Clinical Effectiveness of Ritonavir-Boosted Nirmatrelvir—A Literature Review
Abstract
:Highlights
- Nirmatrelvir/Ritonavir, an oral treatment for COVID-19, effectively reduces the risk of progressing to a more severe disease state for both the Delta and subsequent Omicron variants.
- Unvaccinated COVID-19 patients benefit more from a Nirmatrelvir/Ritonavir prescription than vaccinated ones.
- Although effective at reducing the risk of progressing to a more severe disease state, Nirmatrelvir/Ritonavir cannot replace vaccinations.
- Future subanalyses should focus on pinpointing the role of age, strain, or comorbidities in effectiveness differences.
Abstract
1. Introduction
- -
- Remdesivir (Veklury) [10] is the first available treatment for COVID-19. Countries that authorized the administration of Remdesivir include Singapore, the EU, the USA, the UK, and Australia. Treatment must be administered within seven days of symptom appearance, intravenously, and the treatment duration varies by the patient’s state.
- -
- Molnupiravir (Lagevrio) [11] is taken orally at home. Molnupiravir was authorized, for example, in the UK in November 2021 and by the FDA (USA) in December 2021. It must be administered within five days of symptom appearance and taken every 12 h over five days.
- -
2. Methods
3. Review
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Mathieu, E.; Ritchie, H.; Rodés-Guirao, L.; Appel, C.; Giattino, C.; Hasell, J.; Macdonald, B.; Dattani, S.; Beltekian, D.; Ortiz-Ospina, E.; et al. Coronavirus Pandemic (COVID-19). 2020. Available online: https://ourworldindata.org/coronavirus (accessed on 18 April 2023).
- Le, K.; Nguyen, M. The psychological burden of the COVID-19 pandemic severity. Econ. Hum. Biol. 2021, 41, 100979. [Google Scholar] [CrossRef] [PubMed]
- Ravens-Sieberer, U.; Kaman, A.; Erhart, M.; Devine, J.; Schlack, R.; Otto, C. Impact of the COVID-19 pandemic on quality of life and mental health in children and adolescents in Germany. Eur. Child. Adolesc. Psychiatry 2022, 31, 879–889. [Google Scholar] [CrossRef]
- Skoda, E.-M.; Teufel, M.; Stang, A.; Jöckel, K.H.; Junne, F.; Weismüller, B.; Hetkamp, M.; Musche, V.; Kohler, H.; Dörrie, N.; et al. Psychological burden of healthcare professionals in Germany during the acute phase of the COVID-19 pandemic: Differences and similarities in the international context. J. Public Health 2020, 42, 688–695. [Google Scholar] [CrossRef] [PubMed]
- Holst, H.; Fessler, A.; Niehoff, S. COVID-19, social class and work experience in Germany: Inequalities in work-related health and economic risks. Eur. Soc. 2021, 23, S495–S512. [Google Scholar] [CrossRef]
- European Commission. Safe COVID-19 Vaccines for Europeans. European Commission; European Union: Maastricht, The Netherlands, 2023; Available online: https://commission.europa.eu/strategy-and-policy/coronavirus-response/safe-covid-19-vaccines-europeans_en (accessed on 19 December 2023).
- NHS. Vaccine, Coronavirus (COVID-19). nhs.uk. 2022. Available online: https://www.nhs.uk/conditions/coronavirus-covid-19/coronavirus-vaccination/coronavirus-vaccine/ (accessed on 18 April 2023).
- CDC. Overview of COVID-19 Vaccines. Cdc.gov. 2022. Available online: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/overview-COVID-19-vaccines.html (accessed on 18 April 2023).
- Watson, O.J.; Barnsley, G.; Toor, J.; Hogan, A.B.; Winskill, P.; Ghani, A.C. Global impact of the first year of COVID-19 vaccination: A mathematical modelling study. Lancet Infect. Dis. 2022, 22, 1293–1302. [Google Scholar] [CrossRef] [PubMed]
- Rezagholizadeh, A.; Khiali, S.; Sarbakhsh, P.; Entezari-Maleki, T. Remdesivir for treatment of COVID-19; an updated systematic review and meta-analysis. Eur. J. Pharmacol. 2021, 897, 173926. [Google Scholar] [CrossRef] [PubMed]
- Wen, W.; Chen, C.; Tang, J.; Wang, C.; Zhou, M.; Cheng, Y.; Zhou, X.; Wu, Q.; Zhang, X.; Feng, Z.; et al. Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: A meta-analysis. Ann. Med. 2022, 54, 516–523. [Google Scholar] [CrossRef]
- Gupta, A.; Gonzalez-Rojas, Y.; Juarez, E.; Crespo Casal, M.; Moya, J.; Falci, D.R.; Sarkis, E.; Solis, J.; Zheng, H.; Scott, N.; et al. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N. Engl. J. Med. 2021, 385, 1941–1950. [Google Scholar] [CrossRef]
- Amani, B.; Amani, B. Efficacy and safety of sotrovimab in patients with COVID-19: A rapid review and meta-analysis. Rev. Med. Virol. 2022, 32, e2402. [Google Scholar] [CrossRef]
- Extance, A. COVID-19: What is the evidence for the antiviral Paxlovid? BMJ 2022, 377, o1037. [Google Scholar] [CrossRef]
- FDA. Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19. Fda.gov. 2021. Available online: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19 (accessed on 18 April 2023).
- Pfizer Inc. Fact Sheet for Healthcare Providers: Emergency Use Authorization for PaxlovidTM. Pfizer.com. 2021. Available online: https://labeling.pfizer.com/ShowLabeling.aspx?id=16474 (accessed on 18 April 2023).
- Gentile, I.; Scotto, R.; Schiano Moriello, N.; Pinchera, B.; Villari, R.; Trucillo, E.; Ametrano, L.; Fusco, L.; Castaldo, G.; Buonomo, A.R.; et al. Nirmatrelvir/Ritonavir and Molnupiravir in the Treatment of Mild/Moderate COVID-19: Results of a Real-Life Study. Vaccines 2022, 10, 1731. [Google Scholar] [CrossRef]
- Hammond, J.; Leister-Tebbe, H.; Gardner, A.; Abreu, P.; Bao, W.; Wisemandle, W.; Baniecki, M.; Hendrick, V.M.; Damle, B.; Simón-Campos, A.; et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N. Engl. J. Med. 2022, 386, 1397–1408. [Google Scholar] [CrossRef] [PubMed]
- Faust, J.S.; Kumar, A.; Shah, J.; Khadke, S.; Dani, S.S.; Ganatra, S.; Sax, P.E. Oral Nirmatrelvir and Ritonavir for Covid-19 in Vaccinated, Non-Hospitalized Adults, Ages 18-50 Years. Clin. Infect. Dis. 2023, 77, 1257–1264. [Google Scholar] [CrossRef]
- Hansen, K.; Makkar, S.R.; Sahner, D.; Fessel, J.; Hotaling, N.; Sidky, H. Paxlovid (nirmatrelvir/ritonavir) effectiveness against hospitalization and death in N3C: A target trial emulation study. medRxiv 2023. [Google Scholar] [CrossRef]
- Ganatra, S.; Dani, S.S.; Ahmad, J.; Kumar, A.; Shah, J.; Abraham, G.M.; McQuillen, D.P.; Wachter, R.M.; Sax, P.E. Oral Nirmatrelvir and Ritonavir in Non-hospitalized Vaccinated Patients with COVID-19. Clin. Infect. Dis. 2022, 76, 563–572. [Google Scholar] [CrossRef]
- Bhatia, A.; Preiss, A.J.; Xiao, X.; Brannock, M.D.; Alexander, G.C.; Chew, R.F.; Fitzgerald, M.; Hill, E.; Kelly, E.P.; Mehta, H.B.; et al. Effect of Nirmatrelvir/Ritonavir (Paxlovid) on Hospitalization among Adults with COVID-19: An EHR-based Target Trial Emulation from N3C. medRxiv 2023. preprint. [Google Scholar] [CrossRef]
- Arbel, R.; Wolff Sagy, Y.; Hoshen, M.; Battat, E.; Lavie, G.; Sergienko, R.; Friger, M.; Waxman, J.G.; Dagan, N.; Balicer, R.; et al. Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge. N. Engl. J. Med. 2022, 387, 790–798. [Google Scholar] [CrossRef] [PubMed]
- Cegolon, L.; Pol, R.; Simonetti, O.; Larese Filon, F.; Luzzati, R. Molnupiravir, Nirmatrelvir/Ritonavir, or Sotrovimab for High-Risk COVID-19 Patients Infected by the Omicron Variant: Hospitalization, Mortality, and Time until Negative Swab Test in Real Life. Pharmaceuticals 2023, 16, 721. [Google Scholar] [CrossRef] [PubMed]
- Dryden-Peterson, S.; Kim, A.; Kim, A.Y.; Caniglia, E.C.; Lennes, I.T.; Patel, R.; Gainer, L.; Dutton, L.; Donahue, E.; Gandhi, R.T.; et al. Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System: A Population-Based Cohort Study. Ann. Intern. Med. 2023, 176, 77–84. [Google Scholar] [CrossRef] [PubMed]
- Shah, M.M.; Joyce, B.; Plumb, I.D.; Sahakian, S.; Feldstein, L.R.; Barkley, E.; Paccione, M.; Deckert, J.; Sandmann, D.; Gerhart, J.L.; et al. Paxlovid associated with decreased hospitalization rate among adults with COVID-19—United States, April-September 2022. Am. J. Transplant. 2023, 23, 150–155. [Google Scholar] [CrossRef] [PubMed]
- Najjar-Debbiny, R.; Gronich, N.; Weber, G.; Khoury, J.; Amar, M.; Stein, N.; Goldstein, L.H.; Saliba, W. Effectiveness of Paxlovid in Reducing Severe COVID-19 and Mortality in High Risk Patients. Clin. Infect. Dis. 2022, 11, 1174879. [Google Scholar] [CrossRef]
- Cai, H.; Yan, J.; Liu, S.; Li, P.; Ding, L.; Zhan, Y.; Lu, J.; Li, Z.; Sun, Y.; Zhu, M.; et al. Paxlovid for hospitalized COVID-19 patients with chronic kidney disease. Antivir. Res. 2023, 216, 105659. [Google Scholar] [CrossRef]
- Wong, C.K.H.; Au, I.C.H.; Lau, K.T.K.; Lau, E.H.Y.; Cowling, B.J.; Leung, G.M. Real-world effectiveness of early molnupiravir or nirmatrelvir-ritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong’s omicron BA.2 wave: A retrospective cohort study. Lancet Infect. Dis. 2022, 22, 1681–1693. [Google Scholar] [CrossRef]
- Alsaeed, A.; Alkhalaf, A.; Alomran, A.; Alsfyani, W.; Alhaddad, F.; Alhaddad, M.J. Paxlovid for Treating COVID-19 Patients: A Case-Control Study from Two Hospitals in the Eastern Province of Saudi Arabia. Cureus 2023, 15, e39234. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Pan, X.; Zhang, S.; Li, M.; Ma, K.; Fan, C.; Lv, Y.; Guan, X.; Yang, Y.; Ye, X.; et al. Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: A multicenter randomized controlled study. Lancet Reg. Health West. Pac. 2023, 33, 100694. [Google Scholar] [CrossRef]
- Kim, J.M.; Yoo, M.-G.; Bae, S.J.; Kim, J.; Lee, H. Effectiveness of Paxlovid, an Oral Antiviral Drug, Against the Omicron BA.5 Variant in Korea: Severe Progression and Death Between July and November 2022. J. Korean Med. Sci. 2023, 38, e211. [Google Scholar] [CrossRef]
- Park, H.; Park, Y.J.; Lee, H.Y.; Yu, M.; Song, Y.-J.; Lee, S.E.; Lee, J.-J.; Lee, E.-S.; Kim, Y. The effectiveness of Paxlovid treatment in long-term care facilities in South Korea during the outbreak of the Omicron variant of SARS-CoV-2. Osong Public Health Res. Perspect. 2022, 13, 443–447. [Google Scholar] [CrossRef] [PubMed]
- Shao, J.; Fan, R.; Guo, C.; Huang, X.; Guo, R.; Zhang, F.; Hu, J.; Huang, G.; Cao, L. Composite Interventions on Outcomes of Severely and Critically Ill Patients with COVID-19 in Shanghai, China. Microorganisms 2023, 7, 1859. [Google Scholar] [CrossRef] [PubMed]
- Xie, Y.; Choi, T.; Al-Aly, Z. Association of Treatment with Nirmatrelvir and the Risk of Post-COVID-19 Condition. JAMA Intern. Med. 2023, 183, 554–564. [Google Scholar] [CrossRef]
- Fishbane, S.; Hirsch, J.S.; Nair, V. Special Considerations for Paxlovid Treatment Among Transplant Recipients with SARS-CoV-2 Infection. Am. J. Kidney Dis. 2022, 79, 480–482. [Google Scholar] [CrossRef]
- Marzolini, C.; Kuritzkes, D.R.; Marra, F.; Boyle, A.; Gibbons, S.; Flexner, C.; Pozniak, A.; Boffito, M.; Waters, L.; Burger, D.; et al. Recommendations for the Management of Drug-Drug Interactions Between the COVID-19 Antiviral Nirmatrelvir/Ritonavir (Paxlovid) and Comedications. Clin. Pharmacol. Ther. 2022, 112, 1191–1200. [Google Scholar] [CrossRef] [PubMed]
- Prikis, M.; Cameron, A. Paxlovid (Nirmatelvir/Ritonavir) and Tacrolimus Drug-Drug Interaction in a Kidney Transplant Patient with SARS-2-CoV infection: A Case Report. Transplant. Proc. 2022, 54, 1557–1560. [Google Scholar] [CrossRef]
- Wang, L.; Berger, N.A.; Davis, P.B.; Kaelber, D.C.; Volkow, N.D.; Xu, R. COVID-19 rebound after Paxlovid and Molnupiravir during January-June 2022. medRxiv 2022. preprint. [Google Scholar] [CrossRef]
- Rubin, R. From Positive to Negative to Positive Again-The Mystery of Why COVID-19 Rebounds in Some Patients Who Take Paxlovid. JAMA 2022, 327, 2380–2382. [Google Scholar] [CrossRef]
- Epling, B.P.; Rocco, J.M.; Boswell, K.L.; Laidlaw, E.; Galindo, F.; Kellogg, A.; Das, S.; Roder, A.; Ghedin, E.; Kreitman, A.; et al. Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment. Clin. Infect. Dis. 2023, 76, 573–581. [Google Scholar] [CrossRef] [PubMed]
- Mazzitelli, M.; Mengato, D.; Sasset, L.; Ferrari, A.; Gardin, S.; Scaglione, V.; Bonadiman, N.; Calandrino, L.; Cavinato, S.; Trivellato, S.; et al. Molnupiravir and Nirmatrelvir/Ritonavir: Tolerability, Safety, and Adherence in a Retrospective Cohort Study. Viruses 2023, 15, 384. [Google Scholar] [CrossRef] [PubMed]
- Erman, M. Pfizer to Price COVID Treatment Paxlovid at $1390 Per Course; Reuters: London, UK, 2023. [Google Scholar]
- Iacobucci, G. COVID-19: “Grotesque inequity” that only a quarter of paxlovid courses go to poorer countries. BMJ 2022, 379, o2795. [Google Scholar] [CrossRef]
Publication | Studied Outcome | Treated Group (Events) | Untreated/Placebo Group (Events) | Relative Risk/Hazard Ratio |
---|---|---|---|---|
[18] | Hospitalization or death | 1039 (8) | 1046 (66) | RR 0.101 |
[19] | All-cause ED visit | 2547 (114) | 2547 (138) | OR 0.818 |
Hospitalization | 2547 (15) | 2547 (43) | OR 0.345 | |
Thirty-day mortality | 2547 (0) | 2547 (10) | - | |
Composite of the above | 2547 (125) | 2547 (179) | OR 0.683 | |
[20] | Hospitalization | 98,060 (652) | 914,850 (8285) | RR 0.742 |
Death | 98,060 (35) | 914,850 (1480) | RR 0.269 | |
[21] | Emergency room visit | 1130 (82) | 1130 (142) | RR 0.59 |
Hospitalization | 1130 (10) | 1130 (23) | RR 0.40 | |
Death | 1130 (0) | 1130 (10) | RR 0.00 | |
Composite of the above | 1130 (89) | 1130 (144) | RR 0.55 | |
[22] | Hospitalization | 104,510 (628) | 306,132 (5549) | aOR 0.35 |
[23] | Hospitalization (65+) | 2484 (11) | 40,337 (766) | aHR 0.27 |
Hospitalization (65+, no previous immunity) | NA | NA | aHR 0.15 | |
Hospitalization (65+, previous immunity) | NA | NA | aHR 0.32 | |
Death (65+) | 2484 (2) | 40,337 (158) | aHR 0.21 | |
Hospitalization (40–64) | 1418 (7) | 65,015 (327) | aHR 0.74 | |
Hospitalization (40–64, no previous immunity) | NA | NA | aHR 0.23 | |
Hospitalization (40–64, previous immunity) | NA | NA | aHR 1.13 | |
Death (40–64) | 1418 (1) | 65,015 (16) | aHR 1.32 | |
[24] | Hospitalization | 99 (2) | 103 (8) | aOR 0.16 |
[25] | Hospitalization or death | 12,541 (69) | 32,010 (310) | aRR 0.56 |
Hospitalization or death (not fully vaccinated) | 682 (NA) | 3633 (NA) | aRR 0.19 | |
Hospitalization or death (vaccinated) | 11,859 (NA) | 28,377 (NA) | aRR 0.69 | |
Hospitalization | 12,541 (NA) | 32,010 (NA) | aRR 0.60 | |
Death | 12,541 (NA) | 32,010 (NA) | aRR 0.29 | |
[26] | Hospitalization | 198,927 | 500,921 | HR 0.49 |
Hospitalization (three doses mRNA vaccine) | NA | NA | HR 0.50 | |
Hospitalization (unvaccinated) | NA | NA | HR 0.50 | |
[27] | Hospitalization or death | 4737 (39) | 175,614 (903) | HR 0.54 |
[28] | All-cause death | 195 (11) | 258 (28) | HR 0.4 |
Twenty-eight-day mortality | 195 (9) | 258 (26) | OR 0.43 | |
Invasive ventilation | 195 (12) | 258 (17) | OR 0.93 | |
Non-invasive ventilation | 195 (7) | 258 (20) | OR 0.44 | |
ICU admission | 195 (17) | 258 (42) | OR 0.49 | |
[29] | Death | 890 (32) | 890 (92) | HR 0.34 |
Invasive mechanical ventilation | 890 (6) | 890 (6) | HR 0.97 | |
ICU admission | 890 (0) | 890 (1) | HR NA | |
Needing oxygen therapy | 890 (79) | 890 (102) | HR 0.73 | |
Composite of the above | 890 (101) | 890 (173) | HR 0.57 | |
[30] | ICU admission | 28 (0) | 64 (12) | Not provided |
Death | 28 (1) | 64 (17) | Not provided | |
[31] | Death | 132 (5) | 132 (8) | Not provided |
[32] | Severe/critical illness or death | 420,996 (1362) | 1,515,959 (5229) | OR 0.568 |
Severe/criticalillness or Death (60+) | 377,531 (NA) | 1,117,811 (NA) | OR 0.540 | |
Severe/critical illness or death (70+) | 203,586 (NA) | 481,326 (NA) | OR 0.537 | |
Severe/critical illness or death (80+) | 81,736 (NA) | 157,366 (NA) | OR 0.551 | |
Severe/critical illness or death (unvaccinated) | 17,965 (NA) | 57,829 (NA) | OR 0.392 | |
Severe/critical illness or death (vaccinated) | 403,031 (NA) | 1,458,130 (NA) | OR 0.628 | |
Death | 420,996 (770) | 1,515,959 (2321) | OR 0.689 | |
[33] | Severe illness or death | 623 (23) | 196 (14) | aRR 0.49 |
Death | 623 (22) | 196 (11) | aRR 0.62 | |
[34] | Sixty-day mortality | 280 (NA) | 509 (NA) | aHR 0.71 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Paltra, S.; Conrad, T.O.F. Clinical Effectiveness of Ritonavir-Boosted Nirmatrelvir—A Literature Review. Adv. Respir. Med. 2024, 92, 66-76. https://doi.org/10.3390/arm92010009
Paltra S, Conrad TOF. Clinical Effectiveness of Ritonavir-Boosted Nirmatrelvir—A Literature Review. Advances in Respiratory Medicine. 2024; 92(1):66-76. https://doi.org/10.3390/arm92010009
Chicago/Turabian StylePaltra, Sydney, and Tim O. F. Conrad. 2024. "Clinical Effectiveness of Ritonavir-Boosted Nirmatrelvir—A Literature Review" Advances in Respiratory Medicine 92, no. 1: 66-76. https://doi.org/10.3390/arm92010009