Association of Molnupiravir and Nirmatrelvir-Ritonavir with reduced mortality and sepsis in hospitalized omicron patients: a territory-wide study

This study evaluates the association between antivirals (Molnupiravir and Nirmatrelvir-Ritonavir) and all-cause and respiratory mortality and organ dysfunction among high-risk COVID-19 patients during an Omicron outbreak. Two cohorts, Nirmatrelvir-Ritonavir versus control and Molnupiravir versus control, were constructed with inverse probability treatment weighting to balance baseline characteristics. Cox proportional hazards models evaluated the association of their use with all-cause mortality, respiratory mortality, and all-cause sepsis (a composite of circulatory shock, respiratory failure, acute liver injury, coagulopathy, and acute liver impairment). Patients recruited were hospitalized and diagnosed with the COVID-19 Omicron variant between February 22, 2022 and April 15, 2022, and followed up until May 15, 2022. The study included 17,704 patients. There were 4.67 and 22.7 total mortalities per 1000 person-days in the Nirmatrelvir-Ritonavir and control groups respectively before adjustment (weighted incidence rate ratio, − 18.1 [95% CI − 23.0 to − 13.2]; hazard ratio, 0.18 [95% CI, 0.11–0.29]). There were 6.64 and 25.9 total mortalities per 1000 person-days in the Molnupiravir and control groups respectively before adjustment (weighted incidence rate ratio per 1000 person-days, − 19.3 [95% CI − 22.6 to − 15.9]; hazard ratio, 0.23 [95% CI 0.18–0.30]). In all-cause sepsis, there were 13.7 and 35.4 organ dysfunction events per 1000 person-days in the Nirmatrelvir-Ritonavir and control groups respectively before adjustment (weighted incidence rate ratio per 1000 person-days, − 21.7 [95% CI − 26.3 to − 17.1]; hazard ratio, 0.44 [95% CI 0.38–0.52]). There were 23.7 and 40.8 organ dysfunction events in the Molnupiravir and control groups respectively before adjustment (weighted incidence ratio per 1000 person-days, − 17.1 [95% CI, − 20.6 to − 13.6]; hazard ratio, 0.63 [95% CI 0.58–0.69]). Among COVID-19 hospitalized patients, use of either Nirmatrelvir-Ritonavir or Molnupiravir compared with no antiviral use was associated with a significantly lower incidence of 28-days all-cause and respiratory mortality and sepsis.


Scientific Reports
| (2023) 13:7832 | https://doi.org/10.1038/s41598-023-35068-w www.nature.com/scientificreports/ Interventions. Our exposure of interest was Molnupiravir and Nirmatrelvir-Ritonavir among hospitalized COVID-19 patients, with an increased risk of deterioration, including old-age and chronic disease patients. We included hospitalized patients who were aged ≥ 60 years; or younger patients aged ≥ 18 with at least one chronic disease. Patients with prescription records of Molnupiravir or Nirmatrelvir-Ritonavir within 4 days of hospital admission were allocated into the Molnupiravir and Nirmatrelvir-Ritonavir treatment groups; patients who received both antivirals were excluded from this study. Considering the delayed access to antivirals in early stage of rolling out, patients received Molnupiravir or Nirmatrelvir-Ritonavir later than 4 days from the index date were excluded.
Outcomes. The primary outcomes were 28-days all-cause mortality and respiratory mortality, as detailed in Supplementary Table 1. Secondary outcomes were circulatory shock, respiratory failure, acute kidney injury, coagulopathy, acute liver impairment, and combined organ dysfunction, a composite outcome defined as presence of any one of these other secondary outcomes. Acute organ dysfunction is defined by vasopressor initiation, mechanical ventilation, elevation of lactate, or changes in total bilirubin, platelets or creatinine relative to specified baseline values 23 , and the unprecedented prescription of dexamethasone, as directed by the clinical guideline 24 . We defined these outcomes in reference to a sepsis surveillance toolkit, published by the US Centers for Disease Control and Prevention (CDC), which is a validated approach based on administrative data to facilitate health care facilities to monitor the incidence and outcomes of patients who developed sepsis according to the Sepsis-3 criteria, known as an Adult Sepsis Event (ASE) 25 . ASE is defined as (1) presumed serious infection, signified by obtained microbiological examination (for example, blood culture) and ≥ 4 consecutive days of antimicrobials (or up until 1 day before mortality, discharge to hospice, transfer to another acute care hospital, or transition to comfort measures) starting within 2 calendar days of when blood cultures were obtained, plus (2) evidence of concurrent organ dysfunction, signified by any of 6 binary indicators of cardiovascular, pulmonary, renal, hepatic, coagulation, or perfusion dysfunction. This approach for the identification of sepsis patients in Hong Kong data from CDARS has been validated, with high sensitivity (0.93), high specificity (0.86) and area under receiver operating characteristic curve (0.90) 26 .
The follow-up of each patient was commenced from the index date, defined as the date of hospital admission, for 28 days or until date of mortality. For secondary outcomes, follow-up time was defined as time from the index date to time of event, or loss of follow up.
Covariates. Baseline data was collected for each patient including sex, age, and socioeconomic status. The socioeconomic status of each patient was determined by the Social Deprivation Index (SDI) of their area of residence 27 . SDI is derived from six variables to describe the conditions of social deprivation for each residential district: the proportions of the population with unemployment, monthly household income < US$250, no schooling at all, one-person household, never-married status, and subtenancy. The data comes from population census published by the government. Each of these six variables had significant factor loading for a specific principal factor, and all of them are deemed to be representative indicators of social disadvantage in the published literature and in the setting of the Hong Kong population. SDI for each district was calculated by taking the average of these six selected variables 28 .
Baseline data was also collected for comorbidities (Charlson Comorbidity Index (CCI), diabetes mellitus, hypertension, stroke, congestive heart failure, atrial fibrillation, schizophrenia, cirrhosis, depression, chronic kidney disease, rheumatoid arthritis, obesity and alcohol abuse) and chronic medication use (antiplatelets and anticoagulants, ACE inhibitors and angiotensin receptor blockers, beta blockers, calcium channel blockers, diuretics, statins systemic corticosteroids, bronchodilators and inhaled corticosteroids, cancer drugs, and rheumatological drugs). The differences in patient characteristics between treatment groups were expressed in terms of standardized mean differences (SMD), where covariates with SMD < 0.2 were considered balanced. The International Classification of Diseases, Ninth Revision (ICD-9) codes used for classification of the comorbidities are available in Supplementary Table 2.
Analysis. Baseline characteristics were expressed as the mean (Standard deviation [SD]) for continuous variables and frequency (%) for categorical variables. Inverse probability treatment weighting (IPTW) based on propensity scores using the aforementioned variables was used to construct a weighted cohort of patients to address potential indication bias due to nonrandomized allocation of patients to the treatment group. IPTW balances baseline characteristics in comparator groups by weighting each patient by the inverse probability of receiving the treatment. Hazard ratios (HR) for the association of Nirmatrelvir-Ritonavir or Molnupiravir use and the study outcomes were estimated over the entire follow-up with weighted Cox proportional hazards regression using weights obtained by IPTW.
Alternatively, given the small event rate, we repeated all analyses utilizing bootstrapping methods followed by sampling with replacement to obtain precise estimates of HRs, incidence rate differences (IRD) and their 95% confidence intervals. Details regarding the bootstrapping method are documented in Supplementary Fig. 1.
Prespecified subgroup analyses were conducted by stratifying the study population by age groups (5-years increments from < 60 to ≥ 80), sex, SDI, and presence of diabetes. Further analyses were conducted to investigate the number of mortalities stratified by individual components of organ dysfunction. The number of organ dysfunctions and length of stay were also stratified by survival status at the end of follow-up.
All significance tests were two-tailed and considered significant when the P value was less than 0.05. All analyses were conducted using RStudio version 1.4.1717 29 , using the following packages: tidymodels was used to obtain bootstrapped dataframes 30 , for the subsequent computation of hazard ratios using the survival package 31  www.nature.com/scientificreports/ and weighted incidence rate differences via the fmsb package 32,33 . The package 'WeightIt' was used to compute the propensity scores and inverse probability weights 32 . The package comorbidity was used to compute the CCI 34 .
Ethics approval and consent to participate. This study was approved, and the requirement for obtaining patient informed consent was waived, by the Hospital Authority Hong Kong West Cluster/The University of Hong Kong institutional review board (UW 22-258).

Results
Characteristics of study subjects. From February 22, 2022 to April 15, 2022, 17,925 patients were hospitalized with COVID-19. Of these, 44 patients were excluded for missing demographic data. Nirmatrelvir-Ritonavir was prescribed to 770 patients of whom 105 were excluded either because of the mixed use of antivirals (N = 84) or initiating Nirmatrelvir-Ritonavir beyond 4 days after hospital admission (N = 21), leaving 665 for further analysis. Of 1784 given Molnupiravir, 156 were excluded due to mixed use of antivirals (N = 84) or initiating Molnupiravir beyond 4 days after hospital admission (N = 72), leaving 1628 for analysis. These patients with antivirals were weighted against 15,411 patients without antiviral (control) to generate two study cohorts. Supplementary Fig. 2 documents the selection process for the two study cohorts. Tables 1 and 2 shows patient demographics of patients receiving each antiviral weighted against control, before and after propensity score weighting. Of 665 patients with Nirmatrelvir-Ritonavir use, the mean age was 76.8 (SD, 14) years, 49.9% were men, and 76.1% had a CCI of 0. Among 1,628 with Molnupiravir, the mean age was 80.0 (SD, 13) years, 51.9% were men, and 70.9% had a CCI of 0. In the control group, the mean age was 72.2 years (SD, 25), 54.5% were men, and 71.9% had a CCI of 0.
Results for all secondary outcomes stratified by sex, age, SDI and diabetes are shown in Figs. 2a,b. The number of mortality in the Nirmatrelvir-Ritonavir, Molnupiravir and control groups, stratified by organ dysfunction are shown in Table 3

Limitations
Hong Kong has a robust and comprehensive database from which we acquired real-world clinical data for analysis. However, patients' symptomatology, SARS-CoV-2 vaccination status and vital sign measurements throughout the health care process were not available. Moreover, medical compliance data was not available, and therefore fidelity for these confounders cannot be adjusted.
With the recent availability of these antivirals and the proximity to the outbreak, this study has short follow-up, meaning that late outcomes/effects, for example, prevention of long-term consequences of infection or associated health service utilization, are not assessable during the study period.

Discussion
This analysis from the real-life data among patients infected with the Omicron variant in Hong Kong investigated the association of Molnupiravir and Nirmatrelvir-Ritonavir with reduced mortality and sepsis. In this study, both antivirals were associated with large degrees of reduction in all-cause and respiratory mortalities, which is compatible with published literature 11,[35][36][37] , indicating its potential contribution to contain the infection from the epidemic.
Sepsis is a clinical syndrome that has physiologic and biochemical abnormalities caused by a dysregulated host response to infection. Sepsis and the inflammatory response that ensues can lead to multiple organ dysfunction syndrome and death 12 . In a viral infection neither blood nor lower respiratory tract specimen culture are positive. In COVID-19, the proportion of viral sepsis among all-cause sepsis was reported as 76% 38 . In this study, both Nirmatrelvir-Ritonavir and Molnupiravir were associated with a reduction in organ dysfunction driven by a decrease in circulatory shock and respiratory failure among high-risk hospitalized patients infected with Omicron variant.
SARS-CoV-2 was detected in the highly-vascularized heart, respiratory tract, kidneys, liver, and brain 39 . Endothelial cells express the angiotensin-converting enzyme 2 (ACE2) receptor and the cellular proteases, which are favorable to SARS-CoV-2 and subsequent virus dissemination to various organs through vasculature. A very high level of cytokine facilitates the development of cytokine storm in COVID-19 40 .
Influenza viruses, including influenza A and B, can cause both seasonal epidemics and out-of-season sporadic cases and outbreaks 41 . A previous report from the USA found that the incidence rate of influenza-associated sepsis hospitalization was 8.8/100,000 person-years (95% CI 3.9-16.5) 42 . The relative risk of sepsis and septic shock in 2009 pandemic influenza A was 1.70 (95% CI 1.46-1.97) over seasonal influenza 43 . A report from Wuhan suggesting that COVID-19 (wild-type) associated sepsis and septic shock can be found in 59% and 20% of patients respectively. However, at the time of writing, the data on Omicron variant-associated sepsis and septic shock was not available. In this study. the incidence of sepsis and septic shock among hospitalized patients with Omicron variant was 42.8% (N = 7593) and 5.8% (N = 1029) respectively. Even though the figure is lower than wild-type, an infection with Omicron may pose a huge burden to health care systems due to its highly transmissible nature.
In this study, the effect of Nirmatrelvir-Ritonavir and Molnupiravir on acute kidney injury, acute liver impairment and coagulopathy were not significant. We reproduced the results with bootstrapping methods to obtain precise estimates of incidence rate ratios, hazard ratios and confidence intervals. After bootstrapping, the antivirals were significantly additionally associated with reduced acute liver impairment, suggesting its potential effect on liver or kidney dysfunctions.
The effectiveness and utility of Nirmatrelvir-Ritonavir and Molnupiravir have been evaluated in other observational studies [44][45][46][47] . One Italian study similarly found decreased risk of death and hospitalization associated with COVID-19 antiviral use 44 46 . In terms of cost-effectiveness, both Nirmatrelvir-Ritonavir and Molnupiravir were associated with healthcare system cost savings 47 .
These findings should be interpreted together with vaccination status in the population. In Hong Kong, these antivirals were prescribed for individuals who have not completed vaccination against COVID-19 (either attenuated virus vaccine or messenger Ribonucleic Acid vaccine). The elderly population is largely unvaccinated and more likely to develop severe COVID-19. As of April 15, 2022, only 40.0% of population aged 60 years or above have completed vaccination (3 doses), of which 60 to 69 years 50.0%, 70-79 years 38.4% and 80 years or above 14.9% 48 . These observations warrant further analysis, including the number of vaccine doses, to explore the underlying factors accounting for differences in antiviral efficacy among different age groups.
In subgroup analysis, it was found that antivirals had no significant reduction in outcomes among patients aged 60 or under, in contrary to patients from other age groups. While further analysis is warranted for the underlying cause, these patients have additional risk factors for severe disease, suggesting comorbidities and disease factors, rather than age, contribute more to all-cause sepsis.
In summary, this analysis of real-world application of oral antivirals to patients infected with Omicron variant demonstrated that both Molnupiravir and Nirmatrelvir-Ritonavir were associated with a reduction in all-cause and respiratory mortality, and sepsis. Further research, including from randomized clinical trials, is needed to

Data availability
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.