Is nirmatrelvir treatment of SARS-CoV-2 associated with a lower risk of post–COVID-19 condition?

By Neha MathurMar 27 2023Reviewed by Danielle Ellis, B.Sc.

In a recent article published in the JAMA Internal Medicine Journal, researchers from Missouri in the United States (US) performed an observational cohort study using the US Department of Veterans Affairs (VA) healthcare databases.

The study aimed to examine whether nirmatrelvir treatment during acute coronavirus disease 2019 (COVID-19) reduced the risk of post–COVID-19 condition (PCC), also called long COVID.

Background

Long COVID encompassing the post–acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), has affected millions of humans globally. Although the prevention of PCC is an urgent public health priority, there is no approved medication for its prevention or treatment.

Studies have shown that oral antiviral nirmatrelvir, in combination with ritonavir, marketed as Paxlovid, reduces the risk of progression to severe COVID-19 and, subsequently, the risk of developing PCC. However, the effect of Paxlovid is maximum when initiated within five days of COVID-19 onset.

Since December 2021, when oral nirmatrelvir received emergency use authorization (EUA) in the United States (US), millions of people have received nirmatrelvir therapy. Yet, studies have barely investigated the effect of this treatment in reducing the risk of PCC.

There is an urgent need for more data on Paxlovid use in non-hospitalized cases of COVID-19 that are at a higher risk of progression to severe disease. This will help to guide new treatment approaches for SARS-CoV-2 infections and optimize current PCC prevention and treatment strategies.

About the study

In the present study, researchers first identified patients with acute SARS-CoV-2 infection with at least one preexisting risk factor for developing severe COVID-19. The study screened 281,793 individuals who met the following prespecified criteria, as follows:

i) received a confirmed COVID-19-positive diagnosis between January 3 2022, and December 31 2022;

ii) were not hospitalized from the day of testing COVID-19-positive;

iii) had a minimum of one risk factor to develop severe COVID-19; and

iv) survived the initial 30 days post-COVID-19 diagnosis.

The team divided the study participants into two cohorts. The first cohort comprising 35,717 patients, received oral nirmatrelvir therapy within five days of testing COVID-19-positive. The second cohort comprising 246,076 patients, received no antiviral treatment during the acute phase of the illness.

The primary study outcome was an estimate of nirmatrelvir therapy-related hospitalization, death, or PCC after the acute phase of illness. The team used an inverse probability-weighted survival model to fetch these estimates.

They recorded whether participants had any of the 13 prespecified PCC components (or post–acute sequelae) on a relative scale, recorded as risk (RR) or hazard ratio (HR), and their risk reduction in percentage at 180 days (ARR) as an absolute measure.

Results

The first nirmatrelvir therapy, initiated within five days of receiving a positive SARS-CoV-2 test, reduced the risk of 10 of 13 post–acute sequelae. Its use was also associated with a 26%, 47%, and 24% less risk of PCC, post–acute death, and post–acute hospitalization, respectively.

The extent of risk reduction on the absolute scale due to nirmatrelvir therapy was also significant. Amounting to 0.65, 1.72, and 4.51 fewer cases of post–acute death, post–acute hospitalization, and PCC for 100 persons given oral nirmatrelvir drug therapy between 30 and 180 days of the onset of symptoms.

Moreover, nirmatrelvir therapy was effective across various subgroups, regardless of their vaccination status and COVID-19 history.

The study provides enough evidence to initiate randomized clinical trials to evaluate the benefits of nirmatrelvir in people with no risk factors for progression to severe disease (who currently do not meet the requirements for receiving nirmatrelvir therapy under the current EUA guidelines in the US).

Studies should also evaluate the effects of a longer duration of nirmatrelvir therapy, a higher dose, or both in reducing the risk of PCC. It could lead to the discovery of new information because different molecular mechanisms mediate different post-acute sequelae; thus, some might not be affected by the receipt of antivirals, such as nirmatrelvir. 

Finally, studies should also examine other antivirals with comparable efficacy as nirmatrelvir, e.g., molnupiravir. It could help the researchers understand whether the connotation reported in this work applies to other antivirals and reduce dependence on a single drug, especially with a rising emergence of antiviral resistance.

Conclusions

The current cohort study demonstrated that nirmatrelvir therapy initiated within five days of SARS-CoV-2 infection in people with at least one risk factor for progression to severe disease was associated with a reduced risk of PCC across the whole risk spectrum examined in this cohort.

Indeed, these findings pointed out the multitude of benefits of nirmatrelvir extending to the post–acute phase of COVID-19.