Paxlovid

Why do some patients with Covid-19 develop a rebound after completing a course of Paxlovid (nirmatrelvir/ritonavir) and how common is it?

FA Manian MD, MPH, , , , , , Leave a comment

Covid-19 rebound, characterized by the recurrence of Covid-19 symptom or a new positive viral test after having tested negative, is a poorly understood phenomenon that can occur after completion of therapy with Paxlovid, Molnupiravir (another antiviral Covid-19 drug) and even in patients with acute Covid-19 who never received any specific antiviral therapy. 1-6

Based on very limited number of studies, it appears that rebound is not caused by emergence of drug resistance or absence of neutralizing immunity, rather resumption of SARS-CoV-2 replication following completion of therapy, triggering a secondary immune-mediated response that’s associated with clinical symptoms.2,3

Recent studies suggest that rebound following Paxlovid treatment may not be as common as one may think.  In a cohort of 483 high-risk patients treated with Paxlovid for Covid-19, 0.8% experienced rebound of symptoms within 30 days of diagnosis, which were generally mild at a median of 9 days after treatment, all resolving without additional antiviral therapy.3  In this study, the median age was 63 years and 93% were fully vaccinated; there were no hospitalization related to rebound or deaths. In another study (pre-print) involving over 11,000 patients treated with Paxlovid, rebound symptoms occurred in 2.3% and 5.9% of patients  7 and 30 days following therapy, respectively, with similar rates reported in patients treated with Molnupiravir.4

Interestingly, a preprint article involving 568 untreated patients with mild-moderate Covid-19 found that 27% had symptom rebound after initial improvement with 12% having viral rebound based on nasal swabs with ≥0.5 log viral RNA copies/ml. 5 So antiviral therapy for Covid-19 is not a prerequisite for rebound symptoms.

Although some have suggested that insufficient drug exposure either due to individual pharmacokinetics or insufficient duration may be the cause of rebound in treated patients,2   there is currently no evidence that additional treatment for Covid-19 is needed in these patients.6

Despite reports of rebound, Paxlovid should still be considered in selected patients with mild-moderate Covid-19 at high risk of complications to minimize the risk of hospitalization and death from Covid-19. 

Bonus Pearl: Did you know that, according to CDC, Covid-19 rebound often occurs between 2-8 days following initial recovery? 1

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References

  1. Covid-19 rebound after paxlovid treatment. May 24, 2022. COVID-19 Rebound After Paxlovid Treatment (cdc.gov)
  2. Carlin AF, Clark AE, Chaillon A, et al. Virologic and immunologic characterization of Coronavirus Disease 2019 recrudescence after nirmatrelvir/ritonavir treatment. Clin Infec Dis 2022 (June 20). Virologic and Immunologic Characterization of Coronavirus Disease 2019 Recrudescence After Nirmatrelvir/Ritonavir Treatment | Clinical Infectious Diseases | Oxford Academic (oup.com)
  3. Ranaganath N, O’Horo JC, Challner DW, et al. Rebound phenomenon after nirmatrelvir/ritonavir treatment of Coronavirus Disease-2019 in high-risk persons. Clin Infect Dis 2022 (June 14). https://doi.org/10.1093/cid/ciac481 Rebound Phenomenon after Nirmatrelvir/Ritonavir Treatment of Coronavirus Disease-2019 in High-Risk Persons | Clinical Infectious Diseases | Oxford Academic (oup.com)
  4. Wang L, Berger NA, David PB, et al. Covid-19 rebound after Paxlovid and Molnupiravir during January-June 2022. MedRxiv 2022. COVID-19 rebound after Paxlovid and Molnupiravir during January-June 2022 | medRxiv
  5. Deo R, Choudhary MC, Moser C, et al. Viral and symptom rebound in untreated Covid-19 infection. Medrxiv 2022. Viral and Symptom Rebound in Untreated COVID-19 Infection (medrxiv.org)
  6. Covid-19 rebound after Paxlovid treatment. May 24, 2022. HAN Archive – 00467 | Health Alert Network (HAN) (cdc.gov)

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

 

Why do some patients with Covid-19 develop a rebound after completing a course of Paxlovid (nirmatrelvir/ritonavir) and how common is it?

Why is Paxlovid (nirmatrelvir/ritonavir) a promising new drug in our fight against Covid-19?

FA Manian MD, MPH, , Leave a comment

Based on the manufacturer’s (Pfizer’s) report, there are several reasons why Paxlovid may be a promising drug:1

  • It’s the first oral drug approved by the FDA for Emergency Use Authorization (EUA)
  • It reduces risk of hospitalization or death by ~ 90% (when taken within 3-5 days of symptom onset) in patients at high risk of complications from Covid-19
  • It reduces viral load at day 5 of treatment by 10-fold compared to placebo, theoretically reducing infectivity at least in household settings 2
  • Serious adverse events were comparable to placebo; possible side effects include liver disease, diarrhea, altered sense of taste, hypertension and muscle aches
  • Nirmatrelvir component of Paxlovid has been found to be active against a variety of SARS-CoV-2 variants of concern such as alpha, beta, delta as well as the newer omicron variant. This finding is in contrast to significantly reduced or loss of neutralizing activity of many commercially-available monoclonal antibody products against the omicron variant (eg, Casirivimab/Imdevimab-REGEN-COV, Bamlanivimab/Etesevimab, but not Sotrovimab)  designed to reduce serious Covid-19 complications in mild to moderate disease. 3-4

Few caveats to keep in mind when prescribing Paxlovid at this time:

  • It’s only approved for adults and children 12 years of age or older weighing at least 88 lbs (40kg) who test positive for SARS-CoV-2
  • Patients should be at high risk for progression to severe Covid-19 such as hospitalization or death
  • Per manufacturer (Pfizer), Paxlovid should not be taken if a patient is on certain medications due to the possibility of adverse drug interactions. The list includes colchicine, lovastatin, simvastatin, sildenafil for pulmonary arterial hypertension, some anti-epileptics (eg, carbamazepine, phenytoin), rifampin and St. John’s Wort.
  • There is no experience with treating pregnant women or breastfeeding mothers.
  • Pfizer recommends effective barrier contraception or refraining from sexual activity while taking Paxlovid

Paxlovid comes in a box of blister packs containing 5 days’ worth of medications (two 150 mg tablets of nirmatrelvir plus one 100 mg tablet of ritonavir to be taken 2x/day).  

Bonus Pearl: Another preliminary study of Paxlovid, this time including unvaccinated adults at low risk of hospitalization or death, has found a 70% reduction in hospitalization and no death compared to placebo with marginal statistical significance (P=0.051) but still with a 10-fold drop in viral load. 1

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References

  1. Pfizer announces additional phase 2/3 study results confirming robust efficacy of novel COVID-19 oral antiviral treatment candidate in reducing risk of hospitalization or death. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-additional-phase-23-study-results . Accessed Dec 23, 2021.
  2. Marc A, kerioui M, Blanquart F, et. al. Quantifying the relationship between SARS-CoV-2 viral load and infectiousness. eLife 2021;10:e69302. https://elifesciences.org/articles/69302#:~:text=Based%20on%20the%20current%20knowledge,24%25%20to%2058%25%20in%20household  
  3. Aggarwal A, Stell AO, Walker G, et al. SARS-CoV-2 Omicron:evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern. MedRxiv 2021. Doi:https://doi.org/10.1101/2021.12.14.21267772. https://www.medrxiv.org/content/10.1101/2021.12.14.21267772v1
  4. Planas D, Saunders N, Maes P, et al. Considerable escape of SARS-CoV-2 variant Omicron to antibody neutralization. MedRxiv 2021. https://www.biorxiv.org/content/10.1101/2021.12.14.472630v1

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why is Paxlovid (nirmatrelvir/ritonavir) a promising new drug in our fight against Covid-19?