Nirmatrelvir and Ritonavir (PAXLOVID) as a Treatment for Acute COVID-19 Infection

In 2023, the Food and Drug Administration (FDA) approved nirmatrelvir and ritonavir (PAXLOVID) to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in adults at high risk of progression to severe disease, including hospitalization or death. Tablets of each drug are copackaged for oral use.

Nirmatrelvir and ritonavir is effective in preventing serious COVID-19 in patients with heightened risk if they are treated early in the course of their infection and if the risk of potentially dangerous drug-drug interactions can be appropriately managed. Before the medication is prescribed, all the patient’s medications must be reviewed to determine whether a dose adjustment or temporary stoppage is necessary and whether additional monitoring is needed. An article in the August 2022 issue of Worst Pills, Best Pills News discussed the many important drug interactions for Paxlovid.[1]

The most common adverse reactions from nirmatrelvir and ritonavir are dysgeusia (altered taste) and diarrhea.

Background on COVID-19 and nirmatrelvir and ritonavir

COVID-19 is a SARS-CoV-2 viral infection that has caused at least 6.8 million hospitalizations and 1.1 million deaths in the United States since its emergence in late 2019.[2] Symptoms of infection range from minimal to severe respiratory and flu-like signs and symptoms, including multiorgan dysfunction, which can lead to hospitalization and death in severe cases.[3]

Nirmatrelvir is an antiviral drug that disables an enzyme the virus needs to reproduce itself in the body, and ritonavir (NORVIR and generics) is an HIV medication that inhibits enzymes from degrading the nirmatrelvir.[4] Because the viral enzyme that nirmatrelvir disables is highly conserved across coronaviruses, this treatment is expected to work similarly across SARS-CoV-2 variants.

In December 2021, the FDA first approved nirmatrelvir and ritonavir under Emergency Use Authorization (EUA). In May 2023, the drug received full approval for use in adults.[5] Pediatric (age 12-18 years) use is still allowed under EUA only. Groups with high risk for untreated COVID-19 progression include adults aged 60 or older, current smokers and people who are immunocompromised or have cardiovascular disease, diabetes or other serious illnesses.[6]

When nirmatrelvir and ritonavir is prescribed, it should be started as soon as possible after the diagnosis of COVID-19 and within five days of symptom onset, then taken twice a day for five consecutive days.[7] Three tablets are taken at the same time: two 150-milligram (mg) tablets of nirmatrelvir and one 100-mg tablet of ritonavir. For persons with moderate kidney impairment, the dose of nirmatrelvir is cut in half (150 mg twice daily) but the dose of ritonavir stays the same. This drug is not recommended for patients with severe kidney or liver impairment.

Clinical trials

The prescribing information for nirmatrelvir and ritonavir describes three clinical trials: one supporting its therapeutic effect and two others showing the limits of its efficacy for some groups of patients.

The first trial, known as the EPIC-HR (high risk) trial, enrolled 2,246 adult outpatients (median age was 46 years) with confirmed disease between July and December of 2021 who were not vaccinated. The subjects were randomized to receive either nirmatrelvir and ritonavir or placebo. The study was double-blinded. All subjects had at least one risk factor for disease progression. At 28 days post-treatment, hospitalizations and deaths were tallied for the 1,039 subjects in the treatment group and 1,046 subjects in the placebo group who completed the follow-up assessments. COVID-related hospitalizations or any deaths were observed in 1% and 6% of subjects in those groups, respectively — a significant difference. No one receiving nirmatrelvir and ritonavir died; 12 deaths occurred in the placebo group.

The EPIC-HR trial assessed the proportion of adverse events one to 34 days after treatment initiation and found no differences overall between the treatment and placebo groups. However, adverse events plausibly associated with nirmatrelvir and ritonavir were twice as frequent than with placebo (8% vs. 4%). This difference was largely attributable to the finding of dysgeusia in 5.6% of subjects who received treatment and 0.3% of subjects who received placebo.

The second trial, known as the EPIC-SR (standard risk) trial, was similar in design to EPIC-HR but included only persons who were either unvaccinated and without a risk factor for COVID-19 progression (41% of subjects) or fully vaccinated with at least one risk factor for disease worsening (59% of subjects). This study of 1,075 subjects did not show any statistically significant 28-day differences related to COVID-19 between the treatment and placebo groups.

A third clinical trial, also double-blinded, involved 2,736 subjects who tested negative for SARS-CoV-2 and lived in the same household with someone who was recently diagnosed with the infection. Those subjects were randomized equally into three groups: five days of the drug and five days of placebo, 10 days of the drug, or 10 days of placebo. Subsequent laboratory testing through 14 days after the completion of treatment showed no statistically significant differences between the groups in the frequency of new cases of COVID-19.

More recent trials and systematic reviews confirm the findings of the three trials described above. A Cochrane review concluded that as of May 2023, the best available clinical evidence indicated that nirmatrelvir and ritonavir may reduce hospital admissions and deaths but will probably increase treatment-related dysgeusia and diarrhea risk.[8] These drug effects were evident in participants with mild COVID-19 who were at high risk of disease progression. The review found that it was uncertain whether patients hospitalized with moderate-to-severe COVID-19 would similarly benefit.

A 2023 article in Reviews of Medical Virology reviewed the EPIC-HR study and three other, more recent observational studies involving tens of thousands of subjects in Israel and Hong Kong.[9] These researchers concluded that nirmatrelvir and ritonavir was effective at reducing hospitalization and deaths in patients over the age of 65 years, but similar effects were of low certainty in younger patients.

Moreover, the Israeli and Hong Kong studies were conducted after a later, less severe variant of the virus (Omicron variant) became dominant. A separate observational study from British Columbia, Canada, published in JAMA Network Open in October 2023, also found that nirmatrelvir and ritonavir reduces COVID-19 (Omicron) hospitalizations and deaths, but only in people who were moderately to severely immunocompromised, and regardless of age. This study included 6,866 persons with a median age of 70 years.[10]

Drug-drug interactions

The important and potentially dangerous drug interactions for nirmatrelvir and ritonavir are detailed in the prescribing information (the table of “established and other potentially significant drug interactions” is nine pages long) and an August 2022 Worst Pills, Best Pills News article, “Important Drug Interactions for the Combination Antiviral COVID-19 Drug PAXLOVID.”[11] As examples, such dangerous interactions may occur if nirmatrelvir is used at the same time as many other commonly used drugs, including antibiotics, blood thinners, antidepressants, steroids, immunosuppressants, opioids and medications for high blood pressure or cancer.

Rebound concerns

There has been concern that use of nirmatrelvir and ritonavir can lead to a post-treatment rebound in COVID-19 symptoms. In December 2023, the Centers for Disease Control and Prevention (CDC) analyzed data from one randomized, controlled study and six observational studies. The CDC report found that four of those studies (including the randomized trial) showed no rebound effect related to the use of nirmatrelvir and ritonavir, whereas the three other studies did, though all the effects were small in each of these studies.[12] The CDC concluded that concerns about a potential rebound in COVID-19 symptoms should not deter the use of nirmatrelvir and ritonavir when it is clinically indicated.

What You Can Do

Medications are no substitute for keeping up to date on your COVID-19 vaccinations;[13] that is the best way to avoid serious illness. If you think you have mild-to-moderate COVID-19, especially if you are at heightened risk of serious disease progression (for example, if you are immune-compromised or not up to date on COVID-19 vaccinations), and soon after you first suspect you have COVID-19, consult with a clinician to discuss whether you should take nirmatrelvir and ritonavir. Before using the drug, all your other medications should be reviewed to determine whether the risk of drug-drug interactions can be managed appropriately. When concerns about drug-drug interactions outweigh the potential benefits of treatment — or the potential benefits are small, such as in people at low risk of disease progression — nirmatrelvir and ritonavir should not be used.
 

References

[1] Important drug interactions for the combination antiviral COVID-19 drug PAXLOVID. Worst Pills, Best Pills News. August 2022. https://www.worstpills.org/newsletters/view/1483. Accessed March 26, 2024.

[2] U.S. Centers for Disease Control and Prevention. COVID Data Tracker. https://covid.cdc.gov/covid-data-tracker/#datatracker-home. Accessed March 7, 2024.

[3] Cohen P, Gebo K. COVID-19: Management of adults with acute illness in the outpatient setting. UpToDate. January 29, 2024.

[4] Pfizer. Label: nirmatrelvir and ritonavir (PAXLOVID). May 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217188s000lbl.pdf. Accessed March 6, 2024.

[5] Food and Drug Administration. FDA revises letter of authorization for the emergency use authorization for Paxlovid. January 29, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-letter-authorization-emergency-use-authorization-paxlovid. Accessed March 6, 2024.

[6] Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with covid-19. N Engl J Med. 2022;386(15):1397-1408.

[7] Pfizer. Label: nirmatrelvir and ritonavir (PAXLOVID). May 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217188s000lbl.pdf. Accessed March 6, 2024.

[8] Reis S, Metzendorf MI, Kuehn R, et al. Nirmatrelvir combined with ritonavir for preventing and treating COVID-19. Cochrane Database Syst Rev. 2023;11(11):CD015395.

[9] Zhu CT, Yin JY, Chen XH, et al. Appraisal of evidence reliability and applicability of Paxlovid as treatment for SARS-COV-2 infection: a systematic review. Rev Med Virol. 2023;33(6):e2476.

[10] Dormuth CR, Kim JD, Fisher A, et al. Nirmatrelvir-ritonavir and COVID-19 mortality and hospitalization among patients with vulnerability to COVID-19 complications. JAMA Netw Open. 2023;6(10):e2336678.

[11] Important drug interactions for the combination antiviral COVID-19 drug PAXLOVID. Worst Pills, Best Pills News. August 2022. https://www.worstpills.org/newsletters/view/1483. Accessed March 26, 2024.

[12] Smith DJ, Lambrou A, Patel P. SARS-CoV-2 rebound with and without use of COVID-19 oral antivirals. MMWR Morb Mortal Wkly Rep. 2023;72(51):1357-1364.

[13] Centers for Disease Control and Prevention. Stay up to date with COVID-19 vaccines. March 7, 2024. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html. Accessed March 18, 2024.