Outpatient Treatment of COVID-19 in the Omicron Era

“Better use medicines at the outset than at the last moment.”

- Publilius Syrus, Latin writer (85-43 BCE)

“Substantial progress has been made in therapeutics for non-hospitalized patients with COVID-19, but supply of and access to treatment remain limited.”

- Rajesh T. Ghandhi, MD, professor of medicine, Harvard Medical School

A lot has happened since last fall when I discussed outpatient treatment of COVID-19 in several Germ Gem posts. In December, the U.S. Food and Drug Administration (FDA) gave Emergency Use Authorization (EAU) to Paxlovid and molnupirivir, two first generation oral antivirals. Then the SARS-CoV-2 Omicron variant emerged posing new challenges for treatment, especially with monoclonal antibodies. And of pivotal importance, just this month the federal government began supplying rapid in-home antigen tests for diagnosing SARS-CoV-2, thereby speeding the route to treatment. In this Germ Gems post, I provide updates on these and other developments in the outpatient treatment of COVID-19.

What everybody needs to know. The efficacy of all antiviral medications depends on their early administration. Initiating treatment of SARS-CoV-2, however, requires laboratory confirmation of the diagnosis. Therefore, it is imperative to establish the diagnosis in a timely manner.

This is where the “rapid in-home antigen” tests come in. By now, many Germ Gems readers have received these test kits free from the federal government or purchased the kits at reduced cost at a local pharmacy. (No home should be without them.) But when should you test yourself?

Generally, the answer is whenever you think you may have a cold. Within 2-14 days of SARS-CoV-2 infection a variety of symptoms can occur. Here’s a partial list of symptoms that may develop:

• Fever or chills

• Cough

• Shortness of breath or difficulty breathing

• Fatigue

• Muscle or body aches

• Headache

• New loss of taste or smell

• Sore throat

• Congestion or runny nose

• Nausea or vomiting

• Diarrhea

None of these symptoms is diagnostic. If you develop any of these symptoms you may be infected with any number of other viruses that attack the respiratory tract, and your test will be negative. If your test is positive for SARS-CoV-2, however, your next step is to contact your medical provider for advice about the best treatment. If your provider recommends treatment with an oral drug, you’ll need a prescription.

Some symptoms are more concerning than others. If you develop any of these symptoms or signs, you should call your medical provider immediately regardless of your test results:

• Trouble breathing

• Persistent pain or pressure in the chest

• New confusion

• Inability to wake or stay awake

• Pale, gray, or blue-colored skin, lips, or nail beds

Once the diagnosis of COVID-19 is established there are now several good treatment options available.

Recommended outpatient treatment options. The National Institutes of Health (NIH) has published a list of treatment recommendations. A panel of experts generates and updates these recommendations regularly. In making recommendations, they evaluate, among other things, the results of randomized clinical trials (RCTs) that assess efficacy, safety, and ease of administration of any particular treatment option. As of the publication of this Germ Gems post, the NIH expert panel recommends these agents in rank order: (1) the oral antiviral nirmatrelvir-ritinovir (Paxlovid); (2) the monoclonal antibody sotrovimab; (3) the antiviral drug remdesivir (Veklury); and (4) the oral antiviral molnupiravir.

Paxlovid. The NIH Panel ranked Paxlovid first based on the results of a RCT published February 16, 2022 in the New England Journal of Medicine, “Oral Nirmatrelivir for High-Risk Nonhospitalized Adults with Covid-19.” The authors of this study concluded that symptomatic COVID-19 patients treated with Paxlovid were 89% less likely to have their disease progress to “severe disease” than those treated with a placebo. They also claimed there were no evident safety concerns for patients taking Paxlovid.

Dr. Eric Topol, an eminent American cardiologist and director of Scripps Translational Research Institute, recently provided his opinion about Paxlovid: “A 5-day pill pack with this efficacy and safety is 2nd after vaccines as the most important medical advance for the pandemic.” On February 2, New York City announced that it was offering Paxlovid free to its residents.

Paxlovid is not, however, a one size fits all drug. Other cardiologists have raised valid concerns about Paxlovid. In the article “Caution: Paxlovid Interacts with Many Heart Meds,” appearing on January 17 in MEDPAGE TODAY, cardiologist Anthony Pearson, MD, cautioned against the widespread use of Paxlovid. Therefore, anyone taking heart medications should ask for guidance if their doctor prescribes Paxlovid for treatment of SARS-CoV-2.

Sotorvimab. The NIH COVID-19 expert panel recommends sotorvimab as the only monoclonal antibody for treating SARS-CoV-1 because the Omicron variant proved resistant to several other monoclonal antibody preparations. Sotovimab is highly effective and safe but it has the disadvantage of requiring intravenous or intramuscular administration. The good news is that in many cases your care provider can now potentially arrange for you to receive a single 500 mg infusion at home.

Remdesivir. Remdesivir (Veklury) is ranked third on the list of the NIH COVID-19 Treatment Guidelines. It was the first drug to receive FDA approval for treatment of hospitalized patients with COVID-19 as discussed in my November 18, 2020 Germ Gems post. Like Paxlovid, remdesivir is an antiviral agent that is active against Omicron and other variants, but it cannot be given orally. In January 2022 it was approved for treating COVID-19 patients in an outpatient setting to prevent progression to severe COVID-19. A 3-day course of remdesivir, coordinated by an outpatient infusion center, is suggested.

Molnupiravir. Last, and least promising, on the NIH’s list of outpatient therapies for COVID-19 is the oral antiviral drug, molnupiravir. In October 2021, the pharmaceutical companies Merck and Ridgeback Therapeutics led a global trial where the researchers found that molnupiravir reduced the risk of hospital admission or death from COVID-19 by approximately 50%. Public health officials initially heralded molnupiravir as a “game-changer” in the treatment of COVID-19. But the results of a RCT published in the New England Journal of Medicine in December 2021, suggested that further evaluation of molnupiravir is needed.

Information on current treatments. In addition to the NIH’s COVID-19 Treatment Guidelines, the New York Times’ “Coronavirus Drug and Treatment Tracker” is another timely resource of information on current treatments, as well as on drugs that are in the pipeline. As of mid-February, the biomedical science writers of this on-line site were following 35 coronavirus treatments for their effectiveness and safety and rated the treatments on a scale from “FDA Approved” to “Pseudoscience or Fraud.”

Other options. The FDA gave emergency use authorization (EUA) to the monoclonal antibody belotelovimab for outpatients at high risk of progression of COVID to hospitalization and death. Belotelovimab is active against the Omicron variant including the most recent subvariant BA.2 and may soon be added to the NIH’s list of recommended treatments. (The U.S. government recently agreed to purchase 600,000 doses.)

In December 2021, the FDA issued an EUA for AstraZeneca’s drug Evusheld, a combination of the long-acting monoclonal antibodies tixagevimab and cilgavimab. Evusheld is the first drug the FDA authorized for use in the prevention of COVID-19. It is administered by intramuscular injection for preexposure prophylaxis in people who either have a history of severe allergy that prevents vaccination against COVID-19 or moderate or severe immune compromise leading to an inadequate immune response to vaccination.

In my October 29, 2021 Germ Gems post, “News Flash—Fluvoxamine: An Oral Drug for COVID-19 That’s Effective, Safe, and Cheap,” I suggested that the results of a large RCT in Brazil of fluvoxamine (trade name, Luvox), an anti-depressant that has anti-inflammatory properties, offered great hope for COVID-19 treatment, especially in low- and middle-income countries. Decades ago, the FDA approved fluvoxamine for use as an anti-depressant but has not approved it for COVID-19 treatment therefore it has to be prescribed “off-label.” Additional RCTs of fluvoxamine are now underway in the U.S. so in the near future it may be added to the official armamentarium for treatment of outpatient COVID-19. (Researchers at the University of Minnesota recently submitted an EAU application to the FDA for fluvoxamine to be used for the treatment of COVID-19.)

And the good news is… Only two years after the discovery of SARS-CoV-2 we have at least four drugs that are effective in the outpatient treatment of COVID-19 and more are in the pipeline. More importantly in the management of COVID-19, several highly effective and safe vaccines were released at the end of the first year of the pandemic. These are truly remarkable achievements.