Association of nirmatrelvir/ritonavir treatment on upper respiratory SARS-CoV-2 RT-PCR negative conversion rates among high-risk patients with COVID-19
et al., Clinical Infectious Diseases, doi:10.1093/cid/ciac600, Jul 2022
Retrospective 258 paxlovid patients and 224 patients before paxlovid was available in China, showing significantly faster viral clearance with treatment. Adjusted results are only provided for subgroups (≤5, >5 days from onset). Patients that discontinued treatment due to side effects were excluded. The treatment and control groups were separated in time. Control patients were hospitalized later, median 3 days [2-5] vs. 2 [1-3] for paxlovid patients.
Authors report some rebound events, but may not have monitored all patients for rebound. Authors report testing daily until negative conversion and it is unclear how many or when patients were tested after conversion.
Resistance. Variants may be resistant to paxlovid1-8. Use may promote the emergence of variants that weaken host immunity and potentially contribute to long COVID9. Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid10. 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 paxlovid11. Kidney and liver injury. Studies show significantly increased risk of acute kidney injury12 and liver injury13.
Standard of Care (SOC) for COVID-19 in the study country,
China, is average with moderate efficacy for approved treatments14.
|
risk of no viral clearance, 79.4% lower, HR 0.21, p < 0.001, treatment 18 of 175 (10.3%), control 130 of 224 (58.0%), NNT 2.1, adjusted per study, inverted to make HR<1 favor treatment, model 2, multivariable, day 15.
|
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time to viral-, 41.2% lower, relative time 0.59, p < 0.001, treatment median 10.0 IQR 5.0 n=175, control median 17.0 IQR 9.0 n=224, ≤5 days, primary outcome.
|
|
risk of no viral clearance, 32.0% lower, HR 0.68, p = 0.04, treatment 40 of 83 (48.2%), control 130 of 224 (58.0%), adjusted per study, inverted to make HR<1 favor treatment, >5 days, model 2, multivariable, day 15, late treatment result.
|
| 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.
2.
Moghadasi et al., Rapid resistance profiling of SARS-CoV-2 protease inhibitors, npj Antimicrobials and Resistance, doi:10.1038/s44259-023-00009-0.
3.
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.
4.
Lopez et al., SARS-CoV-2 Resistance to Small Molecule Inhibitors, Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6.
5.
Zvornicanin et al., Molecular Mechanisms of Drug Resistance and Compensation in SARS-CoV-2 Main Protease: The Interplay Between E166 and L50, bioRxiv, doi:10.1101/2025.01.24.634813.
6.
Vukovikj et al., Impact of SARS-CoV-2 variant mutations on susceptibility to monoclonal antibodies and antiviral drugs: a non-systematic review, April 2022 to October 2024, Eurosurveillance, doi:10.2807/1560-7917.ES.2025.30.10.2400252.
7.
Deschenes et al., Functional and structural characterization of treatment-emergent nirmatrelvir resistance mutations at low frequencies in the main protease (Mpro) reveals a unique evolutionary route for SARS-CoV-2 to gain resistance, The Journal of Infectious Diseases, doi:10.1093/infdis/jiaf294.
8.
Zhou (B) et al., SARS-CoV-2 Mpro inhibitor ensitrelvir: asymmetrical cross-resistance with nirmatrelvir and emerging resistance hotspots, Emerging Microbes & Infections, doi:10.1080/22221751.2025.2552716.
9.
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.
10.
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.
11.
FDA, Fact sheet for healthcare providers: emergency use authorization for paxlovid, www.fda.gov/media/155050/download.
12.
Kamo et al., Association of Antiviral Drugs for the Treatment of COVID-19 With Acute Renal Failure, In Vivo, doi:10.21873/invivo.13637.
Li et al., 23 Jul 2022, retrospective, China, peer-reviewed, 20 authors, study period 5 March, 2022 - 5 April, 2022, average treatment delay 2.0 days.
Contact: zhengyang@jlu.edu.cn.
Association of nirmatrelvir/ritonavir treatment on upper respiratory SARS-CoV-2 RT-PCR negative conversion rates among high-risk patients with COVID-19
doi:10.1093/cid/ciac600/6649232
Background: Acceleration of negative respiratory conversion of SARS-CoV-2 in patients with coronavirus disease 2019 (COVID-19) might reduce viral transmission. Nirmatrelvir/ritonavir is a new antiviral agent recently approved for treatment of COVID-19 that has the potential to facilitate negative conversion. Methods: A cohort of hospitalized adult patients with mild-to-moderate COVID-19 who had a high-risk for progression to severe disease were studied. These patients presented with COVID-19 symptoms between March 5 and April 5, 2022. The time from positive to negative upper respiratory RT-PCR conversion was assessed by Kaplan-Meier plots and Cox proportional hazards regression with the adjustment for patients baseline demographic and clinical characteristics. Results: There were 258 patients treated with nirmatrelvir/ritonavir and 224 nontreated patients who had mild-to-moderate COVID-19. The median (interquartile range) time for patients who converted from positive to negative RT-PCR was 10 Conclusion: This cohort study of high-risk patients with mild-to-moderate COVID-19 found an association between nirmatrelvir/ritonavir treatment and accelerated negative RT-PCR respiratory SARS-CoV-2 conversion that might reduce the risk of viral shedding and disease transmission.
Conflict of Interest Disclosures: None reported. Funding/Support: None.
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DOI record:
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>Acceleration of negative respiratory conversion of SARS-CoV-2 in patients with coronavirus disease 2019 (COVID-19) might reduce viral transmission. Nirmatrelvir/ritonavir is a new antiviral agent recently approved for treatment of COVID-19 that has the potential to facilitate negative conversion.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>A cohort of hospitalized adult patients with mild-to-moderate COVID-19 who had a high-risk for progression to severe disease were studied. These patients presented with COVID-19 symptoms between March 5 and April 5, 2022. The time from positive to negative upper respiratory RT-PCR conversion was assessed by Kaplan-Meier plots and Cox proportional hazards regression with the adjustment for patients baseline demographic and clinical characteristics.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>There were 258 patients treated with nirmatrelvir/ritonavir and 224 non-treated patients who had mild-to-moderate COVID-19. The median (interquartile range) time for patients who converted from positive to negative RT-PCR was 10 days (7-12 days) in patients treated ≤5 days after symptom onset and 17 days (12-21 days) in non-treated patients, respectively. The proportions of patients with a negative conversion at day 15 were 89.7% and 42.0% in treated patients and non-treated patients, corresponding to a hazard ratio of 4.33 (95% CI, 3.31-5.65). Adjustment for baseline differences between the groups had little effect on the association. Subgroup analysis on treated patients suggests that time to negative conversion did not vary with the patients’ baseline characteristics.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusion</jats:title>\n <jats:p>This cohort study of high-risk patients with mild-to-moderate COVID-19 found an association between nirmatrelvir/ritonavir treatment and accelerated negative RT-PCR respiratory SARS-CoV-2 conversion that might reduce the risk of viral shedding and disease transmission.</jats:p>\n </jats:sec>",
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