Coronavirus disease 2019 rebounds following nirmatrelvir/ritonavir treatment

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Abstract

Nirmatrelvir/ritonavir (NMV‐r) is an effective anti‐SARS‐CoV‐2 agent and has been recommended in the treatment of nonhospitalized patients with COVID‐19. In rare occasions, some patients experience virologic and symptomatic rebound after initial resolution, which we call COVID‐19 rebound after NMV‐r. Although COVID rebound can also occur after molnupiravir treatment or even no antiviral treatment, we have more serious concern about the rebound after NMV‐r, which remains the most effective antiviral. Due to a lack of information about its frequency, mechanism, outcomes, and management, we conducted this review to provide comprehensive and updated information to address these questions. Based on the limited evidence, the incidence of COVID‐19 rebound after NMV‐r was less than 2%, and most cases developed 5–15 days after initiating NMV‐r treatment. Almost all reported cases had mild symptoms, and the clinical condition gradually subsided without additional treatment. Overall, the clinical outcome was favorable, and only a small number of patients required emergency department visits or hospitalization. Regarding virologic rebound, culturable SARS‐CoV‐2 with possible transmission was observed, so re‐isolation may be needed.

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Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Jonathan A. C. Sterne, Srinivas Murthy, Janet V. Diaz … (2021)

Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support.

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Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19

Jennifer Hammond, Heidi Leister-Tebbe, Annie Gardner … (2022)

Background Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M pro ) inhibitor with potent pan–human-coronavirus activity in vitro. Methods We conducted a phase 2–3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19–related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. Results A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19–related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], −9.04 to −3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of −5.81 percentage points (95% CI, −7.78 to −3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of −0.868 log 10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. Conclusions Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202 .)

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Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

Angélica Jayk Bernal, Monica M. Gomes da Silva, Dany Musungaie … (2021)

Abstract Background New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. Results A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% confidence interval, −11.3 to −2.4; P=0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% confidence interval, −5.9 to −0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. Conclusions Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.)

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Contributors

Po‐Ren Hsueh:

ORCID: http://orcid.org/0000-0002-7502-9225

hsporen@gmail.com

Journal

Journal ID (nlm-ta): J Med Virol

Journal ID (iso-abbrev): J Med Virol

Journal ID (doi): 10.1002/(ISSN)1096-9071

Journal ID (publisher-id): JMV

Title: Journal of Medical Virology

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0146-6615

ISSN (Electronic): 1096-9071

Publication date (Electronic): 09 January 2023

Publication date (Print): February 2023

Publication date PMC-release: 09 January 2023

Volume: 95

Issue: 2 ( doiID: 10.1002/jmv.v95.2 )

Electronic Location Identifier: e28430

Affiliations

[ ¹ ] Department of Internal Medicine, Division of Hospital Medicine Chi Mei Medical Center Tainan Taiwan

[ ² ] Department of Internal Medicine, Division of Infectious Diseases, School of Medicine, China Medical University Hospital China Medical University Taichung Taiwan

[ ³ ] Department of Laboratory Medicine, School of Medicine, China Medical University Hospital China Medical University Taichung Taiwan

[ ⁴ ] PhD Program for Ageing, School of Medicine China Medical University Taichung Taiwan

Author notes

[*] [* ] Correspondence Po‐Ren Hsueh, Department of Laboratory Medicine and Internal Medicine, Division of Infectious Diseases, School of Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan.

Email: hsporen@ 123456gmail.com

Author information

Chih‐Cheng Lai http://orcid.org/0000-0002-6334-2388

Po‐Ren Hsueh http://orcid.org/0000-0002-7502-9225

Article

Publisher ID: JMV28430

DOI: 10.1002/jmv.28430

PMC ID: 9880661

PubMed ID: 36571273

SO-VID: 17e549d0-bb96-4e24-8b6f-64f72405e29e

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This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

History

Date revision received : 30 November 2022

Date received : 02 November 2022

Date accepted : 12 December 2022

Page count

Figures: 1, Tables: 1, Pages: 7, Words: 4516

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source-schema-version-number 2.0

cover-date February 2023

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.4 mode:remove_FC converted:27.01.2023

ScienceOpen disciplines: Microbiology & Virology

Keywords: covid‐19,mechanisms,nirmatrelvir/ritonavir,rebound,sars‐cov‐2,virological rebound

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ScienceOpen disciplines: Microbiology & Virology

Keywords: covid‐19, mechanisms, nirmatrelvir/ritonavir, rebound, sars‐cov‐2, virological rebound

Coronavirus disease 2019 rebounds following nirmatrelvir/ritonavir treatment

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Most cited references 46

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

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