides before it stalls. This stalling mechanism is specific to coronaviruses because the RdRp of Ebola virus can add five RNA nucleotides after RMP incorporation before it stalls.
RdRp-RNA complexes after remdesivir addition to the RNA product 3ʹ-end. One structure contained RMP in the +1 site9, whereas another structure contained RMP in the –1 site10. In both structures, RMP mimics adenosine monophosphate (AMP) and forms standard Watson–Crick base pairs with uridine monophosphate (UMP) in the RNA template strand. These studies explained how RMP is incorporated into RNA instead of AMP. However, they do not explain how remdesivir inhibits the RdRp because RdRp stalling occurs only after three more nucleotides have been added to the RNA.
remdesivir; RNA scaffolds
a Position of RNA scaffolds 1–3 as observed in RdRp-RNA complex structures 1–3. Template and product strands are on the top and bottom, respectively.
b Cryo-EM density of RNA in the active center of structures 1–3. The active site metal ion was modeled41 and is shown as a magenta sphere.
c The C1ʹ-cyano group of the RMP ribose moiety (violet) is accommodated at position –3 (left), but would clash with the side chain of nsp12 residue serine-861 (red) at position –4 (right). Spheres indicate atomic van der Waals surfaces.
Results of this research suggested that remdesivir-induced stalling of the RdRp is due to impaired translocation of the RNA after the RMP reaches register –3.
After intake, remdesivir is intended to allow intracellular delivery of GS-441524 monophosphate which is then metabolized and converted within the body into pharmacologically active GS-441524 triphosphate, a ribonucleotide analogue inhibitor of viral RNA polymerase.
Remdesivir activation
Coronaviruses use an RdRp enzyme to carry out replication and transcription of their RNA genome. The RdRp consists of three non-structural protein (nsp) subunits, the catalytic subunit nsp12 and the accessory subunits nsp8 and nsp7. For RNA-dependent RNA elongation, the 3ʹ-terminal nucleotide of the RNA product chain resides in the –1 site and the incoming nucleoside triphosphate (NTP) substrate binds to the adjacent +1 site. Catalytic nucleotide incorporation then triggers RNA translocation and liberates the +1 site for binding of the next incoming nucleoside triphosphate (NTP).
As an adenosine nucleoside triphosphate analog (GS-443902), the active metabolite of remdesivir interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production. In some viruses, such as the respiratory syncytial virus, it causes the RNA-dependent RNA polymerases to pause, but its predominant effect, as in Ebola, is to induce an irreversible chain termination. This is not mediated by preventing addition of the immediately subsequent nucleotide, but is instead delayed, occurring after five additional bases have been added to the growing RNA chain. For the RNA-Dependent RNA Polymerase of MERS-CoV, SARS-CoV-1, and SARS-CoV-2, arrest of RNA synthesis occurs after incorporation of three additional nucleotides. Hence, remdesivir is classified as a direct-acting antiviral agent that works as a delayed chain terminator.
Using synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling, researchers at the Max Plank Institute in Germany found that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RNA-dependent RNA polymerase (RdRp) and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease.