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    J Korean Med Sci. 2024 Feb 19;39(6):e52. English.
    Published online Jan 29, 2024.
    https://doi.org/10.3346/jkms.2024.39.e52
    © 2024 The Korean Academy of Medical Sciences.
    Original Article

    Determining and Comparing the Real-World Effectiveness of Molnupiravir and Nirmatrelvir-Ritonavir in Patients Hospitalized With COVID-19

    Young Rock Jang,1 Yoonju Oh,2 and Jin Yong Kim1
      • 1Division of Infectious Diseases, Department of Internal Medicine, Incheon Medical Center, Incheon, Korea.
      • 2Division of Metabolism and Endocrinology, Department of Internal Medicine, Incheon Medical Center, Incheon, Korea.
    • Address for Correspondence: Jin Yong Kim, MD, MPH. Division of Infectious Diseases, Department of Internal Medicine, Incheon Medical Center, 217 Bangchuk-ro, Dong-gu, Incheon 22532, Republic of Korea. Email: kjykey@gmail.com
    Received September 24, 2023; Accepted December 06, 2023.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Background

    Current guidelines recommend using nirmatrelvir-ritonavir for coronavirus disease 2019 (COVID-19) treatment, but its potential drug interactions and contraindications limit its applicability in certain categories of patients. The aim of the study was to evaluate the real-world effectiveness of molnupiravir and nirmatrelvir-ritonavir in managing COVID-19 among hospitalized patients.

    Methods

    We conducted a retrospective cohort study among hospitalized COVID-19 patients who received molnupiravir or nirmatrelvir-ritonavir and did not require baseline supplemental oxygen from February 2022 to January 2023. We compared the effectiveness of molnupiravir and nirmatrelvir-ritonavir with a focus on disease progression.

    Results

    The study included 401 high-risk, hospitalized adult COVID-19 patients who received molnupiravir or nirmatrelvir-ritonavir. No significant difference was found in disease progression, the composite outcome of disease progression (4.0% vs. 1.4%, P = 0.782), and O2 supplementation via nasal prong (21.8% vs. 14.8%, P = 0.115) between the patients treated with molnupiravir and those treated with nirmatrelvir-ritonavir. This finding was similar after 1:1 propensity-score matching. In the multivariate analysis, molnupiravir treatment was not significantly associated with progression to severe disease.

    Conclusion

    In conclusion, our findings suggest that similar to nirmatrelvir-ritonavir, molnupiravir has a distinct potential role in COVID-19 treatment, transcending its current perceived status as only a secondary option.

    Graphical Abstract

    Keywords
    Molnupiravir; Nirmatrelvir; COVID-19; COVID-19 Drug Treatment

    INTRODUCTION

    The coronavirus disease 2019 (COVID-19) pandemic has seen the emergence of various effective therapeutic strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including the orally administered antiviral drugs, molnupiravir and nirmatrelvir-ritonavir. The U.S. Food and Drug Administration authorized the use of nirmatrelvir-ritonavir in high-risk groups with mild-to-moderate COVID-19 in December 2021.1 However, the National Institutes of Health’s COVID-19 Treatment Guidelines Panel recommended molnupiravir, owing to its perceived lower efficacy, only as an alternative therapy for when nirmatrelvir-ritonavir and remdesivir are not available or appropriate.2 Despite the high level of effectiveness of nirmatrelvir-ritonavir, concern exists that only a limited proportion of patients with a high risk of disease progression can be treated with it because of its drug interaction and limited role in patients with impaired kidney function.

    The PANORAMIC trial involving mostly vaccinated individuals found that molnupiravir did not reduce the frequency of hospitalization or death.3 However, certain studies that evaluated the use of molnupiravir in non-hospitalized or hospitalized adults who were at high risk of progressing to severe disease, including patients that received COVID-19 vaccines or were unvaccinated, reported that both molnupiravir and nirmatrelvir–ritonavir use showed substantial clinical benefit, including a lower risk of all-cause mortality, in-hospital disease progression, and lower time to reaching a low viral burden in non-hospitalized or hospitalized patients not requiring oxygen therapy.4, 5, 6, 7

    These varying results underscore the need for head-to-head trials that should compare the effectiveness and safety of nirmatrelvir-ritonavir and molnupiravir. This study aim was to provide a comprehensive real-world evaluation of the effectiveness of molnupiravir and nirmatrelvir-ritonavir. Although these oral antivirals are now indicated for non-hospitalized COVID-19 patients who are at high risk of disease progression, the current analysis only focuses on the evaluation their effectiveness in patients with COVID-19 that do not require oxygen therapy on the day of admission.

    METHODS

    Study population and design

    A retrospective observational cohort study was conducted to evaluate the effectiveness of molnupiravir and nirmatrelvir-ritonavir in improving the clinical outcomes of COVID-19 patients who were admitted to the COVID-19-designated public hospital in South Korea between February 2022 and January 2023, which is the period during which omicron was the dominant SARS-CoV-2 variant in South Korea.8 According to the Korea Disease Control and Prevention Agency’s clinical management guidelines for COVID-19,9 patients that had 1) symptom onset within five days before admission, 2) no oxygen requirement (SpO2 > 94% in room air), and 3) high risk for disease progression were recommended to receive molnupiravir or nirmatrelvir-ritonavir (Supplementary Table 1). The guidelines stated that nirmatrelvir-ritonavir should be preferentially administered over molnupiravir, unless the patient is on any concomitant medications contraindicated for nirmatrelvir plus ritonavir. We excluded patients who were younger than 18 years, admitted to hospital before SARS-CoV-2 infection diagnosis, critical status, or dead on or before SARS-CoV-2 infection diagnosis. We also excluded patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min per 1.73 m2, undergoing dialysis, or renal transplantation) at baseline, and who were concurrently taking medications contraindicated for nirmatrelvir-ritonavir.

    Outcomes

    The primary outcome was a composite outcome of disease progression. Disease progression was assessed by ordinal disease severity score according to the KCDC guideline10 and defined when the clinical condition of a patient reached more than a score of 4. The referral to a tertiary hospital due to increased oxygen requirement is also considered as disease progression. Death was defined as all-cause in-hospital mortality. The composite outcome indicating progression to severe disease was defined as progression to a severity score of 4 to 8, including referral to a tertiary care hospital due to increased O2 requirements. Secondary outcomes were requirement for other treatment modalities: dexamethasone, antibiotics, oxygen treatment, and length of hospital stay. The institutional review board decided the study did not require ethical review as the study was conducted as part of a public health response, and minimal risk was expected to the participating patients.

    Data collection

    We collected information about the baseline characteristics of the patients: age, sex, date of symptom onset/diagnosis/admission, underlying diseases, COVID-19 vaccination history, patient management, and clinical outcomes. Clinical status at the time of admission was evaluated using SpO2, complete blood count, chemistry profile, and C-reactive protein levels. The estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula.11 The primary outcomes were assessed based on the ordinal disease severity scores.10 We defined the severity scores as follows: 1) no limitation of daily activities; 2) limitation of daily activities but no need for supplemental oxygen therapy; 3) need for supplemental oxygen therapy via nasal cannula; 4) need for supplemental oxygen therapy via facial mask; 5) need for high-flow supplemental oxygen therapy or noninvasive mechanical ventilation; 6) need for invasive mechanical ventilation; 7) multi-organ failure or the need for extracorporeal membrane oxygenation (ECMO) therapy; 8) death. The composite outcome indicating progression to severe disease was defined as progression to a severity score of 4 to 8, including referral to a tertiary care hospital due to increased O2 requirements.

    Statistical analysis

    Data were analyzed using R software (version 4.3.0). To compare the clinical factors, either the Student’s t-test or Mann-Whitney U test was used for continuous variables, and the χ2 or Fisher’s exact test was used for categorical variables. The Kaplan-Meier method and long-rank test were used to calculate the 21-day probability of disease progression. Cox proportional hazard models were used to evaluate the potential risk factors for disease progression within 21 days. All collected factors relevant to the outcomes were evaluated using univariate analyses, and statistically significant factors were included in the multivariate analyses. A continuous variable that was determined to be statistically significant in the univariate analysis was converted into a categorical variable using interquartile ranges, the receiver operating characteristic curve, or known normal limits, and the variable with the highest hazard ratio was included in the multivariate analysis. To mitigate potential confounding in our comparison of molnupiravir and nirmatrelvir-ritonavir effects, we implemented propensity-score matching (PSM). This technique was utilized to estimate the average marginal effect of molnupiravir on recipients, while adjusting for confounding by the covariates included in our analysis. We conducted 1:1 nearest neighbor PSM without replacement, employing a logistic regression model to estimate the propensity scores based on the covariates. Post-matching assessment revealed suboptimal balance, as indicated by standardized mean differences exceeding 0.1 for covariates such as creatinine and chronic kidney disease (Supplementary Fig. 1).

    Ethics statement

    The study protocol was reviewed and approved by the Institutional Review Board (IRB) of Incheon Medical Center (approval No. 115288-202107-HR-066-09). The need for informed consent was waived by the IRB owing to the retrospective nature of the study.

    RESULTS

    We identified 848 patients with confirmed diagnosis of COVID-19 who were admitted to the hospital between February 1, 2022, and January 31, 2023. Of these, we excluded 401 patients, because of SpO2 ≤ 94% on the admission day (n = 148), no risk factors (n = 127), hospitalization 5 days from the day of onset of symptoms (n = 164), or referred to a tertiary care hospital within 24 hours of admission (n = 8). In the study, 124 molnupiravir and 277 nirmatrelvir-ritonavir recipients who had completed treatment and had no requirement for oxygen therapy at baseline were eligible for inclusion. Table 1 presents the baseline characteristics of the molnupiravir and nirmatrelvir-ritonavir groups before and after 1:1 PSM. The molnupiravir group patients were older and had higher frequency of chronic kidney diseases, neurologic diseases, and dementia compared to the nirmatrelvir-ritonavir group patients.

    Table 1
    Baseline characteristics of molnupiravir recipients and nirmatrelvir-ritonavir recipients

    Table 2 summarizes the treatment outcomes of molnupiravir and nirmatrelvir-ritonavir groups. Overall, 30 patients (7.5%) received dexamethasone, without a significant difference between the groups. The composite outcome of disease progression (4.0% vs. 1.4%, P = 0.782) and O2 supplementation via nasal prong (21.8% vs. 14.8%, P = 0.115) did not differ significantly between the groups. This finding was similar after 1:1 PSM (Table 2). During the study period, a total of five patients (2.7%) were referred to a tertiary care center. The reasons for referral included: increasing O2 requirement (one patient), non-ST elevation myocardial infarction (one patient), increasing pleural effusion (one patient), the need for hemodialysis (one patient), and complications related to urinary catheterization (one patient). We used the Kaplan-Meier method and observed that no statistically significant disparity occurred in the 21-day cumulative incidence of progression to severe disease between the groups, both prior to and after PSM (P = 0.336 in the total cohort and P = 0.861 in the matched cohort; Fig. 1), and no statistically significant disparity occurred in the 21-day cumulative incidence of O2 support between the groups, both prior to and after PSM (P = 0.107 in the total cohort and P = 0.271 in the matched cohort).

    Table 2
    Treatment and outcomes of the molnupiravir recipients and nirmatrelvir-ritonavir recipients

    Fig. 1
    Cumulative incidence of disease progression: the figure displays cumulative incidence plots for progression to severe disease within 21 days in the total cohort (A) and the propensity score-matched cohort (B). No statistically significant differences were identified in either group.

    To adjust for potential confounding factors in the 21-day disease progression probability of the patients, we considered variables of clinical importance in a multivariable analysis. The multivariate analysis showed that molnupiravir treatment was not significantly associated with progression to severe disease compared to the nirmatrelvir-ritonavir treatment (hazard ratio, 1.45; 95% confidence interval, 0.29–7.22; P = 0.649; Table 3).

    Table 3
    Multivariate analysis of progression to severe disease

    DISCUSSION

    We did not observe any difference in progression to severe disease between COVID-19 patients not requiring supplemental oxygen on admission treated with molnupiravir and those treated with nirmatrelvir-ritonavir. Even though our study was conducted within a hospital setting, our patient demographic, which included individuals not requiring baseline supplemental oxygen, likely differed from that in the MOVe-IN trial.12 In the MOVe-IN trial, a substantial portion of the patients exhibited moderate to severe COVID-19 symptoms, with approximately half requiring oxygen therapy. A secondary analysis of the MOVe-OUT trial indicated that molnupiravir recipients had reduced requirement for respiratory interventions compared to those treated with a placebo, including a subgroup of patients who were hospitalized post-randomization.13

    Of note, the molnupiravir-treated patients in our study had a higher number of neurologic disease and dementia. Moreover, molnupiravir patients were more likely to have lower estimated glomerular filtration rate. These differences prompted the prescription of molnupiravir over nirmatrelvir-ritonavir. In clinical trials, nirmatrelvir-ritonavir has shown higher efficacy than molnupiravir, and the present guidelines advocate for its use over molnupiravir in patients with COVID-19 who are at high risk of hospitalization or progression to severe disease, assuming that nirmatrelvir-ritonavir is available and clinically appropriate.14, 15, 16 However, no direct comparative clinical trial have been conducted to date. Moreover, nirmatrelvir-ritonavir can interact with other drugs and should be avoided in certain specific patient categories.17 Approximately 15% of the hospitalized COVID-19 patients had medical contraindications to nirmatrelvir-ritonavir, with these contraindications being more prevalent in men, older patients, and patients with comorbidities such as solid organ transplant recipients on chronic immunosuppressive therapy like tacrolimus or mycophenolate.18, 19, 20 In addition, clinical data on dose adjustments in patients with renal impairment are limited. Therefore, patients prescribed nirmatrelvir-ritonavir should undergo careful screening, including an evaluation of baseline renal function and exclusion of drug-drug interactions. In addition, the decision to discontinue certain drugs during therapy and monitoring for potential adverse reactions is crucial. Moreover, even though the guidelines recommend nirmatrelvir-ritonavir, there is concern that only a limited proportion of patients who have high risk of disease progression could be treated with it in the real-world setting. Conversely, molnupiravir does not require any adjustment based on drug interactions and renal impairment.

    The PANORAMIC study concluded that molnupiravir did not reduce the rate of hospitalization and death compared to a placebo in a highly vaccinated population. However, the average age of participants in the PANORAMIC study was 56.6 years, and only 1.0% of the patients treated with molnupiravir underwent hospitalization or died within 28 days.3 This rate was lower than that observed rate in recent observational studies.4, 5, 6 Older age is a significant risk factor associated with increased mortality due to various comorbidities.21, 22, 23 In our study, most patients were older adults, with approximately 31% aged over 80 years. Although a simple comparison is not suitable, considering that most patients hospitalized with the omicron variant are older adults,24 molnupiravir is highly effective in older adults and other individuals who are at high risk of progression and are not eligible for receiving nirmatrelvir-ritonavir.

    Our findings present a nuanced interpretation of the role that antiviral therapies, specifically nirmatrelvir-ritonavir and molnupiravir, play in the management of COVID-19. Table 3, which presents a multivariate analysis, may lead to the initial impression that these treatments do not significantly influence the risk of progression to severe disease. Previous studies have firmly established the efficacy of both nirmatrelvir-ritonavir and molnupiravir in reducing severe outcomes in COVID-19 patients. Our analysis aimed to compare the relative effectiveness of these two treatments within a specific cohort. The lack of a statistically significant difference in severe disease progression between the two groups in our study should not be interpreted as a lack of efficacy. Instead, it may reflect the comparable effectiveness of these treatments in preventing severe disease when they are appropriately administered.

    In many studies, factors such as diabetes, old age, and high BMI have been identified as significant risk factors for disease progression. However, in our study, these factors did not emerge as statistically significant. Our study population might have a different distribution of these risk factors compared to that in other studies. For instance, if a large proportion of our study population was elderly, the age variable might not show as much variability, affecting its significance in the analysis. In addition, given that all patients in our study received antiviral treatments, it is possible that the early intervention and management strategies employed in our setting mitigated the impact of these traditional risk factors. Moreover, the sample size and event rates in our study might affect the power to detect certain risk factors as significant, especially if the effect sizes are small. There could be interactions between various risk factors that might mask the individual effects of traditionally recognized risk factors.

    A strength of our study is that it used the medical records of hospitalized patients who were closely monitored which made it possible to record details regarding clinical outcomes and procedures. Another advantage is that medication adherence could be guaranteed in an inpatient setting, unlike in a community setting. However, our study has several limitations. First, we cannot rule out the possibility of selection bias or confounding by indication in this observational study. Also, it is possible that patients who received oral antivirals might have been considered more in need of treatment than those who remained untreated, despite balanced PSM. Second, residual confounding by indication could still exist in the clinical decision to prescribe molnupiravir versus nirmatrelvir-ritonavir. Nirmatrelvir-ritonavir has a risk of drug-drug interactions and might be less preferred by clinicians for treating patients taking multiple medications. After excluding patients with drug contraindications for nirmatrelvir-ritonavir and applying PSM, characteristics of patients in the oral antiviral and respective control groups were well balanced at baseline. However, the usual caveats about residual and unmeasured confounding in observational studies still apply.

    We compared the effectiveness of molnupiravir and nirmatrelvir-ritonavir in patients with COVID-19, primarily older adults. The molnupiravir group patients had a higher average age and more comorbidities than the nirmatrelvir-ritonavir group patients. We did not observe a difference in the rate of progression to severe disease between the two groups. Although these antiviral agents are effective treatment for COVID-19 in patients with a risk of progression to severe disease, the expansion of healthcare resources is also essential. A well-controlled prospective study is required for determining the appropriate use of antiviral agents for patients with COVID-19.

    In conclusion, our findings suggest that molnupiravir may have a potential role in the treatment of COVID-19 beyond its current perceived status as a secondary option. However, larger randomized controlled trials are needed to confirm these observations. We emphasize that the choice of antivirals should be determined based on the comorbidities and characteristics of individual patients.

    SUPPLEMENTARY MATERIALS

    Supplementary Table 1

    Indication for the administration of antiviral treatment in patients with COVID-19

    Click here to view.(29K, doc)

    Supplementary Fig. 1

    Propensity-score matching.

    Click here to view.(331K, doc)

    Notes

    Disclosure:The authors have no potential conflicts of interest to disclose.

    Author Contributions:

    • Conceptualization: Jang YR, Oh Y, Kim JY.

    • Data curation: Jang YR, Kim JY.

    • Investigation: Jang YR, Oh Y, Kim JY.

    • Methodology: Jang YR, Kim JY.

    • Project administration: Jang YR, Kim JY.

    • Resources: Jang YR, Kim JY.

    • Supervision: Kim JY.

    • Writing - original draft: Jang YR, Kim JY.

    • Writing- review & editing: Jang YR, Oh Y, Kim JY.

    ACKNOWLEDGMENTS

    We would like to thank Editage (www.editage.co.kr) for English language editing.

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    MeSH Terms
    Adult
    COVID-19*
    Cohort Studies
    Contraindications
    Disease Progression
    Drug Interactions
    Humans
    Multivariate Analysis
    Oxygen
    Retrospective Studies
    Metrics
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