Real-world data concerning the efficacy of molnupiravir in patients vaccinated against COVID-19 during the Omicron surge in Japan

doi:10.21203/rs.3.rs-2451986/v1

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Real-world data concerning the efficacy of molnupiravir in patients vaccinated against COVID-19 during the Omicron surge in Japan

https://doi.org/10.21203/rs.3.rs-2451986/v1

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Molnupiravir is among the antiviral agents used to treat COVID-19; however, reported data on the efficacy of this drug are based on results from unvaccinated patients. As such, the efficacy of molnupiravir among vaccinated patients during the B1.1.529 (Omicron) variant outbreak remains unknown. To address this issue, this study retrospectively analyzed data from 294 vaccinated patients with COVID-19 who had at least one risk factor, between May and October 2022. Patients were divided into the molnupiravir group and the control group to investigate the correlations of molnupiravir and other factors with rates of hospitalization and death (hospitalization/death) within 28 days of admission. Potential risk factors were also examined. The study findings indicated that molnupiravir was not associated with the rate of hospitalization/death, while age ≥ 80 years, residence in a long-term care facility, and presence of chronic obstructive pulmonary disease were significantly associated with the rate of hospitalization/death. Although the current results suggest that the effect of vaccination in preventing severe illness against the Omicron variant is well maintained, additional studies on risk factors and outcomes are required to validate this study’s findings.

Health sciences/Medical research

Health sciences/Medical research/Outcomes research

COVID-19

coronavirus

Omicron

vaccination

molnupiravir

pandemic

variant

risk factors

antiviral

As of 2022, the B1.1.529 (Omicron) variant, especially the BA.5 subvariant, has become the dominant cause of SARS-CoV-2 infection (COVID-19). While the Omicron variant is much more infectious than the conventional variant, it is less lethal^[1], and the conventional vaccine is believed to prevent hospitalization to some extent^[2].

Currently, molnupiravir, nirmatrelvir/ritonavir, and remdesivir are approved antiviral drugs for mild COVID-19, all of which have shown some degree of efficacy in preventing severe disease when compared with placebo^[3–5]. Among them, molnupiravir, a small-molecule ribonucleoside prodrug of N-hydroxycytidine (NHC), has been shown to increase the threshold for developing resistance to treatment^[6–11]. Evidence from the phase III MOVe-OUT trial indicates that molnupiravir can reduce the severity of illness in patients with mild to moderate COVID-19^[3]. However, the clinical trials in which molnupiravir exhibited efficacy were conducted prior to the Omicron outbreak and were conducted among nonvaccinated patients^[4]. Although the efficacy of molnupiravir against Omicron has been demonstrated in vitro^[12], its efficacy in the context of the current climate in Japan—in which vaccination rates are high—remains to be determined, making it difficult to identify the most appropriate drugs and treatment indications for COVID-19. Therefore, the present study aimed at using real-world data to analyze the efficacy of molnupiravir among vaccinated patients in Japan.

Study Design and Population

The data from consecutive patients with COVID-19 who visited Fukuchiyama City Hospital between May 1, 2022, and October 22, 2022, were analyzed. The study was approved by the Local Ethical Committee of Fukuchiyama City Hospital (Code number 4–26 and date of approval: September 28, 2022), and patient consent was waived by the Local Ethical Committee of Fukuchiyama City Hospital due to the retrospective design and the ethics guidelines.

The eligibility criteria were as follows: (i) age ≥ 20 years; (ii) mild or moderate COVID-19 based on the criteria published by the Japanese Association for Infectious Diseases; (iii) presence of one or more risk factors for the development of severe illness due to COVID-19 (age ≥ 65 years, cancer, chronic kidney disease, chronic obstructive pulmonary disease (COPD), body mass index > 30, severe cardiovascular disease, diabetes mellitus, Down syndrome, neurologic diseases, uncontrolled/untreated HIV or acute AIDS, chronic hepatic disease, or organ transplantation) (Fig. 1).

Intervention Given

Molnupiravir was prescribed to eligible patients with the following characteristics, in accordance with guidelines provided by the Japanese Association for Infectious Diseases: symptom onset ≤ 5 days prior, absence of the need for oxygen supplementation, and one or more risk factors. The decision to prescribe molnupiravir was determined by the attending physician and the patients who were prescribed molnupiravir were classified into the molnupiravir group and those who were not prescribed antiviral drugs were classified into the control group.

Statistical Analyses

The primary endpoint was all-cause, nonselective hospital admission and/or death within 28 days of diagnosis. Patients were divided into two groups based on the choice of treatment: the molnupiravir group and the control group. Fisher's exact test was used to compare outcomes between the two groups. Logistic regression analysis was performed to identify factors associated with rates of hospitalization and 28-day mortality. All statistical analyses were performed using EZR version 1.60 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R software version 4.2.1 (The R Foundation for Statistical Computing, Vienna, Austria)^[13].

Patient Characteristics

Among patients with COVID-19 who visited our hospital during the study period, 317 had at least one risk factor. Twenty-three patients were excluded from the study because they were not vaccinated or had an unknown vaccination history. Of the 294 patients included in the study, 84 (28.5%) received molnupiravir. The median age of the study participants was 69.5 years, with 25.1% of them aged > 80 years, and 50.3% were female. The distribution of risk factors was as follows: cancer (7.8%), COPD (10.5%), diabetes mellitus (16.7%), neurologic disease (8.5%), chronic hepatic disease (1.0%), chronic heart failure (7.1%), chronic kidney disease (7.1%), immunosuppression (3.4%), organ transplantation (1.0%), residence in a long-term care facility (2.0%), and body mass index > 30 (3.7%). The majority of patients (65.6%) had only one risk factor, and there were no significant differences in baseline characteristics between the molnupiravir and control groups (Table 1).

Table 1

Baseline characteristics of the included patients
Variables		Total (n = 294)	Molnupiravir group (n = 84)	Control group (n = 210)	p-value
Age, median (range)		69.5 (22–100)	71 (22–99)	68.5 (22–100)	NS
Sex (%)	Male	146 (49.7)	36 (42.9)	110 (52.4)	NS
	Female	148 (50.3)	48 (57.1)	100 (47.6)
Cancer (%)		23 (7.8)	6 (7.1)	17 (8.1)	NS
Chronic obstructive pulmonary disease (%)		31 (10.5)	10 (11.9)	21 (10.0)	NS
Diabetes (%)		49 (16.7)	20 (23.8)	29 (13.8)	NS
Neurologic disease (%)		25 (8.5)	8 (9.5)	17 (8.1)	NS
Chronic hepatic disease (%)		3 (1.0)	0	3 (1.4)	NS
Chronic heart failure (%)		21 (7.1)	6 (7.1)	15 (7.1)	NS
Chronic kidney failure (%)		21 (7.1)	10 (11.9)	11 (5.2)	NS
Immunosuppression (%)		10 (3.4)	5 (6.0)	5 (2.4)	NS
Organ transplantation (%)		3 (1.0)	2 (2.4)	1 (0.5)	NS
Residence in a long-term care facility (%)		6 (2.0)	1 (1.2)	5 (2.4)	NS
Body mass index > 30 (%)		11 (3.7)	3 (3.6)	8 (3.8)	NS
Number of risk factors (%)	1	193 (65.6)	47 (56.0)	146 (69.5)
	2	64 (21.8)	24 (28.6)	40 (19.0)
	3	23 (7.8)	9 (10.7)	14 (6.7)
	4	11 (3.7)	1 (1.2)	10 (4.8)
	≧ 5	3 (1.0)	3 (3.6)	0

NS:

Hospitalization/death

Five patients (6.0%) in the molnupiravir group and eight patients (3.8%) in the control group were hospitalized or dead (Fig. 2). However, only one patient (1.2%) in the control group died. The hospitalization/death rate did not significantly differ between the two groups (6.0% vs. 3.8% p = 0.53).

Risk Factors for Hospitalization/death

Multivariate logistic regression analysis revealed that age ≥ 80 years, residence in a long-term care facility, and COPD were risk factors for hospitalization/death. Among them, residence in a long-term care facility was the most significant (Odds ratio, OR = 85.9). Treatment with molnupiravir did not significantly influence the rate of hospitalization/death (Table 2).

Table 2

Multivariate logistic regression analysis of risk factors for hospitalization/death
	Odds ratio	95% confidence interval	p-value
Molnupiravir	2.39	0.59–9.64	0.22
Sex	2.27	0.50–10.4	0.29
Age over 80 years	6.00	1.43–25.2	0.01
Cancer	0.27	0.02–3.10	0.29
Chronic obstructive pulmonary disease	9.42	1.78–49.9	0.01
Diabetes	1.48	0.24–9.34	0.68
Chronic heart failure	0.40	0.02–7.61	0.54
Chronic kidney failure	0.59	0.05–7.19	0.68
Immunosuppression	4.64	0.50–43.2	0.18
Residence in a long-term care facility	85.9	7.44–992	< 0.001

This study analyzed real-world data from vaccinated patients to investigate the current efficacy of molnupiravir in Japan. The study reports no statistically significant differences in rates of hospitalization/death between the molnupiravir group and the control group among the vaccinated population. However, the multivariate analysis identified age ≥ 80 years, residence in a long-term care facility, and COPD as significant risk factors for hospitalization/death.

Molnupiravir exerts its antiviral effect by inhibiting the viral RNA-dependent RNA polymerase enzyme^[14]. The recent MOVe-OUT trial, which was conducted among nonvaccinated patients before the Omicron variant had become dominant, demonstrated that treatment with molnupiravir reduced the risk of hospitalization or death by 31% (HR 0.69; 95% confidence interval, CI, 0.48–1.01)^[3]. Similarly, multiple meta-analyses of clinical trials conducted among nonvaccinated patients prior to the Omicron variant outbreak reported that molnupiravir significantly reduced the risk of hospitalization or death in mild cases^{[15, 16]}. In addition, several observational studies have reported the safety of molnupiravir in patients with comorbidities^{[17, 18]}. Together, these data emphasize that, prior to the Omicron outbreak, molnupiravir was effective in nonvaccinated patients. However, there is insufficient evidence to determine whether it is also effective against the Omicron variant that is currently endemic worldwide, especially in vaccinated patients.

The B1.1.529 (Omicron) variant is a variant of concern (VOC) first identified in South Africa on November 24, 2021, following which rates of infection rapidly increased worldwide due to its high transmissibility. When compared with conventional variants, its tendency to multiply in the upper respiratory tract rather than the lower respiratory tract and its ability to evade immune surveillance due to mutations in the spike protein are thought to have contributed to the spread of infection^[15]. Relative to infection with conventional variants, Omicron infection has been associated with clinical symptoms such as an increased frequency of nasal discharge/headache/malaise/cough/throat pain, as well as decreased frequency of fever/cough/smell and taste disturbances^[16]. In addition, while it is more infectious than the conventional Delta variant^[17], the rate of severe illness requiring hospitalization is considered to be low^[18]. The risk of hospitalization is 1/3 lower for the Omicron variant than for the Delta variant^[19].

Although mRNA vaccines have shown high efficacy in preventing severe illness, hospitalization, and death in patients with conventional variants^[20], their efficacy against the Omicron variant has been reported to be greatly diminished, with studies noting limited efficacy at approximately 20 weeks after vaccination^[21]. However, some studies have reported that booster vaccination, even against the Omicron variant, remains effective in adequately suppressing severe disease, citing vaccination as an effective means of treatment^[22]. In the current study, oral administration of molnupiravir may have been ineffective in reducing rates of hospitalization and death given that all patients were vaccinated, in contrast to previous studies, suggesting that the effect of vaccination in preventing severe illness against the Omicron variant was well maintained.

The present study findings are in agreement with those of the PANORAMIC trial, a large randomized controlled trial (RCT) conducted in the United Kingdom from December 2021 to April 2022^[27]. In the PANORAMIC trial, 99% of participants were vaccinated, and while molnupiravir reduced the time to the first self-reported recovery and viral load in patients with COVID-19, it did not reduce rates of hospitalization or mortality. However, the PANORAMIC trial did not assess the benefit of molnupiravir in very old adults, as only 2% of patients were over 80 years of age and most patients tended to be relatively young (56.7 years). In this regard, this study population was older than that of the PANORAMIC study, with 25.2% of patients aged ≥ 80 years. However, even under these circumstances, molnupiravir did not reduce rates of hospitalization or death, further supporting the notion that molnupiravir is not effective in older adults who have been vaccinated. In addition, most patients in the PANORAMIC study were white, whereas all patients in this study were Japanese, which demonstrates that molnupiravir does not significantly prevent hospitalization or death rate in vaccinated Japanese patients during the Omicron outbreak. In contrast to the present study findings, a retrospective cohort study conducted in Hong Kong from February to April 2022 reported a sufficient benefit of molnupiravir^[23]; however, the vaccination rate among that study population was very low, with only about 10% of participants having been fully vaccinated, which could be the reason for the discrepancy in the results of the two studies.

In our study, patients residing in long-term care facilities and those with COPD were also at higher risk of hospitalization and death. Residents in long-term care facilities are more likely to be physically fragile and may be more likely to be judged as difficult to care for, even if their illness is medically mild. However, these patients also tended to be older than the overall population, and it is possible that the risk was simply associated with age higher than 65 years. Further, even a slight change in patient status may have prompted caregivers at the facilities to request hospitalization, highlighting the need for additional studies to investigate whether hospitalization accurately reflects the worsening of COVID-19.

Several previous studies have cited COPD as a risk factor for severe COVID-19^{[29, 30]}. Given its pathogenesis, patients with COPD exhibit poor pulmonary reserve, and the infectivity and immunoreactivity of SARS-CoV-2 increase with increased ACE2 expression in the bronchial epithelial cells of patients with COPD^[24]. This study also revealed a correlation between COPD and the rate of hospitalization or death, highlighting the need to exercise caution in the management of COVID-19 in patients with COPD.

The present study had some limitations, including its single-center, retrospective study design. In addition, data related to readmission were not examined, and it is possible that patients had been readmitted or had died at other hospitals. However, in our region, our hospital almost exclusively accepts all admissions related to COVID-19, meaning that the impact of this factor was likely small. It is also possible that patients in relatively good condition did not take the drug. Lastly, although there were no obvious significant differences in risk factors for severe disease between the two groups, the possibility of unknown risk factors cannot be ruled out completely.

The current study provides real-world data on the efficacy of molnupiravir against COVID-19 in vaccinated patients during the Omicron epidemic in Japan. The study findings suggest that molnupiravir may be prescribed to select more effective patients, but since this is a retrospective study, a prospective study is planned to be conducted to further validate the study findings, in the future.

Data Availability Statement: The data sets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Acknowledgments:

We thank Chie Yamamoto., MD, from the Kyoto Prefectural University of Medicine for establishing the COVID-19 medical team system at Fukuchiyama City Hospital.

Funding: This research received no external funding.

Author Contributions:

NN and ND made substantial contributions to the conception of the work. HO, KN, YH, TH, and KO made significant contributions to the data analysis and interpretation. SI drafted the original manuscript. NN and other authors substantially contributed to the revision of the manuscript drafts. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement:

The study was conducted in accordance with the Declaration of Helsinki and approved by the Local Ethical Committee of Fukuchiyama City Hospital (Code number 4-26 and date of approval: September 28, 2022).

Informed Consent Statement:

Patient consent was waived due to the retrospective design and the ethical guidelines.

Competing Interests:

The authors declare no competing interests.

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No competing interests reported.

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Real-world data concerning the efficacy of molnupiravir in patients vaccinated against COVID-19 during the Omicron surge in Japan

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Abstract

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Introduction

Materials And Methods

Study Design and Population

Intervention Given

Statistical Analyses

Results

Patient Characteristics

NS:

Hospitalization/death

Risk Factors for Hospitalization/death

Discussion

Conclusions

Declarations

References

Additional Declarations

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