Ritonavir-Boosted Nirmatrelvir (Paxlovid)

On this page: 

• Overview 
• Clinical Information 
  • Eligibility 
  • Dosing 
  • Decision-Making 
  • Drug-Drug Interactions 
• Safety 
  • Viral Rebound 
  • HIV Screening 
• Clinical Trial & Other Data
  • Clinical Trials 
  • Real-World Observational Data 
• Resources 
• Multimedia 

Last reviewed: July 13, 2022 

Overview

Ritonavir-boosted nirmatrelvir (brand name Paxlovid) has been FDA-authorized for emergency use to treat mild-to-moderate COVID-19 since December 2021. 

Clinical Information

Eligibility: FDA’s ritonavir-boosted nirmatrelvir EUA covers adults and pediatric patients 12 years and older weighing at least 40 kg (88 lb) with positive SARS-CoV-2 test results who are at high risk for progression to severe COVID-19. Ritonavir-boosted nirmatrelvir is not recommended for patients with severe renal impairment, as appropriate dosing has not been determined.

Dosing Information: Ritonavir-boosted nirmatrelvir is dispensed in blister packs that contain 150 mg tablets of nirmatrelvir and 100 mg tablets of ritonavir. Dosing varies by kidney function, as below, so one or two of the nirmatrelvir tablets will be needed, depending on recent kidney function, and a 100 mg ritonavir tablet is always given, regardless of renal function. It is not necessary to draw labs to assess renal function prior to prescribing ritonavir-boosted nirmatrelvir; basing dosing off the most recent known renal function is advised.

EGFR (CKD-EPI formula)	Dose of nirmatrelvir/ritonavir
>60 mL/min	300 mg nirmatrelvir + 100 mg ritonavir, twice daily for 5 days
30≤60 mL/min	50 mg nirmatrelvir + 100 mg ritonavir, twice daily for 5 days
<30 mL/min	Not recommended: Appropriate dosing has not been determined.

Decision-Making: In ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease, IDSA guidelines suggest ritonavir-boosted nirmatrelvir be initiated within 5 days of symptom onset (conditional recommendation, low certainty of evidence). NIH guidelines also suggest ritonavir-boosted nirmatrelvir for nonhospitalized patients with mild-to-moderate COVID-19 who are at high risk of disease progression (AIIa recommendation).

The following resources offer paths to aid clinicians in navigating current U.S. COVID-19 treatment options: 

• Real-Time Learning Network COVID-19 Outpatient Treatment Guidelines Roadmap 

• NIH Outpatient COVID-19 Treatment Guidelines 

• HHS COVID-19 Therapeutics Clinical Decision Aid 

Drug-Drug Interactions

Because this medication is co-formulated with ritonavir as a pharmacokinetic booster, and ritonavir can alter levels of many drugs, clinicians should be aware of and identify any potential drug interactions. At the same time, NIH guidelines advise that “drug-drug interactions that can be safely managed should not preclude the use of this medication.”

The following resources may aid clinical decision-making:

• IDSA Clinical Guide to Management of Nirmatrelvir/Ritonavir Drug Interactions 

This clinical reference lists steps to take in order minimize risk of interactions and provides information on the management of commonly prescribed medications that are known to interact with ritonavir-boosted nirmatrelvir. 

• FDA Patient Eligibility Screening Checklist Tool for Prescribers

This printable checklist includes a patient screening guide and lists drugs with established and/or potentially significant interactions. Drugs are listed as either contraindicated or as requiring additional management (i.e., avoiding and/or holding of the drug, dose adjustment or special monitoring).

• NIH Guide to Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir & Concomitant Medications  
  

This visual guide identifies outpatient medications that have clinically relevant drug-drug interactions and suggests several tiers of management strategies; it also lists commonly prescribed medications with no interactions that may be co-administered without dose adjustment/increased monitoring. 

• HIVMA Treatment Considerations for People With HIV & Hepatitis C  
  

This resource from IDSA’s HIV Medicine Association outlines considerations for treating COVID-19 in people with HCV or HIV, and how to handle their antiretroviral therapy and HCV medications. 

• University of Liverpool COVID-19 Drug Interactions 
  

This guide to COVID-19 medications and drug-drug interactions contains a helpful interaction checker, which provides a recommendation for management of DDIs in addition to a description of the primary data. 

(See also Liverpool’s Quick Guide on Interactions with Outpatient Medicines and Paxlovid [PDF]) 

• University of Liverpool Patient Assessment Flowchart [PDF]

This flowchart provides considerations for assessing a patient for prescribing ritonavir-boosted nirmatrelvir. 

 

Safety

FDA’s EUA fact sheet for providers lists the following side effects that occurred more frequently among the clinical trial participants taking ritonavir-boosted nirmatrelvir than among those taking placebo: dysgeusia (6% and <1%, respectively), diarrhea (3% and 2%), hypertension (1% and <1%) and myalgias (1% and <1%). The proportions of subjects who discontinued treatment due to an adverse event were 2% in the ritonavir-boosted nirmatrelvir group and 4% in the placebo group.

Viral Rebound: According to NIH guidelines, “case reports have described SARS-CoV-2 viral rebound [i.e., recurrence of positive SARS-CoV-2 testing after initially converting to a negative test] and the recurrence of COVID-19 symptoms in some patients who have completed treatment with ritonavir-boosted nirmatrelvir” (see Charness, May 2022 – preprint, not peer-reviewed). A recent cohort of 483 people at high risk of progressive disease who were treated with ritonavir-boosted nirmatrelvir showed that only four out of 483 patients (0.8%) had rebound symptoms at a median of 9 days after treatment initiation, and all were mild and resolved spontaneously (Ranganath, June 2022). According to a review by FDA’s Center for Drug Evaluation and Research as well as the FDA EUA for ritonavir-boosted nirmatrelvir, this phenomenon was also observed in the clinical trials of the drug, and viral rebound at day 10 or day 14 after treatment initiation occurred in 2% of participants on the study drug as well as 1.5% of participants on placebo, a difference that was not statistically significant (Carlin, June 2022). In the initial analysis described in the EUA, there was no clear signal of resistance to ritonavir-boosted nirmatrelvir either at baseline or after treatment, and no difference in possible resistance-associated mutations between the treatment group and the placebo group. One article describing the virological and immunological characterization of a SARS-CoV-2 BA.2 variant that recrudesced after nirmatrelvir/ritonavir treatment found that neither resistance to nirmatrelvir nor absence of neutralizing immunity were likely causes of the recrudescence. Further FDA monitoring of these events is ongoing, and further data and research are needed in order to properly interpret them.

HIV Screening: For individuals with undiagnosed or uncontrolled HIV, administration of this drug could lead to resistance of HIV to protease inhibitors. Screening for HIV should be considered as part of routine care per United States Preventive Services Task Force recommendations.

Clinical Trial & Other Data

Clinical Trials

The drug has been studied in Phase 2/3 trials, including in unvaccinated high-risk participants in the EPIC-HR trial, which used a primary endpoint of 28-day all-cause mortality or COVID-related hospitalization. In the published final results (Hammond, April 2022), nirmatrelvir/ritonavir significantly reduced the risk of hospitalization or death by 88% (p<0.0001) when administered to nonhospitalized, high-risk adults with COVID-19 within 5 days of symptom onset and by 89% when administered within 3 days of symptom onset. The study included 2,246 individuals with confirmed COVID-19 and was stopped early by the Data and Safety Monitoring Board in consultation with FDA due to overwhelming efficacy results. Among the 1,379 individuals in the modified intention-to-treat population (consisting of participants who were treated within 3 days of symptom onset and did not get an anti-SARS-CoV-2 monoclonal antibody), there was a relative risk reduction of 88.9% for COVID-related hospitalization or death with 5/697 in the treatment group compared to 44/682 in the placebo group (absolute risk difference of -5.81 percentage points (95% CI, -7.78 to -3.84; p<0.001). The findings among participants treated within 5 days of symptom onset (rather than 3 days) were similar, with 8/1,039 hospitalizations or deaths in the treatment group as compared to 66/1,046 in placebo recipients for a relative risk reduction of 87.8% (absolute risk reduction, -6.2% (95% CI, -7.21 to -4.03; p<0.001). All deaths occurred in the placebo group, and none in the treatment group. At day 5 after treatment initiation, SARS-CoV-2 viral load was lower in ritonavir-nirmatrelvir recipients than in placebo recipients, with a mean difference of -0.868 log₁₀ copies/mL. Rates of treatment-emergent adverse events of Grade 3 or 4 were lower in the treatment group (4.1%) than in the placebo group (8.3%), and there were fewer serious treatment-emergent adverse effects in the treatment arm (1.6%) than in the placebo arm (6.6%).

Another study, the EPIC-SR study, evaluated Paxlovid in unvaccinated nonhospitalized adults with COVID-19 and low risk of progression to severe disease, as well as vaccinated adults with at least one risk factor for progression to severe disease. It showed in an interim analysis a marked (70%) reduction in hospitalizations in the study drug group: 2/333 (0.6%) in the group treated with nirmatrelvir/ritonavir compared with 8/329 (2.4%) in the group treated with placebo. This study did not meet the primary endpoint of 4 consecutive self-reported symptom-free days. In the final analysis of the EPIC-SR trial, there were 3/428 (0.7%) in the ritonavir-boosted nirmatrelvir group versus 10/426 (2.3%) in the placebo group who met the secondary endpoint of hospitalization or death. This represented a relative risk reduction of 70%, which was not significant. In a subgroup analysis of only vaccinated adults with at least one risk factor for progressive COVID-19, there were 3/361 (0.8%) who had hospitalization or death in the ritonavir-boosted nirmatrelvir group, compared to 7/360 (1.9%) in the placebo group (a 57% relative risk reduction, also not significant). Pfizer elected to terminate enrollment early, because of very low rates of hospitalization or death among patients at standard (low) risk for progressive disease; this meant that the study was underpowered to assess some of its outcomes (Pfizer press release, June 2022). The data will, however, be included in the upcoming FDA New Drug Application submission to FDA. In both the high-risk study and the standard-risk study, the study drug was found to reduce SARS-CoV-2 viral load about a log more at day 5 than did placebo.

 

Real-World Observational Data

As the early trials of ritonavir-boosted nirmatrelvir enrolled only unvaccinated adults and took place prior to the Omicron era, their applicability to vaccinated adults infected with the Omicron variant was uncertain (though often extrapolated). Emerging retrospective data on its real-world use suggests that the use of ritonavir-boosted nirmatrelvir in selected patients is associated with protection from severe outcomes even among vaccinated or previously infected people with Omicron (Arbel, June 2022 - preprint, not peer-reviewed; Wong, May 2022 - preprint, not peer-reviewed; Najjar-Debbiny, June 2022; Dryden-Peterson, June 2022 - preprint, not peer-reviewed). 

For example, a large retrospective study from Israel (Najjar-Debinny, June 2022) examined the relationship between ritonavir-nirmatrelvir receipt and the outcome of risk of severe COVID-19 or death among high-risk patients with COVID-19 between January and February 2022. Out of 180,351 patients, 135,482 (75%) were vaccinated, and 4,737 (2.6%) received ritonavir-boosted nirmatrelvir for treatment. Being adequately vaccinated was associated with an adjusted HR of severe COVID-19 or mortality of 0.20 (95%), and receiving ritonavir-nirmatrelvir was associated with an adjusted HR of 0.54 (95% CI, 0.39-0.75). In a separate analysis including only those patients diagnosed after Jan. 15, 2022, the HR for hospitalization and death among those with versus without ritonavir-nirmatrelvir fell to 0.43 (p<0.001). A subgroup analysis showed similar efficacy of ritonavir-nirmatrelvir among vaccinated and unvaccinated high-risk adults (aHR of 0.62 and 0.54, respectively; the p-value for the interaction between effectiveness of ritonavir-nirmatrelvir treatment and vaccination status was not significant at 0.129). The patients who benefited the most from ritonavir-nirmatrelvir were older or immunosuppressed patients with comorbidities. Important disparities in health and in care were also identified in this study; the people who were given ritonavir-nirmatrelvir were more likely to be male, older, Jewish and of higher socioeconomic class. Importantly, patients were included on the basis of testing positive for SARS-CoV-2, but no data is available on whether or not the people in this cohort treated with ritonavir-nirmatrelvir had symptoms or not (whereas the FDA EUA specifies that it should only be used in symptomatic patients).

Several preprints have shown similar results. A later analysis from the same database in Israel divided the analysis by age, into groups above 65 years and 40-65 years (Arbel, June 2022 - preprint, not peer-reviewed). 109,213 participants were eligible for nirmatrelvir therapy during the two-month study period. For people above age 65, COVID-related hospitalizations occurred in 14/2,504 among the treated and 762/42,819 among the untreated patients, with an aHR of 0.33 (95% CI, 0.19-0.55). Mortality occurred in 2/2,504 treated as compared to 151/42,819 untreated patients among those over age 65, with an aHR of 0.19 (95% CI, 0.05-0.76). However, for the 66,394 people between the ages of 40 and 64, there was no significant reduction in either COVID-related hospitalization or death in the ritonavir-nirmatrelvir group than in the untreated group. 

A cohort of 30,322 patients from Boston showed a 45% relative risk reduction (adjusted risk ratio of 0.55 [95% CI, 0.38-0.80]) in COVID-related hospitalization among those treated with ritonavir-nirmatrelvir compared with those who were not (Dryden-Peterson, June 2022 - preprint, not peer-reviewed). While the majority (87.2%) of that cohort was vaccinated, there was a trend towards greater efficacy of ritonavir-nirmatrelvir among the unvaccinated (84% relative risk reduction; RR, 0.16 [95% CI, 0.04-0.69]; p=0.052) than the vaccinated. Furthermore, BMI >30 kg/m² was associated with higher effectiveness from ritonavir-nirmatrelvir than BMI under 30 kg/m² (RR, 0.21 [95% CI, 0.09-0.50]; p=0.006). All 39 deaths in this observational study occurred in patients who did not receive ritonavir-nirmatrelvir. An observational study from Hong Kong from February to April 2022 (in a 6%-10% fully vaccinated population, though it is unclear which vaccines were available in Hong Kong then) showed significantly lower rates of hospitalization with molnupiravir and with ritonavir-nirmatrelvir (HR, 0.53; 95% CI, 0.46-0.62; p<0.001 and HR, 0.33; 95% CI, 0.24-0.46; p<0.001, respectively) (Wong, May 2022 - preprint, not peer-reviewed). The same was seen for hospitalization (HR, 0.55; 95% CI, 0.47-0.63; p<0.001 and HR, 0.32; 95% CI, 0.23-0.45; p<0.001 for molnupiravir and ritonavir-nirmatrelvir, respectively).

Overall, these observational, retrospective data are vulnerable to residual confounding and selection bias, and some caution is warranted in interpreting them. However, the emerging data on the real-world use of ritonavir-nirmatrelvir is encouraging, and generally in line with the results of the EPIC-HR trial showing marked reduction in progressive disease and death among those treated with ritonavir-nirmatrelvir.

Resources