“Big breakthroughs happen when what is suddenly possible meets what is desperately needed.”
- Thomas Friedman, American author, journalist and commentator
“Treatment without prevention is simply unsustainable.”
- Bill Gates, American business magnate, philanthropist
Last week STAT News announced: “Merck’s antiviral pill reduces hospitalization of COVID patients, a possible game-changer for treatment.” News of improved treatments of outpatients with COVID-19 is most welcome. These treatments are the subject of this week’s Germ Gems post.
Antiviral agents to treat COVID-19. In October 2020, remdesivir was the first antiviral drug to be approved by the U.S. Food & Drug Administration (FDA) for treatment of hospitalized adults and children aged 12 years and older with COVID-19. It works by blocking the virus from copying itself. On October 4, 2021, at the Annual Meeting of the Infectious Diseases Society of America, researchers reported results of a randomized, placebo-controlled trial of remdesivir at the University of Washington showing that a 3-day course of intravenous remdesivir was safe, well-tolerated, and highly effective at preventing COVID-19-related hospitalization or death in high-risk non-hospitalized individuals. The drawback to remdesivir and the other currently authorized drugs for treatment of COVID-19 is that they must be administered intravenously or by subcutaneous injection.
Molnupiravir is a drug manufactured by Merck that is taken orally (800mg twice daily for 5 days.) The recent buzz about outpatient treatment of COVID-19 by molnupiravir began on October 1, when Merck and the co-developer, Ridgeback Biotherapeutics, announced that a clinical trial of molnupiravir was stopped early by an independent board of experts based on an analysis showing that hospitalization and mortality were reduced by 50% without any concerning side effects. To put it simply, this meant that there was no reason to continue the trial as the results with the active drug were so positive. Merck conducted this clinical trial entirely in patients who had not been vaccinated, and all the patients had mild or moderate illness with at least one risk factor for a poor outcome.
Molnupiravir targets an enzyme, RNA-dependent RNA-polymerase, that the virus uses to make copies of itself. According to Merck, molnupiravir is active against all of the known SARS-CoV-2 variants. The results of this molnupiravir trial have yet to be peer reviewed. If the regulators authorize the use of this drug, it will be the first oral space antiviral treatment for COVID-19.
While the news about molnupiravir is welcome and appears to be very positive, molnupiravir is not a silver bullet. Some scientists have raised serious safety concerns, and two Indian drugmakers stopped trials of generic molnupiravir for patients with moderate COVID-19 for lack of evidence that it works in patients with this stage of illness. The cost of the drug is $700 a course. Although this is far less expensive than the costs associated with hospitalization, this is another serious consideration.
Treatments in addition to remdesivir and molnupiravir. In the August 4, 2021 Germ Gems post, “COVID-19 Treatment: Progress and Unmet Needs,” I discussed the clinical trials of monoclonal antibodies (mAbs) in hospitalized COVID-19 patients. These laboratory-generated antibody preparations behave as drugs that target the spike protein of SARS-CoV-2 preventing the virus from entering cells via ACE2 receptors. Since August, several preparations of mAbs have been found effective in outpatients with mild to moderate COVID-19 who are at high risk of developing severe disease.
In the U.S., there are three anti-SARS-CoV-2 mAb preparations with FDA Emergency Use Authorization (EUA) for the treatment of COVID-19: bamlanivimab plus etesevimab, casirivimab plus imdevimab (REGEN-COV), and sotrovimab. Clinical trials of these drugs in outpatients demonstrated significant reductions of severe COVID-19 and death. In the case of REGEN-COV, a single subcutaneous dose prevented symptomatic infection, which suggests this drug may have a potential role in prevention of illness altogether.
Monoclonal antibodies are in high demand. In mid-September, the U.S. government paid roughly $3 billion for mAbs. At the end of September, the World Health Organization recommended REGEN-COV for patients with non-severe COVID-19 who are at highest risk of hospitalization.
In addition to the challenge of keeping pace with increased demand for mAbs for the treatment of outpatients with non-severe COVID-19, several other practical considerations limit their usefulness at present. One hurdle is getting the word out to physicians and patients, especially the underserved, that if mAbs are given early in an outpatient setting, they work. A second practical limitation is the need for additional infusion centers along with improved communication regarding how find to such centers.
Other outpatient treatments of COVID-19. As mentioned in several previous Germ Gems posts, severe inflammation that is provoked during SARS-CoV-2 infection plays a deleterious role in organ damage and mortality. Intravenous administration of high-dose anti-inflammatory corticosteroids, such as, dexamethasone or methylprednisolone, is now standard treatment of critically ill COVID-19 patients.
In September 2021, two reports were published discussing the beneficial effect of inhaled corticosteroids in outpatients with COVID-19. In one study of over 70,000 COVID-19 patients treated at the Cleveland Clinic, researchers found that patients who were using intranasal corticosteroids for other medical conditions prior to COVID-19 illness were 22% less likely to be hospitalized, 23% less likely to be admitted to the ICU, and 24% less likely to die.
Results of the second study appeared in the September 4 issue of the Lancet, “Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomized, controlled, open-label, adaptive platform trial.” Budesonide is an inhaled corticosteroid that works by preventing inflammation in the lungs, which makes asthma attacks less severe. In this multi-center clinical trial, inhaled budesonide improved time to recovery, with a chance of also reducing hospital admissions or deaths in people who are at higher risk of complications.
It is too soon to know exactly where inhaled corticosteroids fit in the recommendations for outpatients with COVID-19. An editorial that accompanied the above mentioned Lancet article, however, reached the following conclusion: “On the basis of the PRINCIPLE trial data, it seems reasonable to consider inhaled corticosteroid use in early COVID-19 in patients similar to the trial population group (people with ongoing symptoms from COVID-19 aged 65 years or older or 50 years or older with specific comorbidities).”
Numerous other medications that can be taken by outpatients with COVID-19 are under investigation. I am waiting for the results of randomized clinical trials of the antidepressant fluoxetine (trade name Prozac), which looks promising if taken early to prevent severe COVID-19. An article on September 10, 2021in Nature Scientific Reports, “Probenecid inhibits SARS-CoV-2 replication in vivo and in vitro,” also caught my eye. Like fluoxetine, probenecid is a repurposed drug (originally used for the treatment of gout) that’s been around forever.
Finally, we can eagerly anticipate results of studies from the National Institute of Allergy and Infectious Disease’s “ACTIV-2: A Study for Outpatients With COVID-19.” This program was launched in 2020 in recognition of the urgent need for one study to efficiently test multiple drugs from more than one company, in people who have tested positive for COVID-19 but who do not currently need hospitalization. With the support of multiple pharmaceutical companies, ACT-2 aims to prevent disease progression to more serious symptoms and complications and the spread of COVID-19 in the community.
Practical considerations in treating outpatients with COVID-19. The good news is that there are now several different treatments that may keep you out of the hospital if you have mild to moderate COVID-19. The approved treatments, in order of ease of access, are: inhaled budesonide, intravenous infusion of mAbs, and infusion or subcutaneous injection of remdesivir. (I sincerely hope that molnupiravir and other oral antiviral drugs will soon be added to this list.) A doctor or other caregiver must prescribe all of these treatments. Your job is to know when to contact your doctor to ask for treatment recommendations for you or for a loved one. Because there are no signs or symptoms of SARS-CoV-2 that are pathognomonic, that is, specifically characteristic or indicative of COVID-19, there is no easy answer to when.
In a recent study published in PLOS Medicine on September 28, 2021, “Predictive symptoms for COVID-19 in the community: REACT-1 study of over 1 million people,” seven symptoms were jointly predictive of SARS-CoV-2 PCR positivity. These symptoms were: loss or change of sense of smell, loss or change of sense of taste, fever, new persistent cough, chills, appetite loss, and muscle aches.
None of these symptoms is unique to COVID-19. They can all occur with many other types of viral upper respiratory tract infections, such as those that cause the “common cold” or influenza. And one thing that is certain, especially during the winter months, is that you and your loved ones will get colds. Thus when you or any one in your family develops any of these symptoms what you really need to know is where you can easily get tested for COVID-19.
Here again there’s good news because rapid COVID-19 home testing programs are proliferating. Finding rapid home tests is getting easier—just search on-line for your state’s Department of Health or a nearby Walgreens or CVS. As part of an initiative called “Say Yes! COVID Test (SYCT),” the National Institutes of Health and Center for Disease Control and Prevention are teaming up in several parts of the country to provide residents age two and older with free home-testing kits for COVID-19. In addition, on October 6, the White House pledged $1 billion for at-home COVID-19 tests.
For detailed guidance on rapid home tests, I highly recommend Tara Parker-Pope’s October 7 New York Times article, “How to use rapid home tests (once you find them).” She provides practical advice about testing in the context of visiting friends, traveling, making decisions about sending kids to school or to visit their grandparents.
Take home message. The recent surge in outpatient treatments of COVID-19 is both encouraging and a reminder of lessons learned previously in the treatment of other potentially deadly viral infections, HIV and influenza—treat early. So if you or a loved one develops any symptoms suggestive of COVID-19, get a rapid home-test kit to rule in or rule out the diagnosis of COVID-19. If the test is positive, contact your health care provider for advice about the next steps.
Finally, don’t let the improved outpatients treatments of COVID-19 distract you from the most important goal—prevention. Make sure you stay up to date on recommendations for COVID-19 vaccines!
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