On August 1, 2022, President Joe Biden once again tested positive for COVID-19 after taking Paxlovid. Rebound positivity can occur regardless of treatment and is not related to worsened prognosis, according to Ashish Jha, MD, MPH, the coordinator of the White House COVID-19 Response committee.

Schnirring L.  CIDRAP News. Biden continues to test positive after COVID treatment rebound. Center for Infectious Disease Research and Policy. August 1, 2022.

 

Biden’s treatment for COVID-19 has shone a light on what really works as treatment among non-hospitalized patients. To date, the FDA has approved only two treatments for the disease, remdesivir and baricitinib, which is an immunomodulator used in some hospitalized patients. The FDA has, however, issued various Emergency Use Authorizations (EUAs).

FDA. Know your treatment options for COVID-19. May 19, 2022.

 

 

The first approval

In October 2020, the FDA approved the intravenous antiviral remdesivir for the treatment of hospitalized adults and children weighing more than 40 kg.

FDA. FDA approves first treatment for COVID-19. October 22, 2020.

This drug takes the form of a nucleoside analog that blocks the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and other coronaviruses. RdRp incorporates the analog into the growing RNA strand; upon addition of three more nucleotides into the RNA the RdRp sputters out—or stalls—prematurely.

Kokic G, Hillen HS, Tegunov D, et al. Mechanism of SARS-CoV-2 polymerase stalling by remdesivir. Nat Commun. 2021;12(1):279.

 

The FDA based its approval in part on a randomized trial done by the National Institute of Allergy and Infectious Diseases that looked at how long it took for hospitalized patients to recover from COVID-19, within 29 days of having received remdesivir or placebo. Median recovery time for the remdesivir group was 10 days vs 15 days in the control arm. Other randomized trials showed symptom improvement in hospitalized patients taking the drug.

 

Oral agents

Paxlovid is the first oral medication to be authorized by the FDA to treat COVID-19, receiving EUA in December 2021. It consists of nirmatrelvir tablets packaged with ritonavir tablets and is indicated to treat adults and children aged 12 or older to help stop progression to severe COVID-19, hospitalization, or death.

FDA. Coronavirus (COVID-19) update: FDA authorizes first oral antiviral for treatment of COVID-19. December 22, 2021.

The drug should be taken upon a patient’s diagnosis with COVID-19 or within 5 days of symptom initiation.

 

It’s important to remember that Paxlovid is not FDA approved but rather has an EUA, which is a balanced decision regarding efficacy based on the totality of scientific evidence available. To date, various monoclonal antibodies also have EUA status. Supporting evidence for the Paxlovid EUA included a trial that showed the drug decreased risk of hospitalization or death from any cause by 88% in high-risk patients, as compared with patients who only received placebo.

One day after Paxlovid earned an EUA, the FDA also anointed molnupiravir (Legevrio) with this designation. Molnupiravir introduces error into the virus’s genetic code that stops viral replication. It’s approved for certain adults who are at high risk for progression to severe COVID-19,or hospitalization, or death, and who have no other treatment options.

FDA. Coronavirus (COVID-19) update: FDA authorizes additional oral antiviral for treatment of COVID-19 in certain adults. December 23, 2021.

 

One key study supporting the molnupiravir EUA involved measuring the decrease in hospitalization rates among high-risk COVID-19 patients who took the drug. Hospitalization or death occurred in 6.8% of patients taking molnupiravir, vs 9.7% of patients receiving placebo.

 

Treatment approach for outpatients

The NIH suggests that treatment of COVID-19 should occur in two stages. During the first, the illness is propelled by SARS-CoV-2 replication, so therapies should directly target the virus early on. Later, when the inflammatory/immune response is threatening tissue damage, immunosuppressants or anti-inflammatories are the appropriate choice.

Based on this calculus, the NIH recommends the following for outpatients who don’t need supplemental oxygen but are at high risk for disease progression:

• Paxlovid as a preferred first agent

• Remdesivir as a preferred second agent

• The monoclonal antibody bebtelovimab as a first-choice alternative treatment

• Molnupiravir as a last choice

The NIH panel also recommends against using steroids in these patients, and stresses that all patients receive symptomatic care.

 

What about antibodies?

According to an editorial published in The New England Journal of Medicine, “Continued evolution of the spike protein is the biggest threat to all monoclonal antibody–based interventions against SARS-CoV-2, and it can be stymied only by decreasing the total global burden of viral replication in human hosts. Although the shifting antigenic landscape of the spike protein may mean that monoclonal antibodies will require periodic updates, the ability to passively immunize persons who have an increased risk of an ineffective immune response is an important leap forward in the ongoing fight against viral evolution.”

Abraham J. Monoclonal antibodies with extended half-life to prevent covid-19 [Editorial]. N Engl J Med. 2022;386(23):2236–2238.

 

In the article, author Jonathan Abraham, MD, PhD, of Harvard Medical School, suggested that one possible method of boosting the efficacy of monoclonal antibodies was to administer a cocktail of monoclonal antibodies that have an extended half-life, as demonstrated in a video published with his article.

 

Hope for the future

A March 2022 article in Nature gave an overview of the more than 100 treatments or vaccines for COVID-19 that are in late-stage trials. This statistic bodes well for the future management of this disease.

Ledford H. Hundreds of COVID trials could provide a deluge of new drugs. Nature. 2022;603(7899):25–27.

 

But until those strategies are approved and available, preventative methods recommended by the CDC remain important reminders to stress to patients:

• Taking vaccines

• Wearing masks

• Regular handwashing

• Ventilation improvements

• Staying home and avoiding contact

• Getting tested as needed