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      Incidence of Viral Rebound After Treatment With Nirmatrelvir-Ritonavir and Molnupiravir

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          Key Points

          Question

          What is the incidence of viral rebound after treatment with nirmatrelvir-ritonavir and molnupiravir?

          Findings

          In this cohort study of 12 629 adults in Hong Kong with COVID-19 who were hospitalized and had serial cycle threshold values measured, viral rebound (defined as a cycle threshold value >40 that decreased to ≤40) occurred in 68 antiviral nonusers (0.6%), 2 (1.0%) nirmatrelvir-ritonavir users, and 6 (0.8%) molnupiravir users.

          Meaning

          In this study, viral rebound was uncommon in adults with COVID-19 after treatment with nirmatrelvir-ritonavir and molnupiravir, suggesting that these novel oral antivirals should be prescribed to more patients with COVID-19 in the early phase of the infection.

          Abstract

          Importance

          Some patients treated with nirmatrelvir-ritonavir have experienced rebound of COVID-19 infections and symptoms; however, data are scarce on whether viral rebound also occurs in patients with COVID-19 receiving or not receiving molnupiravir.

          Objective

          To examine the incidence of viral rebound in patients with COVID-19 who were treated with the oral antiviral agents nirmatrelvir-ritonavir and molnupiravir.

          Design, Setting, and Participants

          This cohort study identified 41 255 patients with COVID-19 who were hospitalized from January 1, 2022, to March 31, 2022, in Hong Kong and assessed 12 629 patients with serial cycle threshold (Ct) values measured. Patients were followed up until the occurrence of the clinical end point of interest, death, date of data retrieval (July 31, 2022), or up to 30 days of follow-up, whichever came first.

          Exposures

          Molnupiravir or nirmatrelvir-ritonavir treatment.

          Main Outcomes and Measures

          Viral rebound, defined as a Ct value greater than 40 that decreased to 40 or less.

          Results

          Of 12 629 patients (mean [SD] age, 65.4 [20.9] years; 6624 [52.5%] male), 11 688 (92.5%) were oral antiviral nonusers, 746 (5.9%) were molnupiravir users, and 195 (1.5%) were nirmatrelvir-ritonavir users. Compared with nonusers, oral antiviral users were older, had more comorbidities, and had lower complete vaccination rates. The mean (SD) baseline Ct value was slightly higher in nirmatrelvir-ritonavir users (22.2 [6.0]) than nonusers (21.0 [5.4]) and molnupiravir users (20.9 [5.4]) ( P = .04). Viral rebound occurred in 68 nonusers (0.6%), 2 nirmatrelvir-ritonavir users (1.0%), and 6 molnupiravir users (0.8%). Among 76 patients with viral rebound, 12 of 68 nonusers, 1 of 6 molnupiravir users, and neither of the nirmatrelvir-ritonavir users died of COVID-19.

          Conclusions and Relevance

          In this cohort study, viral rebound was uncommon in patients taking molnupiravir or nirmatrelvir-ritonavir and was not associated with increased risk of mortality. Given these findings, novel oral antivirals should be considered as a treatment for more patients with COVID-19 in the early phase of the infection.

          Abstract

          This cohort study of patients with COVID-19 compares the incidence rates of viral rebound in patients with COVID-19 treated with molnupiravir or nirmatrelvir-ritonavir.

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          Most cited references15

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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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              Liver injury is independently associated with adverse clinical outcomes in patients with COVID-19

              Terry Cheuk-Fung Yip, Grace Chung-Yan Lui, Vincent Wai-Sun Wong … (2020)
              Objective Data on serial liver biochemistries of patients infected by different human coronaviruses (HCoVs) are lacking. The impact of liver injury on adverse clinical outcomes in coronavirus disease 2019 (COVID-19) patients remains unclear. Design This was a retrospective cohort study using data from a territory-wide database in Hong Kong. COVID-19, severe acute respiratory syndrome (SARS) and other HCoV patients were identified by diagnosis codes and/or virological results. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation was defined as ALT/AST ≥2 × upper limit of normal (ie, 80 U/L). The primary end point was a composite of intensive care unit (ICU) admission, use of invasive mechanical ventilation and/or death. Results We identified 1040 COVID-19 patients (mean age 38 years, 54% men), 1670 SARS patients (mean age 44 years, 44% men) and 675 other HCoV patients (mean age 20 years, 57% men). ALT/AST elevation occurred in 50.3% SARS patients, 22.5% COVID-19 patients and 36.0% other HCoV patients. For COVID-19 patients, 53 (5.1%) were admitted to ICU, 22 (2.1%) received invasive mechanical ventilation and 4 (0.4%) died. ALT/AST elevation was independently associated with primary end point (adjusted OR (aOR) 7.92, 95% CI 4.14 to 15.14, p<0.001) after adjusted for albumin, diabetes and hypertension. Use of lopinavir–ritonavir ±ribavirin + interferon beta (aOR 1.94, 95% CI 1.20 to 3.13, p=0.006) and corticosteroids (aOR 3.92, 95% CI 2.14 to 7.16, p<0.001) was independently associated with ALT/AST elevation. Conclusion ALT/AST elevation was common and independently associated with adverse clinical outcomes in COVID-19 patients. Use of lopinavir–ritonavir, with or without ribavirin, interferon beta and/or corticosteroids was independently associated with ALT/AST elevation.
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                Author and article information

                Journal
                Journal ID (nlm-ta): JAMA Netw Open
                Journal ID (iso-abbrev): JAMA Netw Open
                Title: JAMA Network Open
                Publisher: American Medical Association
                ISSN (Electronic): 2574-3805
                Publication date (Electronic): 6 December 2022
                Publication date Collection: December 2022
                Publication date PMC-release: 6 December 2022
                Volume: 5
                Issue: 12
                Electronic Location Identifier: e2245086
                Affiliations
                [1 ]Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
                [2 ]Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
                [3 ]Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
                [4 ]Stanley Ho Centre for Emerging Infectious Diseases, Jockey Club School of Public Health & Primary Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
                Author notes
                Article Information
                Accepted for Publication: October 11, 2022.
                Published: December 6, 2022. doi:10.1001/jamanetworkopen.2022.45086
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Wong GLH et al. JAMA Network Open.
                Corresponding Authors: Grace Chung-Yan Lui, MD ( gracelui@ 123456cuhk.edu.hk ), and David Shu-Cheong Hui, MD ( dschui@ 123456cuhk.edu.hk ), Department of Medicine and Therapeutics, 9/F Prince of Wales Hospital, Shatin, Hong Kong 99907.
                Author Contributions: Drs G.L.-H. Wong and Yip had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: G.L.-H. Wong, Yip, Lai, Lui.
                Acquisition, analysis, or interpretation of data: G.L.-H. Wong, Lai.
                Drafting of the manuscript: G.L.-H. Wong, Yip, Lai, Lui.
                Critical revision of the manuscript for important intellectual content: All authors.
                Statistical analysis: G.L.-H. Wong, Yip, Lai.
                Obtained funding: G.L.-H. Wong.
                Administrative, technical, or material support: G.L.-H. Wong, Yip, V.W.-S. Wong, Hui.
                Supervision: V.W.-S. Wong, Hui, Lui.
                Conflict of Interest Disclosures: Dr G.L.-H. Wong reported receiving grants from Gilead Sciences and personal fees from Abbott, AbbVie, Bristol-Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen, and Roche outside the submitted work. Dr Yip reported serving as a speaker and consultant for Gilead Sciences outside the submitted work. Dr V.W.-S. Wong reported receiving personal fees from Abbott, AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, and TARGET PharmaSolutions and grants from Gilead Sciences outside the submitted work. Dr Lui reported receiving grants from Gilead Sciences, MSD, and ViiV outside the submitted work. No other disclosures were reported.
                Funding/Support: This study was funded in part by project COVID1903002 of the Health and Medical Research Fund–Food and Health Bureau Commissioned Research on COVID-19 (Dr G. Wong).
                Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Data Sharing Statement : See Supplement 2.
                Article
                Publisher ID: zoi221276
                DOI: 10.1001/jamanetworkopen.2022.45086
                PMC ID: 9856258
                PubMed ID: 36472873
                SO-VID: 470eccd4-aeab-4f5a-96eb-15f655369f08
                Copyright © Copyright 2022 Wong GLH et al. JAMA Network Open.
                License:

                This is an open access article distributed under the terms of the CC-BY License.

                History
                Date received : 20 September 2022
                Date accepted : 11 October 2022
                Categories
                Subject: Research
                Subject: Original Investigation
                Subject: Online Only
                Subject: Infectious Diseases

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