Infectious Disease

Real-world impact of nirmatrelvir plus ritonavir on SARS-CoV-2 infection

January 25, 2023

6 min read


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Percival reports no relevant financial disclosures.


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As the COVID-19 pandemic heads into its 4th year, it is a good time to reflect on strides made for those with mild-to-moderate disease not requiring hospitalization.

The first treatment for this population became available in late 2020 with the emergency use authorization (EUA) of the first monoclonal antibody, bamlanivimab, followed by four EUAs for other monoclonal antibodies.

COVID-19 treatment

The benefit of nirmatrelvir plus ritonavir is limited to those at high risk for progression to severe COVID-19.

Source: YES –

Unfortunately, all the EUAs for treatment monoclonals were revoked because of a loss of activity against circulating variants. The remdesivir label now includes a 3-day course for this population, but it is logistically difficult. The desire for an oral agent to prevent progression to severe disease was high to allow for widespread access to treatment. The first oral therapies, nirmatrelvir/ritonavir and molnupiravir, became available through EUA in December 2021, with an 88% and 30% relative reduction in COVID-19-related hospitalization or death reported for each therapy, respectively.


Nirmatrelvir is a protease inhibitor targeting the SARS-CoV-2 3-chymotrypsin-like cysteine ​​protease enzyme Mpro, which is essential for viral replication. Nirmatrelvir is metabolized mainly by CYP3A4, and co-administration with ritonavir, a CYP3A4 inhibitor, enhances its pharmacokinetics but also leads to numerous drug interactions with other CYP3A4-metabolized drugs. Branded as Paxlovid, it was granted an EUA for people aged 12 years or older with mild-to-moderate disease who are at high risk for progression to severe disease within 5 days of symptom onset and an eGFR greater than 30 mL per minute.

Kelly M. Percival, PharmD, BCPS AQ-ID
Kelly M. Percival

The EPIC-HR study was conducted from July to December 2021, when the main variant circulating was delta, and it included adults with symptoms for fewer than 5 days who had at least one symptom of COVID-19 and one characteristic associated with high-risk progression to severe disease. Exclusion criteria included previous confirmed infection, anticipated hospitalization within 48 hours after randomization and prior receipt of SARS-CoV-2 convalescent plasma or vaccine. The primary outcome was comparison of COVID-19-related hospitalization or death through day 28 among those who initiated treatment within 3 days after onset of symptoms. Those treated within 5 days were evaluated in the secondary outcome. The median age of patients was 46 years, with 66% receiving therapy within 3 days of symptom onset. The most common high-risk factors were BMI of at least 25, smoking and hypertension, with 61% of individuals having two or more risk factors.

In a modified intent-to-treat population of 1,379 patients who began treatment within 3 days of experiencing symptoms, 0.72% (5/697) of participants in the nirmatrelvir plus ritonavir (NVM/r) group were hospitalized — none died — compared with 6.45% (44/682) in the placebo group, in which there were nine deaths, resulting in an 88.9% RR reduction. The RR reduction was still high at 87.8% for those who started therapy within 5 days.

Results from subgroup analyzes were consistent regardless of age, sex, BMI, serology status and coexisting conditions, although the effect appeared larger among those aged 65 years or older and those with negative serology at baseline. The incidence of adverse events was similar at 22.6% in the treatment group vs. 23.9% in the placebo group.

The data are promising, although questions remained about the benefit in the era of the omicron variant, its effect in vaccinated patients, where the most benefit is and whether it is well accepted and tolerated.

Other Studies

There have been a handful of studies evaluating the real-world impact of NVM/r during the omicron wave that began late 2021 and continues today. The first evaluation of patients in Israel from January to February 2022 showed that 2.6% of 180,351 patients deemed eligible for the treatment had received it, with 75% of those eligible having adequate COVID-19 vaccination. NVM/r was associated with a significant reduction in severe disease and death – 46% relative reduction (HR = 0.54; 95% CI, 0.39-0.75) – with the greatest effect seen in older or immunosuppressed patients and those with neurological or cardiovascular disease . The degree of effectiveness of NVM/r was unaffected by vaccination status in this study.

Another study from January to March 2022 in Israel found that patients aged older than 65 years who received the treatment experienced a significant reduction in hospitalization compared with those who did not (adjusted HR = 0.27; 95% CI, 0.15-0.49). Individuals aged 40 to 64 years did not experience a significant reduction (aHR = 0.74; 95% CI, 0.35-1.58), suggesting a benefit only in older patients.

A retrospective cohort case-control matched study from Hong Kong demonstrated a 66% (HR = 0.34; 95% CI 0.22-0.52) and 24% (HR = 0.76; 95% CI 0.67-0.86) relative reduction in death and hospitalization among people who received NVM/r, with a majority of patients being aged older than 60 years and only 33% being vaccinated.

A descriptive study in Italy of people with high vaccination rates who received oral antivirals showed a low rate of hospitalization and death. Adverse effects were limited in the study, but dysgeusia was noted in 9% of patients, which was higher than the 5.6% in the EPIC-HR study.

The real-world impact and effectiveness of NVM/r in the US were evaluated in vaccinated patients in a retrospective propensity-matched cohort study with a primary composite outcome of ED visits, hospitalizations and death at 30 days. Those who received NVM/r experienced a 45% RR reduction in primary outcome compared with those without treatment, suggesting the benefit is retained in vaccinated patients.

An MMWR evaluating NVM/r from April to September 2022 with a focus on 30 days hospitalization showed that about 28% of those eligible were being treated. Use was associated with a 51% lower rate of hospitalization, and this was maintained even in those with three or more doses of COVID-19 vaccine. Contrary to the Israel study, benefit was maintained in those aged 50 to 64 years old.

Use of NVM/r in the US has increased over time, according to data from a cohort of more than 700,000 patients seeking care for COVID-19, from 0.6% of patients in January 2022 to 20.2% in April and 34% in July, although certain racial and ethnic groups were 20% to 36% less likely to be prescribed NVM/r than white patients.

These studies demonstrate a lower but still significant reduction in rate of progression to severe disease and death after receiving NVM/r, even among those who are vaccinated and during omicron. Real-world patients tend to be older and have more or higher risk comorbidities than those in the initial trial, although it remains to be determined if the benefit is limited to only those aged older than 65 years. The benefit of NVM/r does appear limited to those with a risk factor for severe disease because press release data from standard risk patients in the EPIC-SR study showed a nonsignificant reduction in symptom alleviation, hospitalization or death.

Benefits for high-risk patients

The EUA for NVM/r offers a more convenient and accessible treatment for those at high risk for progression to severe disease, but the therapy still has significant limitations, including a high number of drug interactions with ritonavir and the need for an eGFR less than 30 mL per minute. This limits its use in some of the most vulnerable populations, like solid organ transplant patients, in whom the interaction with tacrolimus has been demonstrated to be rapid and significant, leading to tacrolimus toxicity. The magnitude of this interaction makes it difficult to manage in most settings and necessitates the use of alternative agents, which may have lower efficacy or require multiday infusions.

Over the past 3 years, there has been significant progress in the ability to treat mild-to-moderate COVID-19 to prevent progression to severe disease with the availability of NVM/r, although more equitable prescribing is needed and more options are still needed for some of the highest risk immunosuppressed patients. The benefit of NVM/r treatment remains, even during the omicron wave and in vaccinated patients, but is limited to those at high risk for progression.


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