News & Resources
December 20, 2023

Like It? Share It

Paxlovid (Nirmatrelvir – Ritonavir) in the Season of Omicron?

COVID-19 Resources
On behalf of the TeamHealth Emerging Infectious Disease Task Force

Some antiviral medications have demonstrated efficacy against the SARS-CoV-2 virus. Often this efficacy is limited to the laboratory, specific populations or viral variants. However, Paxlovid has demonstrated high effectiveness in certain high-risk populations and is the most commonly used antiviral agent in the United States for COVID-19.

The severity of acute disease in the population with the Omicron sub-variants seems to be decreasing compared with the initial variants. This apparent drop has raised a number of questions for clinicians. Is there still a use for Paxlovid against the Omicron variants? Is there actually a decline in the pathogenicity and risks from COVID-19 with the current Omicron variants? And finally, assuming there is a clear indication for Paxlovid use, are clinicians missing opportunities to recommend this agent?

Current Status of Paxlovid use in the United States

In December of 2021, the United States Food and Drug Administration (FDA) approved an Emergency Use Authorization (EUA) for Paxlovid, a combination of nirmatrelvir and ritonavir, for a select age range and population type. In particular, outpatient use of Paxlovid was approved under this EUA for patients meeting the following criteria:

  • Age 12 and older weighing at least 40kg.
  • A positive direct SARS-CoV-2 test.
  • A high risk of progression to severe disease including hospitalization and death.

Initially, after the approval of the EUA by the CDC, availability of Paxlovid was limited; however, there is a current adequate supply and availability in most communities. For Paxlovid treatment, format and duration, clinicians should consult the specific prescribing information linked in the references of this post. In addition, as there are a number of adverse drug interactions with the components of Paxlovid, clinicians must review this information as part of the process in recommending and using Paxlovid in their patients.

Primary Support for Paxlovid Use: EPIC-HR Study

The initial FDA approval for Paxlovid is based primarily on the results of the EPIC-HR and EPIC-SR studies. EIPC-HR was a randomized, double-blind, placebo-controlled clinical trial. It included non-hospitalized symptomatic adults, who had not received a COVID-19 vaccine nor were previously infected, with a laboratory confirmed diagnosis of SARS-COV-2 infection. These patients also had a pre-specified set of risk factors for progression to severe disease or were 60 years of age or older.

The participants all started treatment within five days of symptom onset and none received the then-available monoclonal antibody therapy. Paxlovid treatment was completed by 1,053 patients, and 1,049 completed the placebo course for a total of 2,102 cases in the final analysis. Treatment with Paxlovid resulted in a risk reduction for progression to severe COVID-19 of 89% compared to placebo. There were 13 deaths in the study, all in the placebo group. Viral loads were also significantly lower in the treatment group after three to five days of treatment. No evident safety concerns were noted in the treatment population. Only 0.9% of the Paxlovid patients were hospitalized due to COVID-19 as opposed to 6.5% of the placebo patients. So overall, Paxlovid treatment reduced COVID-19 related hospitalization and death from any cause by 86% compared to placebo in high-risk patients.

Primary Support for Paxlovid Use: EPIC-SR Study

The EPIC-SR study was a well-designed randomized clinical trial that looked at Paxlovid in the context of standard risk individuals who lacked any high-risk criteria and could also have received a COVID-19 vaccine or have had a prior COVID-19 infection. No statistical impact was noted in treated patients. In fact, the study was terminated due to a very low rate of hospitalization or death observed in the standard-risk patient population. There was a trend in these non-high risk patients towards a reduction of hospitalization with Paxlovid treatment, but again, this was not statistically significant.

What about “COVID Rebound” from Paxlovid?

Both EPIC-HR and EPIC-SR provide information about COVID-19 rebound. Data from these two trials showed that rebound in SARS-CoV-2 virus shedding or COVID-19 symptoms did occur in a small subset of patients in both groups. Based on the data currently available there is no clear association between Paxlovid treatment and COVID-19 rebound. When patients having SARS-CoV-2 antibodies – from a vaccine or prior infection – were evaluated, a small benefit was noted. The risk of COVID-19-related-hospitalization or death from any cause in the antibody-positive group was 0.2% in the 490 treated patients compared and 1.7% in the 479 patients receiving placebo. This benefit is low and likely to be of little help except in individuals with high-risk criteria.

The Omicron Variants

With the arrival of the Omicron variants, the rate of hospitalization for COVID-19 in the general population has substantially declined nationally. However, hospitalization and mortality rates in high-risk individuals continue to be significantly greater than the general population, so there is still likely a substantial benefit to be gained through the use of Paxlovid. Studies also support the continued effectiveness of Paxlovid against core Omicron variants. Importantly, even though the number of reported COVID-19 cases is declining, the impacts of this virus remain substantial. SARS-CoV-2 infections have declined from the third most common cause of death in the United States during 2020-2021 to about the fourth most common cause of death currently. This is not an insignificant virus.


Although reports of long-term impacts from COVID-19 are declining in the general population, long-term impacts of this virus still remain substantial. Just as a COVID-19 vaccine likely results in a lower risk of long-COVID, there is a possibility that Paxlovid use in the high risk population may also have a beneficial impact. It is thought that this might happen due to the drug shortening the duration and decreasing the intensity of the inflammatory response to the virus. Neither of these suppositions are strongly supported by research but are based on clinical intuition. However, given the low incidence of severe adverse effects along with its positive impacts on acute complications in the high-risk population, it is worth consideration.

Current Attitudes and Use of Paxlovid in Eligible Patients

Overall, it seems decidedly likely that the use of Paxlovid in the high-risk and older (> 60 yr.), population can have a substantial impact in the reduction of hospitalization and death. This conclusion holds true with the current crop of Omicron variants. This view is also supported by the current recommendations of the National Institutes of Health, the FDA, CDC and multiple medical specialty organizations.

Unfortunately, determining the attitudes and knowledge of the public and clinicians regarding antiviral use for COVID-19 is a difficult task. A 2022 survey found that of the 24,142 poll respondents, 43% reported they had suffered a bout of COVID-19 since January; however, only 11% of eligible patients indicated that they were offered antiviral treatment. Although there are a number of likely confounders in that report, it does indicate that appropriate use is likely to be low. According to a non-peer-reviewed convenience survey available on Medscape®, the primary reasons providers who considered but did not use Paxlovid in eligible patients was due to concerns over drug interactions and renal function.

The Potential Impact of Paxlovid Use in Eligible Patients

It is estimated that since the FDA EUA release and Paxlovid was made available, approximately 200,000 additional lives may have been saved had the product been used by eligible patients. Additional data from the FDA on the relative risk reduction spanning both clinical studies and real-world epidemiologic information from March 2023 estimates that more than 1,500 lives could be saved, and 13,000 hospitalizations avoided each week. At the same time, a recent report by the National Bureau of Health Statistics (NBHS) indicates that the United States has currently experienced the largest decline in life expectancy since 1996, with deaths from COVID-19 and opioid abuse as the primary reasons.

Reasons for Low Use of Antiviral Therapy

A number of issues have been cited for the relatively poor response for Paxlovid use. These include –among other things;

  • Severe pandemic fatigue among clinicians and patients
  • Lack of knowledge on the part of clinicians regarding Paxlovid eligibility
  • Lack of knowledge on the part of the clinician regarding the background studies and scientific evidence for Paxlovid use
  • Tight timeline for initiation of therapy – within 5 days
  • Testing requirement for SARS-CoV-2
  • Paxlovid availability – mostly resolved
  • Numerous Paxlovid drug interactions
  • Perceived or real financial motivation on the part of Pfizer to promote Paxlovid
  • As well as other issues

Paxlovid in the Season of Omicron?

The SARS-CoV-2 virus, including the current Omicron variants, continue to have a substantial impact on populations. There has been a welcome decline in the numbers of reported cases, admissions and deaths from this virus. However, these declines can mask the continued severe impacts of this disease in the minds of many people – including clinicians.

The serious impacts of SARS-CoV-2 are particularly high when sone looks at the continued elevation of hospitalization and mortality rates for high-risk segments of the population. This group is where antiviral interventions have the greatest impact in saving lives. The evidence and all major and regulatory organizations currently support rapid and appropriate use of Paxlovid in eligible patients. Recent survey data indicates that only a fraction of patients in the high-risk population strata are offered antiviral therapy by their clinicians, pointing to a need for education and support for those clinicians caring for these patients.

Learn more about TeamHealth’s Emerging Infectious Disease Taskforce (EIDT) and see a full list of references here.