Molnupiravir's real-world effectiveness in COVID-19 outpatients at high risk of severe disease: a single-center study

Abstract

Introduction: The coronavirus disease 2019 (COVID-19) pandemic started in March 2020. Since then, there has been an urgent need for effective therapeutic methods to manage the disease. We aimed to assess the effectiveness of molnupiravir in reducing the need for hospitalization in at-risk, non-hospitalized COVID-19 patients. Methodology: This was a single-center, non-randomized, observational retrospective study of non-hospitalized patients with confirmed COVID-19, treated at the Clinic for Infectious and Tropical Diseases, University Clinical Center in Belgrade, Serbia. Results: The study was conducted between 15 December 2021 and 15 February 2022 and included 320 patients. Of these, 165 (51.6%) received treatment with molnupiravir. The study and control groups were similar in gender and age distribution. The study group had a higher proportion of vaccination (75.2% vs. 51%, p < 0.001). There was no statistically significant difference in presence of comorbidity within the groups. Majority of the patients who received molnupiravir did not require hospitalization; and this was statistically significant in comparison to control group (92.7 vs. 24.5%, p < 0.001). Oxygen supplementation was less frequently required in the study group compared to the control group (0.6% vs. 31%, p < 0.001). During the follow-up period of 12.12 ± 3.5 days, significantly less patients from the study group were admitted to the intensive care unit (p < 0.001). Molnupiravir significantly reduced the risk of hospitalization by 97.9% (HR 0.021; 95% CI 0.005-0.089; p < 0.001). Conclusions: Molnupiravir is an effective therapy in preventing the development of severe forms of COVID-19 and hospitalization.

Full text

Coronavirus Pandemic
Molnupiravir's real-world effectiveness in COVID-19 outpatients at high risk
of severe disease: a single-center study
Ivana I Gmizic1, Aleksandra Barac1,2, Nevena Todorovic1, Milos Sabanovic1, Natalija Kekic1, Nikola
Boskovic3, Ankica Vujovic1,2, Natasa Nikolic1,2, Natasa Knezevic1, Ivana Milosevic1,2, Goran Stevanovic1,2
1 Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Belgrade, Serbia
2 Faculty of Medicine, University of Belgrade, Belgrade, Serbia
3 Clinic for Cardiology, University Clinical Center of Serbia, Belgrade, Serbia
Abstract
Introduction: The coronavirus disease 2019 (COVID-19) pandemic started in March 2020. Since then, there has been an urgent need for
effective therapeutic methods to manage the disease. We aimed to assess the effectiveness of molnupiravir in reducing the need for
hospitalization in at-risk, non-hospitalized COVID-19 patients.
Methodology: This was a single-center, non-randomized, observational retrospective study of non-hospitalized patients with confirmed
COVID-19, treated at the Clinic for Infectious and Tropical Diseases, University Clinical Center in Belgrade, Serbia.
Results: The study was conducted between 15 December 2021 and 15 February 2022 and included 320 patients. Of these, 165 (51.6%) received
treatment with molnupiravir. The study and control groups were similar in gender and age distribution. The study group had a higher proportion
of vaccination (75.2% vs. 51%, p < 0.001). There was no statistically significant difference in presence of comorbidity within the groups.
Majority of the patients who received molnupiravir did not require hospitalization; and this was statistically significant in comparison to control
group (92.7 vs. 24.5%, p < 0.001). Oxygen supplementation was less frequently required in the study group compared to the control group
(0.6% vs. 31%, p < 0.001). During the follow-up period of 12.12 ± 3.5 days, significantly less patients from the study group were admitted to
the intensive care unit (p < 0.001). Molnupiravir significantly reduced the risk of hospitalization by 97.9% (HR 0.021; 95% CI 0.005-0.089; p
< 0.001).
Conclusions: Molnupiravir is an effective therapy in preventing the development of severe forms of COVID-19 and hospitalization.
Key words: molnupiravir; COVID-19; therapy; hospitalization; comorbidities.
J Infect Dev Ctries 2024; 18(5):694-700. doi:10.3855/jidc.18802
(Received 25 June 2023 – Accepted 14 September 2023)
Copyright © 2024 Gmizic et al. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction
The World Health Organization (WHO) declared
coronavirus disease 2019 (COVID-19), caused by
severe-acute-respiratory-syndrome-related-
coronavirus-2 (SARS-CoV-2), a pandemic at the
beginning of March 2020 [1]. The clinical appearance
varied from mild to severe, and led to a substantial
increase in morbidity and mortality worldwide. Many
patients, especially the elderly and those with pre-
existing illnesses (e.g., obesity, diabetes mellitus, and
major heart problems), required hospitalization, and
many died as a result of respiratory failure, shock, and
multiple organ failure [2-4]. The genetic diversity of the
virus presented an additional challenge; successive
variants differed not only in infectivity and
pathogenicity but also in antiviral medication
effectiveness. There has been an urgent need for
effective forms of therapy to reduce the global health
burden since the outbreak.
Many clinical trials have shown that treatment
should begin as soon as possible after the onset of
symptoms and that it should ideally be readily available
and easily administered by the patients themselves
[5,6]. It takes time to develop a new medicine;
therefore, researchers have focused their efforts on
repurposing existing pharmaceuticals for new
applications. Molnupiravir, an antiviral medication that
was initially studied in preclinical studies with
influenza, has risen to prominence during this time
[7,8]. Molnupiravir is a polymerase inhibitor prodrug
that acts as a synthetic nucleoside. It is orally
administered, and it is used to treat COVID-19 because
it facilitates therapy in the out-of-hospital setting [9,10].
Based on the phase two and three MOVe-OUT clinical
study in non-hospitalized patients with SARS-CoV-2
infection, the Food and Drug Administration (FDA)
approved molnupiravir for emergency use in the
treatment of mild to moderate SARS-CoV-2 illness in

Gmizic et al. – Molnupiravir's effectiveness in COVID-19 treatment J Infect Dev Ctries 2024; 18(5):694-700.
695
December 2021 [11]. This study showed that early
treatment with molnupiravir reduces the risk of
hospitalization or death in at-risk, unvaccinated adults
with COVID-19 [11].
Our study aimed to assess the real-world
effectiveness of molnupiravir in reducing the need for
hospitalization in at-risk, non-hospitalized patients with
confirmed COVID-19.
Methodology
In this single-center, non-randomized,
observational retrospective study, we included data
from the electronic medical database Heliant for non-
hospitalized patients treated at the Clinic for Infectious
and Tropical Diseases, University Clinical Center in
Belgrade, Serbia [12]. We included patients treated
between 15 December 2021, and 15 February 2022,
which is considered the period of dominance of the
Omicron SARS-CoV-2 variant in Serbia. The decision
about the treatment regimen was taken entirely by the
treating physician, concerning current knowledge and
recommendations of the National Protocol of Serbia for
COVID-19 [13]. All the patients were diagnosed with
COVID-19 based on positive results of the real-time
reverse transcriptase polymerase chain reaction (RT-
PCR) or an antigen test from the nasopharyngeal swab
specimen. All the patients were non-hospitalized adults
aged ≥ 18 years, with mild or moderate COVID-19, and
with associated risk factors for the development of
severe illness from COVID-19 (age > 60 years; active
cancer; chronic kidney disease; chronic obstructive
pulmonary disease; obesity, defined by a body mass
index (weight in kilograms divided by square of the
height in meters) of 30; serious heart conditions [heart
failure, coronary artery disease, or cardiomyopathies];
or diabetes mellitus). Mild or moderate illness was
determined on the basis of definitions adapted based on
WHO guidance [1]. According to the National Protocol
of Serbia for COVID-19, molnupiravir may be used for
the treatment of mild-to-moderate COVID-19 in people
18 years of age or older, who are at risk for progression
to severe COVID-19, including hospitalization or
death, and for whom other COVID-19 treatment
options are not available [13]. Our study group included
patients who started molnupiravir in the first 5 days
after the onset of symptoms. Molnupiravir was
administered orally twice daily at 800 mg for 5 days
according to the National Protocol of Serbia for
COVID-19 [13]. The control group included patients
who did not take molnupiravir due to multiple reasons:
the medicine was not available, they refused to take it,
or they were diagnosed after the 5th day of their
symptoms. Patients for the control group were collected
simultaneously and in such a way that they
corresponded to the clinical criteria for the use of
molnupiravir and they had a similar distribution in
terms of gender and age. Age, gender, symptoms with
duration, risk factors (old age, active malignancy,
chronic kidney disease (CKD), chronic obstructive
pulmonary disease (COPD), obesity, a heart condition,
diabetes mellitus, autoimmune disease), use of other
non-antiviral medications against COVID-19,
vaccination status reported by patients, and time since
the last vaccination were all included in the baseline
data. We included laboratory measurements taken
during the first and last examinations, including C-
reactive protein (CRP), white blood cells (WBC),
platelets, d-dimer, aspartate transaminase (AST), and
alanine transaminase (ALT). The primary effectiveness
end point was the incidence of hospitalization for any
cause (defined as 24 hours of acute care in a hospital or
any similar facility). Patients were followed-up for 25
days or until the day of hospitalization. Moreover, the
final outcome was analyzed using ordinal scale
categories as follows: 0) unhospitalized; 1)
hospitalized, requiring no oxygen supplementation but
requiring medical care; 2) hospitalized, requiring
oxygen supplementation via simple face mask; 3)
hospitalized, on non-invasive ventilation with high-
flow oxygen equipment; 4) hospitalized, on invasive
mechanical ventilation.
Statistical analysis
Continuous variables with normal distribution of
the data were presented as mean value ± standard
deviation, while continuous heterogeneous variables
were presented as median value (interquartile range
25th–75th percentile). The normal distribution of the data
was checked using Kolmogorov-Smirnov and Shapiro-
Wilk tests. Categorical variables were presented as the
frequencies (percentage). Intergroup differences for
continuous variables, were tested using two-sided t test
if the distribution of the data was normal and Mann-
Whitney’s test if it wasn’t, and the χ2 or Fisher exact test
was used to compare the distribution of categorical
variables among groups. Univariate Cox regression
model was used to identify the candidate predictors of
hospitalization due to COVID-19. All the univariate
predictors with statistical significance of p < 0.05 were
included in the multivariate Cox regression analysis to
identify independent predictors. A p value of < 0.05
defined statistical significance. The statistical analyses
were performed using the IBM SPSS software v21.

Gmizic et al. – Molnupiravir's effectiveness in COVID-19 treatment J Infect Dev Ctries 2024; 18(5):694-700.
696
Results
Our study group included 165 patients and the
control group included 155 patients. Demographic and
clinical characteristics with laboratory results of all the
patients are summarized in Table 1. The study groups
were similar in terms of gender and age. Most patients
in both groups were aged over 60 years (62.4% in study
group vs. 69.7% in control group). The study group had
statistically significant more patients with heart
diseases and active malignancy, while the control group
had more chronic kidney patients and asthmatics. The
vaccination status differed significantly between the
Table 1. Demographic and clinical characteristics of study and control group.
Gender
Patients on molnupiravir
(N = 165, 51.6%)
Control group
(N = 155, 48.4%)
p value
Male
80 (48.5%)
79 (51%)
0.657
Female
85 (51.5%)
76 (49%)
Age (years)
64 ± 13
66 ± 16
0.297
Age ≥ 60 years
103 (62.4%)
108 (69.7%)
0.171
Risk factors
Old age
100 (60.6%)
118 (76.1%)
< 0.001
Active malignancy
14 (8.5%)
2 (1.3%)
0.003
CKD
10 (0.6%)
60 (38.7%)
< 0.001
COPD
11 (6.7%)
6 (3.9%)
0.265
Obesity
0
1 (0.6%)
0.484
Heart condition
102 (61.8%)
21 (13.5%)
< 0.001
Obesity
0
1 (0.6%)
0.484
Diabetes
19 (11.5%)
21 (13.5%)
0.877
Autoimmune disease
7 (4.2%)
3 (1.9%)
0.236
Asthma
0
12 (7.7%)
< 0.001
Hypothyroidism
7 (4.2%)
14 (9%)
0.084
More than 1 risk factor
108 (65.5%)
101 (65.2%)
0.956
Duration of the symptoms (days) before 1st examination
2.8 ± 1.2
6.6 ± 3.4
< 0.001
Follow-up period (Min-Max)
12.12 ± 3.5 days (5-25)
4.59 ± 5.8 (0–25)
< 0.001
Vaccination
Number of patients
124 (75.2%)
79 (51%)
<0.001
Number of doses of the vaccine
median 3 (1.5–3)
median 0.5 (0–3)
< 0.001
Vaccine type
None
45 (27.3%)
76 (49%)
< 0.001
Pfizer
28 (17%)
6 (3.9%)
< 0.001
Sputnik V
26 (15.8%)
9 (5.8%)
0.004
Sinopharm
55 (33.3%)
51 (32.9%)
0.935
Other
1 (0.6%)
4 (2.6%)
0.202
Unknown
10 (6.1%)
9 (5.8%)
0.923
Non-antiviral medication before 1st examination
Symptomatic
137 (83%)
63 (40.6%)
< 0.001
Antibiotic
15 (9.1%)
87 (56.1%)
< 0.001
Corticosteroids
7 (4.2%)
2 (1.3%)
0.175
CT
2 (1.2%)
0
0.499
Nolvadex
4 (2.4%)
0
0.123
Corticosteroids
7 (4.2%)
2 (1.3%)
0.175
Symptoms
Cough
108 (65.5%)
124 (80%)
0.004
Sore throat
48 (29.1%)
0
< 0.001
Stuffy nose
19 (11.5%)
3 (1.9%)
0.001
Runny nose
33 (20.1%)
10 (6.5%)
< 0.001
Dyspnea
10 (6.1%)
59 (38.1%)
< 0.001
Muscle pain
37 (22.4%)
51 (32.9%)
0.036
Fatigue
105 (63.6%)
114 (73.5%)
0.057
High fever
137 (83%)
135 (87.1%)
0.309
Headache
36 (21.8%)
14 (9%)
0.002
Nausea
14 (8.5%)
25 (16.1%)
0.037
Vomiting
8 (4.8%)
12 (7.7%)
0.285
Diarrhea
8 (4.8%)
17 (11%)
0.042
Loss of the sense of taste
0
7 (4.5%)
0.006
Anosmia
0
7 (4.5%)
0.006
Laboratory results
WBC at first examination (x 109)
median 6 (5.2–7.4)
median 5.85 (4.15–8.05)
0.074
WBC on the last examination (x 109)
7 ± 2.1
8.2 ± 3.7
0.006
Platelets at first examination (x 109)
median 206 (173–245)
median 212.5 (168–289)
0.930
Platelets on the last examination (x 109)
249.3 ± 72.8
269 ± 124.3
0.209
CRP at first examination (mg/L)
median 13 (4.5–23.8)
median 34.4 (8.9–60.4)
< 0.001
CRP on the last examination (mg/L)
median 3.4 (1.1–12.7)
median 9.1 (2.5–53.6)
< 0.001
D-dimer at first examination (mg/L)
median 0.48 (0.34–0.84)
median 0.6 (0.4–1.1)
< 0.001
D-dimer on the last examination (mg/L)
median 0.48 (0.3–0.82)
median 0.59 (0.34–0.91)
0.183
AST at first examination (U/L)
median 23 (19–31)
median 25 (21–40)
0.001
AST on the last examination (U/L)
median 22 )16–28)
median 26 (19–35)
0.023
ALT at first examination (U/L)
median 33 (24–42)
median 32 (21–41)
0.450
ALT on the last examination (U/L)
median 32 (25–44)
median 38 (27–62)
0.496
Pneumonia
23 (13.9%)
116 (74.8%)
< 0.001
ALT: alanine aminotransferase; AST: aspartate aminotransferase; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CRP: C reactive
protein; CT: chemotherapy; WBC: white blood cell.

Gmizic et al. – Molnupiravir's effectiveness in COVID-19 treatment J Infect Dev Ctries 2024; 18(5):694-700.
697
groups; 75.2% patients in study group were fully
vaccinated and 51% patients in control group were
vaccinated. Among those who were vaccinated, in the
study group, most of the patients received three doses
of vaccine while in the control group most of the
patients received one dose. The prevalence of
symptoms was similar between groups, but the majority
of patients in the control group complained of coughing
(80%) and dyspnea (38%), whereas in the study group
65.5% complained of coughing and 6.1% of dyspnea.
The duration of COVID-19 symptoms before their first
examination was longer in the control group (6.6 days)
compared to study group (2.8 days). During the follow-
up period, the control group had a higher frequency of
radiographically confirmed pneumonia (78.4%) than
the study group (13.9%). Regarding laboratory
analysis, there was a significant difference in WBC,
CRP, and AST values among groups, including
measurements at the first examination compared to the
last ones. In the study group, 92.7% of patients did not
require hospitalization, whereas 24.5% of patients in
the control group did not require hospitalization. The
majority of the patients in the control group (75.5%)
needed hospitalization. During the 12.1 ± 3.5-day
follow-up period, none of the study group patients were
admitted to the intensive care unit, while 10.3% of the
control group patients required this type of treatment
(Table 2). In multivariate analysis molnupiravir was
one of the independent predictors of hospitalization and
reduced the possibility of hospitalization by 97.9%,
while age and CRP were also independent predictors of
hospitalization. An increase of one year in age,
increased the possibility of hospitalization by 3.2%. An
increase of CRP level by one unit, increased the
possibility of hospitalization by 0.4% (Table 3).
Discussion
Our study used real-world data to demonstrate the
effectiveness of molnupiravir against SARS-CoV-2 in
outpatients who are at high risk of disease progression,
in a single-center study. The analysis included 320 adult
non-hospitalized patients who were being treated for
COVID-19. Our results showed that molnupiravir
reduced the risk of hospitalization (HR 0.021, 95% CI
0.005–0.089). Numerous studies on the effectiveness of
molnupiravir have shown differences from our research
results; while some favored its use, others did not show
greater significance. Previous real-world effectiveness
studies showed that molnupiravir use was associated
with a lower risk of hospitalization in treated patients
compared to non-recipients, including studies by Evans
et al. (HR 0.49), Paraskevis et al. (OR 0.40), and Wai
et al. (OR 0.72) [14–16]. In a study conducted among
US veterans aged 65 years and older, molnupiravir was
associated with a lower 30-day risk of hospitalization or
death (RR 0.67, 95% CI 0.46–0.99), but the overall
result between treated and untreated patients was
similar [17]. The meta-analysis by Huang et al., which
included six studies involving 89,480 patients (22,355
of whom received molnupiravir therapy and 67,125
received placebo therapy), indicated that the risk of
mortality was reduced by 34% and the risk of the
composite outcome of disease progression was reduced
by 37% among patients who received molnupiravir
[18]. On the other hand, Wong et al. reported that
molnupiravir recipients in Hong Kong had a
significantly lower risk of all-cause mortality than non-
recipients (HR 0.76, 95% CI 0.61–0.95; p = 0013), but
the risk of hospitalization was comparable to the control
group (0.98 [CI 0.89-1.06]; p = 058) [19]. In another
study by Yip et al. molnupiravir usage showed no
statistically significant difference in reducing the risk
for hospitalization versus the non-users [20]. In
addition, the recently published 25,000 participant
prospective, open-label study, PANORAMIC trial,
found only a 1% risk of all-cause hospitalization, and
concluded that molnupiravir did not reduce the
frequency of COVID-19-associated hospitalizations or
death among adults over 50 years of age or adults over
18 years with other risk factors, in the community [21].
Table 2. Assessment of clinical worsening in the study and control group.
Patients on molnupiravir
(N = 165, 51.6%)
Control group
(N = 155, 48.4%)
p value
Clinical worsening
No worsening
153 (92.7%)
38 (24.5%)
< 0.001
General care without oxygen supplementation
10 (6.1%)
38 (24.5%)
< 0.001
General care with oxygen supplementation
1 (0.6%)
48 (31%)
< 0.001
Semi-intensive care unit
1 (0.6%)
15 (9.7%)
< 0.001
Intensive care unit
0
16 (10.3%)
< 0.001
Follow-up in days (min–max)
8.92 ± 3.55 (5–15)
2.83 ± 4.95 (0–25)
< 0.001
Reason for clinical worsening
None
153 (92.7%)
38 (24.5%)
< 0.001
COVID-19
12 (7.3%)
109 (70.3%)
< 0.001
Chronic illness
0
8 (5.2%)
0.003

Gmizic et al. – Molnupiravir's effectiveness in COVID-19 treatment J Infect Dev Ctries 2024; 18(5):694-700.
698
In our study, considering that the groups were very
similar in terms of demographic data, and the sole
notable difference was in the number of vaccinated
individuals, there was a reason to suspect that
vaccination had an impact on the more favorable course
of the disease of those who were treated. However, that
doubt is dispelled by the fact that the Omicron variant
diverged immunologically from the earlier variants on
the basis of which the vaccine was developed and with
which patients may have previously come into contact
[22,23]. We believe that prior immune status could not
have had a significant impact on the efficacy of an
antiviral drug devoid of immunomodulatory activity.
Our patients taking molnupiravir had a milder clinical
course of disease and a lower frequency of pneumonia,
but they were examined earlier and started therapy on
Table 3. Univariate and multivariate Cox regression analysis of risk factors for hospitalisation in COVID-19 non-hospitalised patients.
Univariate analysis
Multivariate analysis
B p value HR
95% CI
p value HR
95% CI
lower
upper
lower
upper
Gender: Male
-0.244
0.167
0.783
0.553–1.108
Age (years)
0.023
0.001
1.023
1.010–1.037
0.022
1.032
1.005–1.059
Age > 60 years
0.537
0.008
1.711
1.147–2.553
0.665
1.225
0.489–3.067
Duration of the symptoms (days)
0.175
< 0.001
1.191
1.144–1.241
0.118
1.063
0.985–1.148
Risk factors
Without
/
/
/
/
Old age
1.609
< 0.001
4.996
3.387–7.369
0.137
0.504
0.205–1.243
Active malignancy
-0.957
0.102
0.384
0.122–1.207
CKD
0.263
0.794
1.301
0.182–9.315
COPD
-0.748
0.143
0.473
0.174–1.286
Obesity
-3.005
0.734
0.050
/
Heart condition
-1.767
< 0.001
0.171
0.096–0.304
0.674
1.328
0.354–4.981
Diabetes
0.139
0.615
1.149
0.669–1.971
Autoimmune disease
-1.499
0.136
0.223
0.031–1.599
More than 1 risk factor
0.110
0.560
1.116
0.772–1.613
Vaccinated patients
-0.764
< 0.001
0.466
0.329–0.659
0.461
1.821
0.370–8.954
Time from the vaccination to the
symptoms onset (days)
-0.136 0.001 0.873 0.804–0.949 0.240 0.894 0.742–1.078
Number of vaccine doses
-0.309
< 0.001
0.734
0.646–0.833
0.579
0.854
0.489–1.491
Vaccine type
None
0.725
< 0.001
2.065
1.460-2.919
Pfizer
-1.696
0.001
0.183
0.067–0.505
0.598
0.709
0.197–2.550
Sputnik V
-0.561
0.105
0.571
0.289–1.125
Sinopharm
-0.106
0.579
0.900
0.619–1.308
Other
0.193
0.787
1.213
0.299–4.913
Unknown
0.007
0.987
1.007
0.470–2.158
Non-antiviral medication before 1st examination
Symptomatic
-0.888
< 0.001
0.411
0.290–0.584
0.405
0.503
0.100–2.536
Antibiotic
0.998
< 0.001
2.712
1.912–3.847
0.245
0.384
0.077–1.926
Corticosteroids
-0.340
0.561
0.712
0.226–2.240
CT
-3.016
0.495
0.049
/
Nolvadex
-3.031
0.325
0.048
/
Cough
1.218
< 0.001
3.382
1.941–5.892
0.311
1.496
0.686–3.262
Sore throat
-2.071
< 0.001
0.067
0.017–0.727
0.945
/
/
Stuffy nose
-1.324
0.024
0.266
0.085–0.937
0.241
3.607
0.423–30.766
Runny nose
-1.305
0.002
0.271
0.119–0.616
0.813
0.833
0.184–3.775
Dyspnea
1.431
< 0.001
4.183
2.920–5.992
0.699
1.121
0.629–1.997
Muscle pain
0.137
0.478
1.147
0.785–1.676
Fatigue
0.493
0.017
1.637
1.093–2.454
0.744
0.900
0.479–1.692
High fever
0.704
0.025
2.023
1.090–3.753
0.544
1.347
0.515–3.524
Headache
-0.468
0.089
0626
0.365–1.073
Nausea
0.523
0.026
1.687
1.065–2.674
0.596
1.196
0.617–2.319
Vomiting
0.123
0.724
1.130
0.573–2.231
Diarrhea
0.366
0.212
1.441
0.812–2.559
Loss of the sense of taste
0.099
0.868
1.104
0.345–3.531
Anosmia
0.096
0.872
1.101
0.344–3.520
Pneumonia
-0.281
0.010
0.755
0.611–0.934
0.106
1.703
0.893–3.250
WBC at first examination (× 109)
0.052
0.001
1.053
1.022–1.085
0.884
1.003
0.960–1.048
WBC on the last examination (× 109)
0.139
< 0.001
1.149
1.066–1.238
Platelets at first examination (× 109)
0
0.779
1.00
0.998–1.003
Platelets on the last examination (× 109)
-0.001
0.591
0.999
0.996–1.002
CRP at first examination (mg/L)
0.009
< 0.001
1.009
1.007–1.011
0.029
1.004
1.000–1.007
CRP on the last examination (mg/L)
0.012
< 0.001
1.012
1.010–1.015
D-dimer at first examination (mg/L)
0.076
0.001
1.079
1.033–1.126
0.708
0.985
0.909–1.067
D-dimer on the last examination (mg/L)
0.021
0.006
1.021
1.006–1.036
AST at first examination (U/L)
0.014
< 0.001
1.014
1.008–1.020
0.252
1.007
0.995–1.020
AST on the last examination (U/L)
0.018
< 0.001
1.018
1.012–1.024
ALT at first examination (U/L)
0.007
0.028
1.007
1.001–1.13
0.953
1.000
0.989–1.012
ALT on the last examination (U/L)
0.005
0.119
1.005
0.999–1.012
Molnupiravir
-3.127
< 0.001
0.044
0.024–0.081
< 0.001
0.021
0.005–0.089
ALT: alanine aminotransferase; AST: aspartate aminotransferase; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CRP: C reactive
protein; CT: chemotherapy; WBC: white blood cell.

Gmizic et al. – Molnupiravir's effectiveness in COVID-19 treatment J Infect Dev Ctries 2024; 18(5):694-700.
699
time. Based on data on follow-up time until
hospitalization, regardless of the favorable course of
most treated patients, they should be followed for at
least 15 days after starting treatment, and those who are
not receiving therapy should be followed for up to 25
days.
Our study had some inherent limitations due to its
real-world and single-center observational nature,
which might lead to bias. The main limitation of our
study was the short duration of treatment as well as the
small sample size. This limitation was overcome by the
fact that the groups of patients proved to be similar in
terms of gender and age, and this result came about by
chance, without an a priori desire for matching. Our
data provide significant support for expanding the base,
and a multicenter, national study is being planned.
Another potential limitation was the lack of data on
viral subvariants.
Conclusions
The results of our study showed that, the use of
molnupiravir further reduced the risk for
hospitalization, with the effect being more pronounced
in highly vulnerable populations. Thus, its use in high-
risk populations is strongly indicated to reduce the
burden of disease and unfavorable outcomes.
Authors’ contributions
Conceptualization, GI, TN, SM, KN; methodology, GI, SG;
validation, AB, SG; formal analysis, GI; investigation, GI,
TN, SM, KN; resources, GI, TN, SM, KN; data curation, IG,
BA, SG; writing—original draft preparation, GI, TN, SM,
KN, VA, NN, MI; writing—review and editing, GI, BA, SG;
visualization, GI; supervision, SG; project administration,
GI. All authors have read and agreed to the published version
of the manuscript.
References
1. WHO (nd) Coronavirus (COVID-19) dashboard. Available:
https://covid19.who.int/. Accessed: 25 June 25, 2023.
2. Ko JY, Danielson ML, Town M, Derado G, Greenlund KJ,
Kirley PD, Alden NB, Yousey-Hindes K, Anderson EJ, Ryan
PA, Kim S, Lynfield R, Torres SM, Barney GR, Bennett NM,
Sutton M, Talbot HK, Hill M, Hall AJ, Fry AM, Garg S, Kim
L, COVID-NET Surveillance Team (2021). Risk factors for
coronavirus disease 2019 (COVID-19)-associated
hospitalization: COVID-19-associated hospitalization
surveillance network and behavioral risk factor surveillance
system. Clin Infect Dis 72: e695-e703. doi:
10.1093/cid/ciaa1419.
3. Stokes EK, Zambrano LD, Anderson KN, Marder EP, Raz
KM, El Burai Felix S, Tie Y, Fullerton KE (2020) Coronavirus
disease 2019 case surveillance-United States, January 22-May
30, 2020. Morb Mortal Wkly Rep MMWR 69: 759-765. doi:
10.15585/mmwr.mm6924e2.
4. Kompaniyets L, Goodman AB, Belay B, Freedman DS,
Sucosky MS, Lange SJ, Gundlapalli AV, Boehmer TK, Blanck
H (2021) Body mass index and risk for COVID-19-related
hospitalization, intensive care unit admission, invasive
mechanical ventilation, and death-United States, March-
December 2020. Morb Mortal Wkly Rep MMWR 70: 355-361.
doi: 10.15585/mmwr.mm7010e4.
5. Arribas JR, Bhagani S, Lobo SM, Khaertynova I, Mateu L,
Fishchuk R, Park WY, Hussein K, Kim SW, Ghosn J, Brown
ML, Zhang Y, Gao W, Assaid C, Grobler JA, Strizki J,
Vesnesky M, Paschke A, Butterton JR, De Anda C (2022)
Randomized trial of molnupiravir or placebo in patients
hospitalized with COVID-19. NEJM Evid 1: EVIDoa2100044.
doi: 10.1056/EVIDoa2100044.
6. Cohen MS, Wohl DA, Fischer WA, Smith DM, Eron JJ (2021)
Outpatient treatment of severe acute respiratory syndrome
coronavirus 2 infection to prevent coronavirus disease 2019
progression. Clin Infect Dis 73: 1717-1721. doi:
10.1093/cid/ciab494.
7. Painter GR, Natchus MG, Cohen O, Holman W, Painter WP
(2021) Developing a direct acting, orally available antiviral
agent in a pandemic: the evolution of molnupiravir as a
potential treatment for COVID-19. Curr Opin Virol 50: 17-22.
doi: 10.1016/j.coviro.2021.06.003.
8. Sinha S, Kumarasamy N, Suram VK, Chary SS, Naik S, Singh
VB, Jain MK, Suthar CP, Borthakur S, Sawardekar V, Sk N,
Reddy N, Talluri L, Thakur P, Reddy M, Panapakam M,
Vattipalli R (2022). Efficacy and safety of molnupiravir in mild
COVID-19 patients in India. Cureus 14: e31508. doi:
10.7759/cureus.31508.
9. Abdelnabi R, Foo CS, De Jonghe S, Maes P, Weynand B,
Neyts J (2021) Molnupiravir inhibits replication of the
emerging SARS-CoV-2 variants of concern in a hamster
infection model. J Infect Dis 224: 749-753. doi:
10.1093/infdis/jiab361.
10. Gordon CJ, Tchesnokov EP, Schinazi RF, Götte M (2021)
Molnupiravir promotes SARS-CoV-2 mutagenesis via the
RNA template. J Biol Chem 297: 100770. doi:
10.1016/j.jbc.2021.100770.
11. Jayk Bernal A, Gomes Da Silva MM, Musungaie DB,
Kovalchuk E, Gonzalez A, Delos Reyes V, Martín-Quirós A,
Caraco Y, Williams-Diaz A, Brown ML, Du J, Pedley A,
Assaid C, Strizki J, Grobler JA, Shamsuddin HH, Tipping R,
Wan H, Paschke A, Butterton JR, Johnson MG, De Anda C,
MOVe-OUT Study Group (2022) Molnupiravir for oral
treatment of COVID-19 in nonhospitalized patients. N Engl J
Med 386: 509-520. doi: 10.1056/NEJMoa2116044.
12. Heliant Health (2021) Healthcare information system.
Available: https://heliant.rs/our-products/health/?lang=en.
Accessed: 25 June 25, 2023.
13. Pelemis M, Stevanovic G, Turkulov V, Vucinic V, Matijasevic
J, Milosevic B, Milosevic I, Gajovic O, Ladjevic N, Vrbic M,
Barac B, Udovicic I, Jankovic R, Mikic D, Antic D, Mujovic
N, Djordjevic M, Korac M, Ranin J, Bukarica Lj, Dragovic G
(2022) National protocol of the Republic of Serbia for the
treatment of COVID-19 infection, Version 13. IOPHOS -
Batut: Home. Org.Rs. Available:
https://batut.org.rs/index.php?lang=2. Accessed: 12 September
2023. [Article in Serbian].
14. Evans A, Qi C, Adebayo JO, Underwood J, Coulson J, Bailey
R, Lyons R, Edwards A, Cooper A, John G, Akbari A (2023)

Gmizic et al. – Molnupiravir's effectiveness in COVID-19 treatment J Infect Dev Ctries 2024; 18(5):694-700.
700
Real-world effectiveness of molnupiravir, nirmatrelvir-
ritonavir, and sotrovimab on preventing hospital admission
among higher-risk patients with COVID-19 in Wales: a
retrospective cohort study. J Infect 86: 352-360. doi:
10.1016/j.jinf.2023.02.012.
15. Paraskevis D, Gkova M, Mellou K, Gerolymatos G, Psalida P,
Gkolfinopoulou K, Kostaki EG, Loukides S, Kotanidou A,
Skoutelis A, Thiraios E, Saroglou G, Zografopoulos D,
Mossialos E, Zaoutis T, Gaga M, Tsiodras S, Antoniadou A
(2023) Real-world effectiveness of molnupiravir and
nirmatrelvir/ritonavir as treatment for COVID-19 in patients at
high risk. J Infect Dis 228: 1667-1674. doi:
10.1093/infdis/jiad324.
16. Wai AK-C, Chan CY, Cheung AW-L, Wang K, Chan SC-L,
Lee TT-L, Luk LY-F, Yip ET-F, Ho JW-K, Tsui OW-K,
Cheung KW-Y, Lee S, Tong C, Yamamoto T, Rainer TH,
Wong EL-Y (2023) Association of molnupiravir and
nirmatrelvir-ritonavir with preventable mortality, hospital
admissions and related avoidable healthcare system cost
among high-risk patients with mild to moderate COVID-19.
Lancet Reg Health West Pac 30: 100602. doi:
10.1016/j.lanwpc.2022.100602.
17. Bajema KL, Berry K, Streja E, Rajeevan N, Li Y, Yan L,
Cunningham F, Hynes DM, Rowneki M, Bohnert A, Boyko EJ,
Iwashyna TJ, Maciejewski ML, Osborne TF, Viglianti EM,
Aslan M, Huang GD, Ioannou GN (2023) Effectiveness of
COVID-19 treatment with nirmatrelvir-ritonavir or
molnupiravir among US veterans: target trial emulation studies
with one-month and six-month outcomes. Ann Intern Med 176:
807-816. doi: 10.7326/M22-3565.
18. Huang C, Lu T-L, Lin L (2023) Real-world clinical outcomes
of molnupiravir for the treatment of mild to moderate COVID-
19 in adult patients during the dominance of the Omicron
variant: a meta-analysis. Antibiotics 12: 393. doi:
10.3390/antibiotics12020393.
19. Wong CKH, Au ICH, Lau KTK, Lau EHY, Cowling BJ, Leung
GM (2022). Real-world effectiveness of molnupiravir and
nirmatrelvir plus ritonavir against mortality, hospitalisation,
and in-hospital outcomes among community-dwelling,
ambulatory patients with confirmed SARS-CoV-2 infection
during the omicron wave in Hong Kong: an observational
study. Lancet 400: 1213-1222. doi: 10.1016/S0140-
6736(22)01586-0.
20. Yip TC-F, Lui GC-Y, Lai MS-M, Wong VW-S, Tse Y-K, Ma
BH-M, Hui E, Leung MKW, Chan HL-Y, Hui DS-C, Wong
GL-H (2023) Impact of the use of oral antiviral agents on the
risk of hospitalization in community coronavirus disease 2019
patients (COVID-19). Clin Infect Dis 76: e26-e33. doi:
10.1093/cid/ciac687.
21. Butler CC, Hobbs FDR, Gbinigie OA, Rahman NM, Hayward
G, Richards DB, Dorward J, Lowe DM, Standing JF, Breuer J,
Khoo S, Petrou S, Hood K, Nguyen-Van-Tam JS, Patel MG,
Saville BR, Marion J, Ogburn E, Allen J, Rutter H, Francis N,
Thomas NPB, Evans P, Dobson M, Madden TA, Holmes J,
Harris V, Png ME, Lown M, van Hecke O, Detry MA,
Saunders CT, Fitzgerald M, Berry NS, Mwandigha L, Galal U,
Mort S, Jani BD, Hart ND, Ahmed H, Butler D, McKenna M,
Chalk J, Lavallee L, Hadley E, Cureton L, Benysek M,
Andersson M, Coates M, Barrett S, Bateman C, Davies JC,
Raymundo-Wood I, Ustianowski A, Carson-Stevens A, Yu
LM, Little P (2023) Molnupiravir plus usual care versus usual
care alone as early treatment for adults with COVID-19 at
increased risk of adverse outcomes (PANORAMIC): an open-
label, platform-adaptive randomised controlled trial. Lancet
401: 281-293. doi: 10.1016/S0140-6736(22)02597-1.
22. Flisiak R, Zarębska-Michaluk D, Rogalska M, Kryńska JA,
Kowalska J, Dutkiewicz E, Dobrowolska K, Jaroszewicz J,
Moniuszko-Malinowska A, Rorat M, Podlasin R, Tronina O,
Rzymski P (2022) Real-world experience with molnupiravir
during the period of SARS-CoV-2 Omicron variant
dominance. Pharmacol Rep 74: 1279-1285. doi:
10.1007/s43440-022-00408-6.
23. De Gier B, Huiberts AJ, Hoeve CE, Den Hartog G, Van
Werkhoven H, Van Binnendijk R, Hahné SJM, De Melker HE,
Van Den Hof S, Knol MJ (2023) Effects of COVID-19
vaccination and previous infection on Omicron SARS-CoV-2
infection and relation with serology. Nat Commun 14: 4793.
doi: 10.1038/s41467-023-40195-z.
Corresponding author
Ivana Gmizic, MD, ID Specialist.
Bulevar Oslobodjenja 16,
11000 Belgrade, Serbia.
Tel: +381621296982
Fax: +381112684272
Email: gmizic_ivana@yahoo.com
Conflict of interests: No conflict of interests is declared.