Clinical Outcome and 7-Day Virological Clearance in High-Risk Patients with Mild-Moderate COVID-19 Treated with Molnupiravir, Nirmatrelvir/Ritonavir, or Remdesivir

Abstract

Introduction: We compared the effectiveness and virological clearance (VC) at day 7 (T7) post-treatment with molnupiravir, nirmatrelvir/ritonavir, and remdesivir in SARS-CoV-2-infected patients at high risk (HR) for clinical progression.
Methods: We conducted a retrospective study enrolling HR patients with mild-to-moderate COVID-19 (Jan–Oct 2022) treated with nirmatrelvir/ritonavir or molnupiravir or 3 days of remdesivir. We investigated clinical recovery at T7 (resolution of symptoms for ≥ 72 h or all-cause death), VC at T7 (PCR/antigenic negative nasopharyngeal swab), and median time to VC (days from symptom onset to the first negative swab). Factors associated with VC were investigated by logistic regression.
Results: In the study, 92/376 (43.8%) patients received molnupiravir, 150/376 (24.7%) nirmatrelvir/ritonavir, and 134/376 (31.5%) remdesivir. Forty-nine (13%) patients were unvaccinated or incompletely vaccinated. Patients treated with nirmatrelvir/ritonavir were younger and presented immunodeficiencies more frequently; remdesivir was used more commonly in patients hospitalized for other diseases. A high proportion of patients obtained clinical recovery without differences among the therapies (97.5% for molnupiravir, 98.3% for nirmatrelvir/ritonavir, and 93.6% for remdesivir); 12 (3.7%) patients died. Nirmatrelvir/ritonavir was associated with a higher proportion of T7 VC and a shorter time to VC compared to molnupiravir/remdesivir, also after adjustment for age and immunodeficiency (AOR 0.445 RDV vs. NMV-r, 95% CI 0.240–0.826, p = 0.010; AOR 0.222 MNP vs. NMV-r, 95% CI 0.105–0.472, p < 0.001).
Conclusions: SARS-COV-2 antiviral treatments are an excellent therapeutic strategy in HR patients. Nirmatrelvir/ritonavir showed a higher proportion of VC as early as 7 days after treatment, confirming its likely superiority in indirect comparisons.

Full text

Vol.:(0123456789)
Infect Dis Ther
https://doi.org/10.1007/s40121-024-00994-3
ORIGINAL RESEARCH
Clinical Outcome and7‑Day Virological Clearance
inHigh‑Risk Patients withMild–Moderate COVID‑19
Treated withMolnupiravir, Nirmatrelvir/Ritonavir,
orRemdesivir
FrancescaBai · TomasoBeringheli· VirginiaVitaletti· AndreaSantoro· FrancescoMolà· AlessandroCopes·
NicoleGemignani· SoaPettenuzzo· RobertoCastoldi· BenedettaVarisco· RiccardoNardo·
LorenzoBrandoLundgren· RiccardoLigresti· MatteoSala· LorenzoAlbertini· MatteoAugello·
LorenzoBiasioli· ValeriaBono· RobertaRovito· TeresaBini· SabrinaPassarella· NicolaVincenzoOrfeo·
Antonellad’ArminioMonforte· GiuliaMarchetti
Received: April 4, 2024 / Accepted: May 13, 2024
© The Author(s) 2024
ABSTRACT
Introduction: We compared the effectiveness
and virological clearance (VC) at day 7 (T7)
post-treatment with molnupiravir, nirmatrel-
vir/ritonavir, and remdesivir in SARS-CoV-
2-infected patients at high risk(HR) for clinical
progression.
Methods: We conducted a retrospective study
enrolling HR patients with mild-to-moderate
COVID-19 (Jan–Oct 2022) treated with nir-
matrelvir/ritonavir or molnupiravir or 3days
of remdesivir. We investigated clinical recov-
ery at T7 (resolution of symptoms for ≥ 72h
or all-cause death), VC at T7 (PCR/antigenic
negative nasopharyngeal swab), and median
time to VC (days from symptom onset to the
first negative swab). Factors associated with
VC were investigated by logistic regression.
Results: In the study, 92/376 (43.8%)
patients received molnupiravir, 150/376
(24.7%) nirmatrelvir/ritonavir, and 134/376
(31.5%) remdesivir. Forty-nine (13%) patients
were unvaccinated or incompletely vacci-
nated. Patients treated with nirmatrelvir/
ritonavir were younger and presented immu-
nodeficiencies more frequently; remdesivir
was used more commonly in patients hospi-
talized for other diseases. A high proportion
of patients obtained clinical recovery without
differences among the therapies (97.5% for
molnupiravir, 98.3% for nirmatrelvir/rito-
navir, and 93.6% for remdesivir); 12 (3.7%)
patients died. Nirmatrelvir/ritonavir was asso-
ciated with a higher proportion of T7 VC and
a shorter time to VC compared to molnupira-
vir/remdesivir, also after adjustment for age
Prior Presentation: Preliminary results were presented at
the HIV Drug Therapy Glasgow Conference, 23rd–26th
October, 2022.
Supplementary Information The online version
contains supplementary material available at
https:// doi. org/ 10. 1007/ s40121- 024- 00994-3.
F.Bai(*)· T.Beringheli· V.Vitaletti· A.Santoro·
F.Molà· A.Copes· N.Gemignani· S.Pettenuzzo·
R.Castoldi· B.Varisco· R.Nardo· L.B.Lundgren·
R.Ligresti· M.Sala· L.Albertini· M.Augello·
L.Biasioli· V.Bono· R.Rovito· T.Bini·
A.d.Monforte· G.Marchetti
Clinic ofInfectious Diseases, Department ofHealth
Sciences, San Paolo Hospital, ASST Santi Paolo e
Carlo, University ofMilan, Via A. Di Rudinì, 8,
20142Milan, Italy
e-mail: francesca.bai@asst-santipaolocarlo.it
S.Passarella· N.V.Orfeo
Strategic Hospital Management, ASST Santi Paolo e
Carlo, Milan, Italy

Infect Dis Ther
and immunodeficiency (AOR 0.445 RDV vs.
NMV-r, 95% CI 0.240–0.826, p = 0.010; AOR
0.222 MNP vs. NMV-r, 95% CI 0.105–0.472,
p < 0.001).
Conclusions: SARS-COV-2 antiviral treat-
ments are an excellent therapeutic strategy in
HR patients. Nirmatrelvir/ritonavir showed a
higher proportion of VC as early as 7days after
treatment, conrming its likely superiority in
indirect comparisons.
PLAIN LANGUAGE SUMMARY
Nirmatrelvir-ritonavir, molnupiravir, and a
3-day course of remdesivir are antiviral therapies
recommended in patients with a mild-to-mod-
erate COVID-19 disease at high risk of clinical
progression. Randomized controlled trials and
observational studies have shown their efcacy
in reducing all-cause mortality and clinical pro-
gression. Few data are available about a direct
comparison among the three drugs; further-
more, the possible role of nirmatrelvir-ritonavir
in increasing viral clearance and in reducing the
duration of viral shedding needs to be further
elucidated. We thus investigated the effective-
ness, safety, and virological clearance 7days
after treatment with these three antivirals in
our retrospective cohort. We included in the
analysis patients that have received these treat-
ments from January 2022 and October 2022; we
observed that patients receiving nirmatrelvir-
ritonavir displayed a shorter median time from
symptoms’ onset to virological clearance and a
higher proportion of virological clearance at day
7, also after adjustment for possible confound-
ers, compared to molnupiravir and remdesivir.
Our data might help in understanding which
COVID-19 patients may benet mostly from
antiviral therapies and in the choice of antiviral
therapy.
Keywords: Antiviral SARS CoV-2 treatment;
COVID-19; Molnupiravir; Nirmatrelvir/
ritonavir; Remdesivir
Key Summary Points
We observed a high proportion of clinical
recovery in patients with a mild-to-moderate
COVID-19 and at high risk of clinical pro-
gression following antiviral treatment.
No differences in clinical recovery were
observed among nirmatrelvir/ritonavir, mol-
nupiravir, and a short-course of remdesivir.
All three of the antiviral therapies are well
tolerated with few adverse events.
Nirmatrelvir/ritonavir was associated with a
higher proportion of virological clearance at
day 7 after starting the antiviral treatment,
compared to molnupiravir and a short course
of remdesivir.
Nirmatrelvir/ritonavir was also associated
with a shorter time to virological clearance,
compared to molnupiravir and a short course
of remdesivir.
INTRODUCTION
The SARS-CoV-2 pandemic has led to the intro-
duction of new drugs and the recovery of old
antiviral molecules tested for other infections,
such as hepatitis C virus (HCV) or Ebola [1]. So
far, the main therapeutic strategies for COVID-
19 have included antiviral therapies with dif-
ferent mechanisms of action (remdesivir,
molnupiravir, and nirmatrelvir/ritonavir) in
outpatients and hospitalized individuals [2].
Antiviral treatments are recommended within
5–7days from onset of symptoms for patients
diagnosed with a mild-to-moderate COVID-19
disease and risk factors for clinical progression
to severe disease. The “Agenzia Italiana del Far-
maco” (AIFA) dened age > 65years or chronic
comorbidities as well as diabetes, cardiovascular
diseases, chronic obstructive pulmonary disease
(COPD), asthma or other chronic pulmonary
diseases, immunodeciencies, active cancers,
neurological diseases and chronic liver or kid-
ney failure as risk factors for severe disease [3].

Infect Dis Ther
Among antivirals, nirmatrelvir/ritonavir
(NMV/r) is an oral protease inhibitor charac-
terized by a potent pan-human-coronavirus
activity invitro; its target is the viral main pro-
tease Mpro [4]. It resulted in 89% relative risk
reduction of hospitalization or death in unvac-
cinated symptomatic high-risk patients before
Omicron era, as demonstrated by the EPIC-HR
trial [5]. Furthermore, its antiviral activity does
not seem to reduce invitro against the Omi-
cron variant [6]; in fact, observational studies
report a reduction in hospitalization and mor-
tality rates also among vaccinated patients dur-
ing the Omicron era [7–14].
Similar efficacy in reducing clinical pro-
gression was observed for remdesivir (RDV), a
nucleotide prodrug that is metabolized intra-
cellularly to the active nucleoside triphosphate
(ATP), which interferes with viral RNA-depend-
ent polymerase activity [15]. This drug has
been approved for emergency use since the rst
phase of the pandemic in hospitalized patients
and afterwards also in outpatients [16–18]. The
PINETREE trial, in fact, involved non-hospital-
ized patients who were at high risk for COVID-
19 progression and demonstrated that a 3-day
course of this intravenous antiviral was associ-
ated with a 87% lower risk of progression to
severe disease or death than placebo; similarly,
data from observational studies and real-life
settings conrmed its efcacy [19–21].
Finally, a third antiviral, molnupiravir
(MNP), an oral, small-molecule prodrug that
is metabolized and phosphorylated to active
ribonucleoside triphosphate (NHC-TP) and
then incorporated into SARS-CoV-2 RNA, caus-
ing errors during viral replication with subse-
quent inhibition [4], was able to reduce the risk
of hospitalization or death by 30% in at-risk,
unvaccinated adults with COVID-19, as high-
lighted by the MOVe-OUT trial [22].
Retrospective data during the Omicron wave
conrmed that MNP and NMV-r were associ-
ated with a signicant reduction of all-cause
mortality and in-hospital disease progression,
while only NMV-r reduced the risk of COVID-
19-related hospitalizations [23, 24].
Furthermore, in the EPIC-HR trial, NMV-r
was able to reduce viral load in nasopharynx
at day 5 compared to placebo [5], but similar
virological data in real-life settings and data
on direct comparisons of the different antiviral
treatments also regarding virological efcacy
are still scarce [23, 25–27].
We thus compared the effectiveness, safety,
and virological clearance 7days after the start of
treatment with NMV-r, MNP, and RDV in SARS-
CoV-2-infected patients at high risk of clinical
progression during the Omicron era.
METHODS
Study Design and Population
We conducted a retrospective study enrolling
patients with documented COVID-19 by anti-
gen or reverse transcriptase-polymerase chain
reaction (RT-PCR) test on a nasopharyngeal
swab who received one antiviral treatment at the
COVID-19 antiviral therapy outpatient service
or during hospitalization for other reasons than
COVID-19 at the San Paolo Hospital in Milan,
Italy, from January 2022 to October 2022.
Inclusion criteria were mild-to-moderate dis-
ease, no need for supplemental oxygen therapy
or hospitalization for COVID-19, one or more
comorbidities indicated by the “Agenzia Italiana
del Farmaco” (AIFA) as risk factor of developing
severe COVID-19 disease, and symptoms onset
within 5–7days. Risk factors for clinical pro-
gression included body mass index (BMI) ≥ 30,
primary or acquired immunodeficiencies,
decompensated diabetes, cardio-cerebrovascu-
lar diseases, chronic hepatic or renal failure,
chronic pulmonary or neurological diseases,
or age ≥ 65years. Mild-to-moderate disease was
dened as signs and symptoms of COVID-19 and
oxygen saturation ≥ 94% on room air. Patients
hospitalized for COVID-19 were excluded from
the analysis; patients were included irrespective
of their COVID-19 vaccination status.
Study Procedures
Antiviral treatments that were available in Italy
during the study period were (i) oral nirmatrel-
vir/ritonavir (NMV-r): 300mg/100mg twice
daily for 5days (or adjusted dose according to

Infect Dis Ther
renal glomerular ltrate rate); (ii) molnupira-
vir (MPN): 800mg twice daily for 5days; (iii)
intravenous remdesivir (RDV): 200mgday 1,
followed by 100mg on days 2–3.
Patients were referred to the outpatient clinic
by their primary care physician, other special-
ists or the Emergency Department of San Paolo
and San Carlo Hospital or were evaluated after
testing positive for SARS CoV-2 infection during
hospitalization for other causes. The outpatient
clinic was active 7days a week.
At the rst access to the clinic, the patients
were visited by an infectious disease specialist
and underwent routine blood tests (complete
blood count, creatinine, GOT, GPT, lactate
dehydrogenase, prothrombin time, C-reactive
protein).
On the same day, antiviral treatment was
started; the choice of antiviral therapy was made
according to AIFA recommendations by the
attending physician according to the patients’
clinical characteristics and drug properties
(comorbidities, renal failure, drug–drug inter-
actions, and possibility of undergoing intrave-
nous treatment for 3days). The patients were
also evaluated 7days after starting the antiviral
treatment (T7): at T7 patients underwent medi-
cal examination, routine blood tests, and a PCR
or antigenic nasopharyngeal swab, according
to the rst method used for diagnosis, to assess
virological clearance.
For each patient we collected demographic
and clinical data about age, sex, comorbidities,
symptoms onset and type of symptoms, day of
rst SARS-CoV-2-positive test, COVID-19 vacci-
nation status, concomitant therapy with hepa-
rin or corticosteroids, outcome at day 7. All
data were recorded in an electronic dataset in
an anonymous form.
The study has received approval by the
Ethic Committee Milano Area 1 (no. 0000677,
01/04/2020) and all the subjects provided
informed consent to participate in the study.
The study has been conducted according to the
World Medical Association and theDeclaration
of Helsinki.
Statistical Analyses
Categorical data were presented as absolute
numbers and percentages, quantitative vari-
ables as median, and interquartile range (IQR).
Study outcomes were: clinical recovery at day 7
(T7), dened as complete resolution of COVID-
19 symptoms for at least 72h or non-resolu-
tion of symptoms or all-cause death; virological
clearance at T7, dened by a negative PCR or
antigenic swab. We also collected median time
to virological clearance (days from symptom
onset to the rst negative PCR or antigenic naso-
pharyngeal swab). The occurrence of adverse
events was collected at T7.
Comparison among the three treatment
groups (NMV-r, MNP, and RDV) were performed
by non-parametric Kruskal–Wallis test, Chi-
squared test, or Fisher’s exact test, as appropri-
ate. Factors associated with virological clearance
at T7 were analyzed by univariable and multi-
variable logistic regression analyses, adjusting
for possible confounders. We also performed
the logistic regression analysis on outpatients,
excluding patients who received the antiviral
treatment during hospitalization. We also com-
pared patients treated within the rst 3days of
symptoms onset (very early treated patients)
versus patients treated after the third day (early
patients), as well as unvaccinated versus vac-
cinated patients by Mann–Whitney test, Chi-
squared test or Fisher’s exact test. Statistical
analyses were performed by SPSS software, ver-
sion 21.0.
RESULTS
Study Population
We enrolled 376 patients in the study period:
150/376 (39.9%) received NMV-r, 92/376
(24.5%) MNP, and 134/376 (35.6%) RDV. Table1
shows the demographic and clinical characteris-
tics of the study population.
The majority of patients were outpatients (284,
75.5%), while 92 (24.5%) were hospitalized for
other reasons than COVID-19. The main reasons
for hospitalization were: neurological diseases

Infect Dis Ther
Table 1 Demographic and clinical characteristics of patients with mild/moderate COVID-19, according to anti-SARS-
CoV-2 antiviral treatment
Characteristics Study population
N 376
NMV-r
N 150
(39.9%)
MNP
N 92
(24.5%)
RDV
N 134
(35.6%)
p value
Age [years], median (IQR) 75 (63–84) 70 (56–80) 79 (67–84) 78 (68–86) < 0.001
Female sex, n (%) 167 (44.4%) 78 (52%) 33 (35.9%) 56 (41.8%) 0.037
COVID-19 vaccination, n (%): 0.015
No 29 (7.7%) 14 (9.3%) 6 (6.5%) 9 (6.7%)
Yes 327 (87%) 121 (80.7%) 84 (91.3%) 121 (91%)
Unknown 20 (5.3%) 15 (10%) 2 (2.2%) 3 (2.2%)
COVID-19 vaccination, n of doses:
Only 1 dose 4 (1.3%) 0 3 (3.6%) 1 (0.8%) 0.227
Complete rst schedule 35 (10.7%) 14 (11.6%) 10 (11.9%) 11 (9.1%)
First booster 247 (75.5%) 92 (76%) 64 (76.2%) 91 (75.2%)
Second booster 40 (12.2%) 14 (11.6%) 7 (8.3%) 18 (14.9%)
Unknown 1 (0.3%) 1 (0.8%) 0 0
COVID-19 vaccination,timing, n (%): N 293 N 100 N 80 N 113 0.661
Last vaccination > 120 days 168 (57.3%) 71 (71%) 31 (38.8%) 66 (58.4%)
Last vaccination ≤ 120 days 125 (42.7%) 29 (29%) 49 (61.3%) 47 (41.6%)
Calendar period: < 0.001
Jan–May 176 (46.8%) 41 (27.3%) 79 (85.9%) 56 (41.8%)
Jun–Oct 200 (53.2%) 109 (72.7%) 13 (14.1%) 78 (58.2%)
Risk factor, n (%):
Age ≥ 65 years 234 (62.2%) 68 (45.3%) 66 (71.7%) 100 (74.6%) < 0.001
BMI ≥ 30 28 (7.4%) 11 (7.3%) 7 (7.6%) 10 (7.5%) 0.997
Cardiovascular disease 139 (37%) 34 (22.7%) 47 (51.1%) 58 (43.3%) < 0.001
COPD or other respiratory disease 76 (20.2%) 33 (22%) 17 (18.5%) 26 (19.4%) 0.770
Neurological disease 35 (9.3%) 13 (8.7%) 4 (4.3%) 18 (13.4%) 0.065
Diabetes mellitus 63 (16.8%) 16 (10.7%) 16 (17.4%) 31 (23.1%) 0.019
Chronic kidney failure 21 (5.6%) 3 (2%) 7 (7.6%) 11 (8.2%) 0.047
Cancer 30 (8%) 9 (6%) 7 (7.6%) 14 (10.4%) 0.381
Immunodeciency 49 (13%) 30 (20%) 8 (8.7%) 11 (8.2%) 0.005
Treatments for COVID-19, n (%):
Heparin 59 (15.7%) 13 (8.7%) 3 (3.3%) 43 (32.1%) < 0.001

Infect Dis Ther
(16/92, 17.4%), cardiological diseases (14/92,
15.2%), abdominal/urinary diseases (12/92,
13.1%), lung diseases (10/92, 10.9%), cancers
(8/92, 8.7%), infectious diseases (7/92, 7.6%),
kidney diseases (5/92, 5.4%), orthopedic dis-
eases (4/92, 4.3%), hematological diseases (4/92,
4.3%), and other conditions (12/92, 13.1%).
Median age of study population was 75years
(IQR 63–84) and 167 (44.4%) were females.
High-risk criteria were more commonly older
age (≥ 65years, 62.2%), cardiovascular disease
(37%) and COPD or chronic pulmonary disease
(20.2%). Forty-nine patients were immunocom-
promised; the main immunodeciencies were:
onco-hematological diseases (22/49, 44.9%),
solid organ and bone marrow transplantation
(3/49, 6.1%), HIV infection (12/49, 24.5%), and
autoimmune diseases (12/49, 24.5%).
uantitative variables are presented as median, interquartile range (1st and 3rd percentile); qualitative variables are pre-
sented as absolute numbers and percentages. Kruskal–Wallis nonparametric test and Chi-square test or Fisher’s exact test
were used for analyses, as appropriate
Days from symptom onset to virological clearance was dened as days from onset of symptoms to the rst antigenic- or
PCR-negative nasopharyngeal swab; virological clearance at day 7 was dened as patients with antigenic- or PCR-negative
nasopharyngeal swab at day 7 aer treatment start
N M V- r nirmatrelvir/ritonavir, MNP molnupiravir, RDV remdesivir, BMI body mass index, COPD chronic obstructive pul-
monary disease
Table 1 continue d
Characteristics Study population
N 376
NMV-r
N 150
(39.9%)
MNP
N 92
(24.5%)
RDV
N 134
(35.6%)
p value
Corticosteroid therapy 15 (4%) 3 (2%) 1 (1.1%) 11 (8.2%) 0.007
Setting, n (%): < 0.001
Outpatient service 284 (75.5%) 130 (86.7%) 89 (96.7%) 65 (48.5%)
Hospitalization because of diseases other than
COVID-19
92 (24.5%) 20 (13.3%) 3 (3.3%) 69 (51.5%)
Days from symptom onset to antiviral treatment,
median (IQR)
3 (1–4) 2 (1–3) 3 (2–4) 2 (1–4) 0.161
Outcome, n (%): N 322 N 117 N 79 N 126 0.185
Recovery 310 (96.3%) 115 (98.3%) 77 (97.5%) 118 (93.6%)
Death 12 (3.7%) 2 (1.7%) 2 (2.5%) 8 (6.4%)
Adverse events, n (%): N 322 N 117 N 79 < 0.001
No 311 (82.7%) 108 (72%) 78 (84.8%) 125 (93.3%)
Yes 11 (2.9%) 9 (6%) 1 (1.1%) 1 (0.7%)
Days from symptom onset to virological clearance,
median (IQR)
13 (10–17) 10 (8–15) 14 (11–18) 13 (10–19) 0.002
Virological clearance at day 7 from treatment
start, n (%):
N 250 N 85 N 59 N 109 < 0.001
No 139 (37%) 32 (37.6%) 44 (74.6%) 66 (60.6%)
Yes 111 (29.5%) 53 (62.4%) 15 (25.4%) 43 (39.4%)

Infect Dis Ther
About vaccination status, 87% of patients
were vaccinated for SARS-CoV-2 with at least
one dose; 75.5% had received their rst booster,
and 57.3% received the last dose of vaccine more
than 120days before SARS-CoV-2 infection.
All outpatients have a mild COVID-19 and
did not receive oxygen support; 14/92 (15%)
patients who were treated with a short course
of RDV during hospitalization received oxygen
support: low flows oxygen therapy in 11/14
(78%) patients (nasal cannula or Venturi mask)
and high ows oxygen therapy in 3/14 (22%)
patients (Reservoir mask).
Comparison of Demographic and Clinical
Characteristics Among the Patients
Receiving the Three Different Antiviral
Therapies
As shown in Table1, patients treated with
NMV-r were younger and more commonly
females, compared to patients treated with MNP
or RDV. Furthermore, patients receiving NMV-r
presented more frequently age < 65years and
immunodeciency as risk factor for severity of
COVID-19; patients suffering from cardiovascu-
lar diseases, diabetes, and chronic kidney failure
received mainly MNP or RDV. Short-course RDV
was more frequently used in older patients and
in those hospitalized for conditions other than
COVID-19.
Outcome and Safety at Day 7 Post Treatment
According to Antiviral Treatment
Of 322 patients for whom post-treatment fol-
low-up was available, 309 (96%) patients com-
pletely recovered at T7. Twelve (3.7%) patients
died (two patients receiving NMV-r, two patients
receiving MNP, and eight patients receiving
RDV); five of 12 (41.7%) patients died from
malignancy, ve (41.7%) for sepsis, one (8.3%)
for acute cardiovascular failure, and one (8.3%)
for cerebral hemorrhage. No difference in T7
outcome was observed among the three differ-
ent treatments (recovery was 98.3% in NMV-r
group, 97.5% in MNP group and 93.6% in RDV
group) (Table1).
All the three therapies were well tolerated
with few and mild adverse events (11/322,
2.9%). NMV-r was characterized by a higher
proportion of adverse events (9, 6%), mostly
dysgeusia; no serious event was displayed
(Table1). Blood tests showed higher median
levels of CRP at start of treatment in patients
treated with RDV (RDV: 10.9, IQR 5.4–42.3mg/l;
NMV-r: 4.9, IQR 4.9–8.3; MNP: 5.9, IQR 4.9–9.4;
p < 0.001); no increase in GOT/GPT or creatinine
was observed for any treatments between start
of treatment and T7.
Virological Clearance According to Antiviral
Treatment
There were 250 of 376 patients that underwent
nasopharyngeal swab at day 7 (T7) after starting
therapy. Virological clearance at T7 was obtained
in nearly one-third of patients (111/250, 29.5%).
Interestingly, a higher percentage of patients
reached virological clearance at T7 in the NMV-r
group (53/85, 62.4%) in comparison with
MNP (15/59, 25.4%) and RDV (43/109, 39.4%;
p < 0.001). Patients treated with NMV-r also
showed a shorter median time from symptom
onset to the rst negative nasopharyngeal swab
compared to the other treatments (10days, IQR
8–15 for NMV-r; 14, IQR 11–18 for MNP; 13, IQR
10–19 for RDV; p = 0.002) (Table1).
The association between NMV-r and higher
proportion of virological clearance at T7 was
also investigated by fitting a multivariable
logistic regression analysis, adjusting for pos-
sible confounders (age and immunodeciency,
which are well-known risk factors for viral per-
sistence). Table2 shows the results of univariable
and multivariable logistic regression analyses.
After correction for age and immunodeciency,
treatment with NMV-r was confirmed to be
associated with a higher proportion of virologi-
cal clearance (AOR 0.445 RDV versus NMV-r,
95% CI 0.240–0.826, p = 0.010; AOR 0.22 MNP
versus NMV-r, 95% CI 0.105–0.472, p < 0.001).
The higher probability of viral clearance fol-
lowing treatment with NMV-r compared to
RDV and MNP was also conrmed in the analy-
ses restricted to outpatients (Supplementary
Table1).

Infect Dis Ther
Efcacy and Safety of Antiviral Treatment
According to Timing of Treatment and
Vaccination Status
Two hundred and fifty-seven of 346 (74%)
patients received very early antiviral treatment
(within the rst 3 days of symptoms onset); no
difference in efcacy and safety of the three anti-
viral treatments was shown according to the time
of treatment (very early treatment versus early
treatment, i.e., at least 3 days after symptoms
onset) (Table3). Median time to virological clear-
ance was shorter in very early treated patients,
while no difference in the proportion of virologi-
cal clearance at T7 was observed.
Twenty-nine of 356 (8.2%) patients were
unvaccinated against COVID-19 (Table4). Inter-
estingly, while displaying similar clinical recovery
and adverse events, unvaccinated patients showed
a longer time to virological clearance.
Table 2 Factors associated with virological clearance at T7 (negative antigenic or RNA nasopharyngeal swab at day 7 aer
beginning of antiviral treatment) by tting a logistic regression analysis
Multivariable logistic regression model is adjusted for age and immunodeciency
OR odds ratio, AOR adjusted odds ratio, 95%CI 95% condence interval
Parameters OR 95% CI p values AOR 95% CI p values
Age:
Each year more 0.978 0.963–0.994 0.007 0.984 0.967–1.001 0.069
Sex: 0.493–1.336 0.412
Female 1
Male 0.812
Vaccination:
 > 120 days 1
 ≤ 120 days 0.735 0.424–1.275 0.273
Immunodeciency:
Yes 1 1
No 0.752 0.365–1.550 0.440 1.295 0.574–2.924 0.534
Days from symptoms onset to
treatment:
Each day more 0.992 0.968–1.018 0.543
Antiviral treatment:
Nirmatrelvir/ritonavir 1 < 0.001 1 < 0.001
Remdesivir 0.393 0.220–0.705 0.002 0.445 0.240–0.826 0.010
Molnupiravir 0.206 0.099–0.428 < 0.001 0.222 0.105–0.472 < 0.001

Infect Dis Ther
Table 3 Comparison between very early and early-treated COVID-19 patients
Characteristics ≤ 3 days (N = 257) > 3 days (N = 89) p value
Age [years], median (IQR) 77 (64–84) 73 (59–81) 0.066
Female sex, n (%) 119 (46.3%) 35 (39.3%) 0.254
COVID-19 vaccination, n (%): 0.275
No 24 (9.3%) 5 (5.6%)
Yes 233 (90.7%) 84 (94.4%)
N 214 N 78 0.710
Yes, last vaccination > 120 days 121 (56.5%) 46 (59%)
Yes, last vaccination ≤ 120 days) 93 (43.5%) 32 (41%)
Calendar period: 0.004
Jan–May 110 (42.8%) 54 (60.7%)
Jun–Oct 147 (57.2%) 35 (39.3%)
Risk factor, n (%):
Age ≥ 65 years 174 (67.7%) 58 (65.2%) 0.661
BMI ≥ 30 20 (7.8%) 8 (9%) 0.719
Cardiovascular disease 97 (38%) 41 (46%) 0.167
COPD or other respiratory disease 58 (22.6%) 18 (20.2%) 0.645
Neurological disease 29 (11.3%) 6 (6.7%) 0.221
Diabetes mellitus 40 (15.6%) 22 (24.7%) 0.052
Chronic kidney failure 14 (5.4%) 7 (7.9%) 0.410
Cancer 21 (8.2%) 8 (9%) 0.810
Immunodeciency 34 (13.2%) 15 (16.9%) 0.398
Treatments for COVID-19, n (%):
Heparin 46 (17.9%) 12 (13.5%) 0.336
Corticosteroid therapy 9 (3.5%) 6 (6.7%) 0.227
Antiviral treatment: 0.095
Nirmatrelvir/ritonavir 102 (39.7%) 26 (29.2%)
Molnupiravir 68 (26.5%) 22 (24.7%)
Remdesivir 87 (33.9%) 41 (46.1%)
Setting, n (%): 0.05
Outpatient service 187 (72.8%) 74 (83.1%)
Hospitalization because of diseases other than COVID-19 70 (27.2%) 15 (16.9%)

Infect Dis Ther
DISCUSSION
Randomized controlled trials and observational
studies have shown the efcacy and safety of
antiviral treatments for SARS-CoV-2 infection
also during the Omicron wave and in vacci-
nated patients: NMV-r, MNP, and RDV are asso-
ciated with a reduced risk of clinical progres-
sion and death, especially in older patients or
patients at high risk for clinical progression [5,
8, 9, 11–13, 19, 22–24, 28, 29].
In our retrospective study, we observed that
antiviral treatments succeeded in obtaining a
clinical cure in more than 90% of patients with-
out differences among the three drugs; RDV
has a slight non-signicant minor proportion
of clinical recovery, but appears also more com-
monly prescribed in older hospitalized patients.
Few deaths were recorded and about half of
patients died from complications not directly
related to COVID-19, but to the underlying
oncological disease.
These data conrmed results from randomized
trials that were all conducted in a period before
Omicron variant and in unvaccinated patients
[5, 19, 22]; afterwards, observational studies
including emulation trials have reported effec-
tiveness of NMV-r, MNP, or RDV, also in vac-
cinated patients, in Omicron era and compared
to patients that have not received any antiviral
treatment [7, 8, 23, 24, 29, 30]. In fact, all three
treatments retain effectiveness against the Omi-
cron variant, as demonstrated by Vangeel etal.
and other authors [6, 31]. The effectiveness of
these treatments is evident despite the reduced
mortality due to COVID-19 observed with the
currently circulating viral variants and is in
any case associated with cost savings thanks to
avoided hospitalizations [32].
Among these treatments, MNP seems char-
acterized by a lower reduction in the risk of
hospitalization and mortality: in the MOVe-
OUT trial its relative risk reduction was only
30% compared to placebo; likewise, no effect
was observed in reducing COVID-19-associated
hospital admissions or death versus standard
Table 3 continue d
Characteristics ≤ 3 days (N = 257) > 3 days (N = 89) p value
Outcome, n (%): N 225 N 84 0.260
Recovery 217 (96.4%) 81 (96.4%)
Death 8 (3.6%) 3 (3.6%)
Adverse events, n (%) 0.561
No 248 (96.5%) 87 (97.8%)
Yes 9 (3.5%) 2 (2.2%)
Days from symptom onset to virological clearance, median (IQR) 12 (9–16) 15 (11–19) 0.002
Virological clearance at day 7 from treatment start, n (%): N 176 N 70 0.899
No 77 (43.8%) 30 (42.9%)
Yes 99 (56.3%) 40 (57.1%)
uantitative variables are presented as median, interquartile range (1st and 3rd percentile); qualitative variables are pre-
sented as absolute numbers and percentages. Mann–Whitney nonparametric test and Chi-square test or Fisher’s exact test
were used for analyses, as appropriate
Days from symptom onset to virological clearance was dened as days from onset of symptoms to the rst antigenic- or
PCR-negative nasopharyngeal swab; virological clearance at day 7 was dened as patients with antigenic- or PCR-negative
nasopharyngeal swab at day 7 aer treatment start
BMI body mass index, COPD chronic obstructive pulmonary disease

Infect Dis Ther
Table 4 Comparison between patients that received complete COVID-19 vaccination schedule and unvaccinated patients
Characteristics (N = 356) Vaccinated patients
N = 327
(91.8%)
Unvaccinated
patients
N = 29
(8.2%)
p value
Age [years], median (IQR) 76 (63–84) 78 (61–86) 0.946
Male sex, n (%) 183 (56%) 14 (48.3%) 0.425
Risk factor, n (%):
Age ≥ 65 years 214 (65.4%) 20 (69%) 0.702
BMI ≥ 30 26 (8%) 2 (6.9%) 0.840
Cardiovascular disease 127 (38.8%) 12 (41.4%) 0.788
COPD or other respiratory disease 68 (20.8%) 8 (27.6%) 0.392
Neurological disease 32 (9.8%) 3 (10.3%) 0.923
Diabetes mellitus 58 (17.7%) 5 (17.2%) 0.947
Chronic kidney failure 19 (5.8%) 2 (6.9%) 0.812
Cancer 28 (8.6%) 2 (6.9%) 0.757
Immunodeciency 46 (14.1%) 3 (10.3%) 0.577
Calendar period: 0.803
Jan–May 150 (45.9%) 14 (48.3%)
Jun–Oct 177 (54.1%) 15 (51.7%)
Antiviral treatment: 0.487
Nirmatrelvir/ritonavir 121 (37%) 14 (48.3%)
Molnupiravir 84 (25.7%) 6 (20.7%)
Remdesivir 122 (37.3%) 9 (31%)
Setting, n (%): 0.388
Outpatient service 249 (76.1%) 20 (69%)
Hospitalization for diseases other than COVID-19 78 (23.9%) 9 (31%)
Days from symptom onset to antiviral treatment, median (IQR) 2 (1–4) 2 (1–3) 0.310
Days from symptom onset to virological clearance, median (IQR) 12 (9–17) 16 (12–21) 0.012
Outcome, n (%): N 288 N 27 0.530
Recovery 277 (96.2%) 27 (100%)
Death 11 (3.8%) 0
Adverse events, n (%): 0.907
No 317 (96.9%) 28 (96.6%)
Yes 10 (3.1%) 1 (3.4%)

Infect Dis Ther
of care in PANORAMIC trial [33]. Furthermore,
other trials and observational studies displayed
a reduction in all-cause mortality, but not all
found an effect of MNP in reduction of disease
progression [29, 34, 35]. However, we observed
a high proportion of clinical recovery also in
MNP-treated patients, similarly to the other two
therapies, in line with another Italian retrospec-
tive analysis [36].
As regards safety issues, all the three drugs
were well tolerated with a very low prevalence of
adverse events, conrming data from trials and
real-life data [5, 7, 22, 23]. A higher proportion
of adverse events was reported with NMV-r com-
pared to MNP and RDV, but no severe adverse
events and no discontinuation were observed.
The prevalence of side effects was comparable to
that reported by other retrospective studies and
NMV-r was not associated with a higher propor-
tion of adverse events compared to placebo in
both trials and meta-analyses [4, 37, 38].
Interestingly, in our study NMV-r seemed to
have a better and faster virological response:
virological clearance 1week after the start of
treatment was reached in more than half of
patients receiving NMV-r, but only in about
a third of patients treated with MNP or RDV.
NMV-r also showed a shorter time to the rst
negative PCR or antigenic nasopharyngeal swab.
The higher proportion of viral response in a
short period for NMV-r, compared to RDV and
MNP, was independent from age and immuno-
suppression conditions.
A faster trend of conversion from positive to
negative RT-PCR RNA with NMV-r versus pla-
cebo was expected and already known [26, 39];
furthermore, the higher probability of having
a negative SARS-CoV-2 swab within 10days
from the rst positive one following treatment
with NMV-r was previously described, also after
controlling for possible confounders, but in
comparison only with RDV and not MNP [36].
Nevertheless, a recent Cochrane systematic
review failed to nd a certain effect of NMV-r
in increasing viral clearance at 7 and 14days
and other authors found that NMV-r effec-
tively reduced viral loads, but was not able to
decrease the length of virus shedding [27, 40].
Obtaining a faster virological response is
crucial to shorten time of isolation and conta-
giousness, mainly in patients who need diag-
nostic procedures or the continuation of life-
saving therapies.
A shorter time to viral clearance was reported
also for patients treated very early after symp-
toms onset and for vaccinated patients, sug-
gesting the importance of a timely initiation
of antiviral treatment and the completion of
vaccination schedule especially in patients who
would be disadvantaged by long periods of iso-
lation due to concomitant pathologies.
Our study has some limitations: the ret-
rospective nature and the lack of a control
Table 4 continue d
Characteristics (N = 356) Vaccinated patients
N = 327
(91.8%)
Unvaccinated
patients
N = 29
(8.2%)
p value
Virological clearance at day 7 from symptoms onset, n (%): N = 231 N = 16 0.012
No 131 (56.7%) 9 (56.3%)
Yes 100 (43.3%) 7 (43.8%)
uantitative data are presented as median, interquartile range; categorical data are presented as absolute numbers, percent-
ages. Mann–Whitney and Chi-squared test for comparison among the three groups, as appropriate
Days from symptom onset to virological clearance was dened as days from onset of symptoms to the rst antigenic- or
PCR-negative nasopharyngeal swab; virological clearance at day 7 was dened as patients with antigenic- or PCR-negative
nasopharyngeal swab at day 7 aer treatment start
BMI body mass index, COPD chronic obstructive pulmonary disease

Infect Dis Ther
group of patients not receiving any antiviral
treatment; unmeasured confounders for the
association between antiviral treatment and
virological clearance; the lack of daily naso-
pharyngeal swabs to assess the actual time
to viral response; the limited sample size and
losses to follow-up. This is, however, one of the
rst studies directly comparing three different
antiviral treatments for high-risk outpatients
in a real-life setting during the Omicron era.
CONCLUSIONS
In conclusion, NMV-r, MNP, and RDV have been
conrmed as a therapeutic strategy for high-risk
patients diagnosed with mild COVID-19 disease
in order to reduce disease progression without
differences among the three drugs; NMV-r was
associated with a higher, but still overall low
proportion, of adverse events. A possible bet-
ter performance of this antiviral, compared to
the other therapies, is its ability to shorten the
period of viral shedding and disease transmis-
sion, which is even now essential for some cat-
egories of patients such as subjects diagnosed
with hematological malignancies.
ACKNOWLEDGEMENTS
We are thankful to all the patients who partici-
pated in the study and their families. We would
like to thank all the staff of the Clinic of Infec-
tious Diseases and Tropical Medicine, San Paolo
Hospital, ASST Santi Paolo e Carlo, Department
of Health Sciences, University of Milan who
cared for the patients.
Author Contributions. Giulia Marchetti,
Antonella d’Arminio Monforte, and Francesca
Bai developed the question research and the
study protocol. Francesca Bai, Tomaso Bering-
heli, Virginia Vitaletti, Andrea Santoro, Franc-
esco Molà, Alessandro Copes, Nicole Gemignani,
Soa Pettenuzzo, Roberto Castoldi, Benedetta
Varisco, Riccardo Nardo, Lorenzo Brando Lund-
gren, Lorenzo Albertini, Riccardo Ligresti, Mat-
teo Sala, Matteo Augello, Lorenzo Biasioli, and
Teresa Bini helped with patients’ recruitment;
Valeria Bono and Roberta Rovito helped with
collection of data. Francesca Bai performed sta-
tistical analyses. Sabrina Passarella and Nicola
Vincenzo Orfeo were in charge of the manage-
ment of the COVID-19 inpatient and outpatient
services organization. Francesca Bai and Tomaso
Beringheli analyzed and interpreted the data
and wrote the manuscript. Giulia Marchetti and
Antonella d’Arminio Monforte helped in analyz-
ing and interpreting the data. Giulia Marchetti
and Antonella d’Arminio Monforte contributed
to the nal data interpretation. All authors con-
tributed to the editing of the manuscript.
Funding. EuCARE project, funded by the
European Union’s Horizon Europe Research and
Innovation Programme under Grant Agreement
No 101046016.The journal’s Rapid Service fee
was funded by the authors.
Data Availability. The datasets generated
during and/or analyzed during the current study
are available from the corresponding author on
reasonable request.
Declarations
Conict of Interest. Francesca Bai, Tomaso
Beringheli, Virginia Vitaletti, Andrea Santoro,
Francesco Molà, Alessandro Copes, Nicole
Gemignani, Soa Pettenuzzo, Roberto Castoldi,
Benedetta Varisco, Riccardo Ligresti, Matteo
Sala, Lorenzo Albertini, Matteo Augello, Lorenzo
Biasioli, Valeria Bono, Roberta Rovito, Teresa
Bini, Sabrina Passarella, Nicola Vincenzo Orfeo,
Antonella d’Arminio Monforte, and Giulia Mar-
chetti declare that the research was conducted in
the absence of any commercial or nancial rela-
tionships that could be interpreted as a potential
conict of interest.
Ethical Approval. The study has received
approval by the Ethic Committee Milano Area
1 (n. 0000677, 01/04/2020) and all the subjects
provided informed consent to participate in the
study. The study has been conducted according
to the World Medical Association and theDec-
laration of Helsinki.

Infect Dis Ther
Open Access. This article is licensed under a
Creative Commons Attribution-NonCommercial
4.0 International License, which permits any
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bution and reproduction in any medium or for-
mat, as long as you give appropriate credit to the
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the permitted use, you will need to obtain per-
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