Nirmatrelvir/ritonavir for patients with SARS-CoV-2 infection and impaired kidney function during the Omicron surge

Yan et al., Frontiers in Pharmacology, doi:10.3389/fphar.2023.1147980

Mar 2023

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Retrospective 195 patients with impaired kidney function in China, showing lower combined mortality/ICU/cardiovascular events, and improved viral clearance with paxlovid.

Resistance. Variants may be resistant to paxlovid1-3. Use may promote the emergence of variants that weaken host immunity and potentially contribute to long COVID4.

Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid5. Retrospective studies that do not exclude contraindicated patients may significantly overestimate efficacy.

Black box warning. The FDA notes that "severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with paxlovid"6.

AKI. Kamo et al. show significantly increased risk of acute kidney injury.

Important missing comments or errors? Let us know.

risk of death, 31.2% lower, RR 0.69, p = 0.50, treatment 7 of 73 (9.6%), control 17 of 122 (13.9%), NNT 23.

mortality/ICU/cardiovascular events, 44.0% lower, HR 0.56, p = 0.04, treatment 73, control 122, adjusted per study, multivariable, model 2, primary outcome.

risk of ICU admission, 13.9% lower, RR 0.86, p = 0.61, treatment 17 of 73 (23.3%), control 33 of 122 (27.0%), NNT 27.

hospitalization time, 8.6% lower, relative time 0.91, p = 0.03, treatment 73, control 122.

time to viral-, 61.5% lower, relative time 0.38, p = 0.001, treatment 73, control 122.

risk of no viral clearance, 73.0% lower, HR 0.27, p < 0.001, treatment 73, control 122, adjusted per study, inverted to make HR<1 favor treatment, viral shedding, multivariable, model 2.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. Zhou et al., Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system, Science Advances, doi:10.1126/sciadv.add7197.science.org, doi.org.

2. Jochmans et al., The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir, mBio, doi:10.1128/mbio.02815-22.asm.org, doi.org.

3. Lopez et al., SARS-CoV-2 Resistance to Small Molecule Inhibitors, Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6.springer.com, doi.org.

4. Thomas et al., Nirmatrelvir-Resistant Mutations in SARS-CoV-2 Mpro Enhance Host Immune Evasion via Cleavage of NF-κB Essential Modulator, bioRxiv, doi:10.1101/2024.10.18.619137.biorxiv.org, doi.org.

5. Hoertel et al., Prevalence of Contraindications to Nirmatrelvir-Ritonavir Among Hospitalized Patients With COVID-19 at Risk for Progression to Severe Disease, JAMA Network Open, doi:10.1001/jamanetworkopen.2022.42140.jamanetwork.com, doi.org.

6. FDA, Fact sheet for healthcare providers: emergency use authorization for paxlovid, www.fda.gov/media/155050/download.fda.gov.

7. Kamo et al., Association of Antiviral Drugs for the Treatment of COVID-19 With Acute Renal Failure, In Vivo, doi:10.21873/invivo.13637.iiarjournals.org, doi.org.

Yan et al., 22 Mar 2023, retrospective, placebo-controlled, China, peer-reviewed, median age 74.0, 10 authors, study period 1 April, 2022 - 30 June, 2022. Contact: shan_mou@shsmu.edu.cn, guleyi@aliyun.com, monsoon585@foxmail.com.

This Paper Paxlovid All

Nirmatrelvir/ritonavir for patients with SARS-CoV-2 infection and impaired kidney function during the Omicron surge

Jiayi Yan, Hong Cai, Jieying Wang, Mingli Zhu, Ping Li, Peiying Li, Bin Wu, Xiajing Che, Leyi Gu, Shan Mou

Frontiers in Pharmacology, doi:10.3389/fphar.2023.1147980

Background: Nirmatrelvir/ritonavir has demonstrated effectiveness in high-risk patients with coronavirus disease 2019 . However, investigations on the efficacy and safety of nirmatrelvir/ritonavir in patients with kidney dysfunction are limited. Methods: Data were collected from the patients admitted to a COVID-19 referral center in Shanghai, China. Patients were at least 18 years of age and had a baseline estimated glomerular filtration rate (eGFR) of <60 ml/min/1•73 m 2 . The primary endpoint was a composite of all-cause mortality, intensive care unit admission, or cardiovascular events. The secondary endpoint was viral shedding. Results: Among the 195 participants, 73 received nirmatrelvir/ritonavir. A lower risk of the primary endpoint was observed in nirmatrelvir/ritonavir recipients compared with non-recipients [adjusted HR 0.56 (95% CI: 0.32-0.96); p = 0.035]. Nirmatrelvir/ritonavir recipients experienced a shorter duration of viral shedding ; p < 0.001) and faster viral load clearance versus non-recipients. Among the nirmatrelvir/ritonavir users, earlier initiation of nirmatrelvir/ritonavir within 5 days since COVID-19 diagnosis was related with shorter viral shedding time ; p < 0.001) compared to late initiation. No patients reported serious adverse events during treatment. Conclusion: Our findings support the early initiation of nirmatrelvir/ritonavir for high-risk patients with impaired kidney function. This could improve patient outcomes and shorten the viral shedding period.

Ethics statement The studies involving human participants were reviewed and approved by Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. The ethics committee waived the requirement of written informed consent for participation. Author contributions JY, SM, and LG designed the study. JY, HC, and JW analyzed the data and revised the manuscript. JY and SM drafted and edited the final manuscript. All authors took part in collecting and verifying the Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Supplementary material The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2023.1147980/ full#supplementary-material

References

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Dejnirattisai, Huo, Zhou, Zahradnik, Supasa et al., None

Gnanenthiran, Borghi, Burger, Caramelli, Charchar et al., Renin-angiotensin system inhibitors in patients with COVID-19: A metaanalysis of randomized controlled trials led by the international society of hypertension, J. Am. Heart Assoc, doi:10.1161/JAHA.122.026143

Graham, Daily briefing: Omicron coronavirus variant puts scientists on alert, Nature, doi:10.1038/d41586-021-03564-6

Hammond, Leister-Tebbe, Gardner, Abreu, Bao et al., Risk factors for intensive care unit admission and in-hospital mortality among hospitalized adults identified through the US coronavirus disease 2019 (COVID-19)-Associated hospitalization surveillance network (COVID-NET), Nat. Rev. Microbiol, doi:10.1093/cid/ciaa1012

Levey, Stevens, Schmid, Zhang, Castro et al., None

Lingscheid, Kinzig, Kruger, Muller, Bolke et al., Pharmacokinetics of nirmatrelvir and ritonavir in COVID-19 patients with endstage renal disease on intermittent hemodialysis, Antimicrob. Agents Chemother

Lu, Zhang, Zhang, Ai, He et al., Geriatric risk and protective factors for serious COVID-19 outcomes among older adults in Shanghai Omicron wave, Emerg. Microbes Infect, doi:10.1080/22221751.2022.2109517

Mahase, Nahhas, Webster, Owen, The promising use of nanomolecular imprinted templates for improved SARS-CoV-2 detection, drug delivery and research, doi:10.1126/science.abl4784

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Toussi, Neutel, Navarro, Preston, Shi et al., Pharmacokinetics of oral nirmatrelvir/ritonavir, a protease inhibitor for treatment of COVID-19, in subjects with renal impairment, Clin. Pharmacol. Ther, doi:10.1002/cpt.2688

Wang, Peng, Ye, Li, Li et al., Renin-angiotensin system inhibitor is associated with the reduced risk of all-cause mortality in COVID-19 among patients with/without hypertension, Front. Med, doi:10.1007/s11684-021-0850-9

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Zhang, Zhou ; Flythe, Assimon, Tugman, Chang et al., Characteristics and outcomes of individuals with pre-existing kidney disease and COVID-19 admitted to intensive care units in the United States, doi:10.1002/jmv.27491

Zhu, Xiao, Meng, Tang, Li et al., Nanovesicles derived from bispecific CAR-T cells targeting the spike protein of SARS-CoV-2 for treating COVID-19, J. Nanobiotechnology, doi:10.1186/s12951-021-01148-0

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