# Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry

Jon Salmanton-García, F. Marchesi, Maria Gomes da Silva, Francesca Farina, Julio Dávila-Valls, Yavuz M. Bilgin, Andreas Birkedal Glenthøj, Iker Falces-Romero, Jaap A. van Doesum, Jorge Labrador, et al.

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## To cite this version:

Jon Salmanton-García, F. Marchesi, Maria Gomes da Silva, Francesca Farina, Julio Dávila-Valls, et al.. Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry. EClinicalMedicine, 2023, 58, 10.1016/j.eclinm.2023.101939. hal-04233279

HAL Id: hal-04233279

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Submitted on 26 Oct 2023

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# Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry

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Jon Salmanton-García,ª,b,c,bv,* Francesco Marchesi,<fnref n="1" />,d,bv Maria Gomes da Silva,ª Francesca Farina,<fnref n="1" /> Julio Dávila-Valls,<fnref n="9" /> Yavuz M. Bilgin,<fnref n="1" />
Andreas Glenthaj,<fnref n="1" /> Iker Falces-Romero,<fnref n="1" />,⁷ Jaap Van Doesum,<fnref n="1" /> Jorge Labrador,<fnref n="1" />,⁷ Caterina Buquicchio,<fnref n="9" /> Shaimaa El-Ashwah,<fnref n="1" /> Verena Petzer,<fnref n="9" />
Jens Van Praet,<fnref n="1" /> Martin Schönlein,<fnref n="9" /> Michelina Dargenio,<fnref n="1" /> Gustavo-Adolfo Méndez,<fnref n="1" /> Stef Meers,<fnref n="1" /> Federico Itri,<fnref n="1" /> Antonio Giordano,<fnref n="1" />
László Imre Pinczés,<fnref n="9" /> Ildefonso Espigado,<fnref n="9" /> Zlate Stojanoski,aa Alberto López-García,ab Lucia Prezioso,ac Ozren Jaksic,ad Antonio Vena,ae
Nicola S. Fracchiolla,af Tomás José González-López,ag Natasa Colović,ah Mario Delia,al Barbora Weinbergerová,aj Monia Marchetti,ak
Joyce Marques de Almeida,al Olimpia Finizio,am Caroline Besson,an,bv Monika M. Biernat,ao Toni Valković,ap,aq,ar Tobias Lahmer,as
Annarosa Cuccaro,at Irati Ormazabal-Vélez,au Josip Batinić,av,aw Noemí Fernández,ax Nick De Jonge,ay Carlo Tascini,az Amalia N. Anastasopoulou,ba
Rémy Duléry,bb Maria Ilaria Del Principe,be Gaëtan Planteveve,bd Mario Virgilio Papa,be Marcio Nucci,bf Moraima Jiménez,bg,bh Avinash Aujayeb,bi
José-Ángel Hernández-Rivas,bj,bk Maria Merelli,az Chiara Cattaneo,bl Ola Blennow,bm Anna Nordlander,bm Alba Cabirta,bg Gina Varricchio,be
Maria Vittoria Sacchi,ak Raul Cordoba,ab Elena Arellano,bn Stefanie K. Gräfe,b,bo,bp,bq Dominik Wolf,q Ziad Emarah,p Emanuele Ammatuna,l
Ditte Stampe Hersby,l Sonia Martín-Pérez,g Raquel Nunes Rodrigues,e Laman Rahimli,b,q Livio Pagano,x,br,bw and Oliver A. Cornely,a,b,c,bs,bt,bw,** on behalf of the EPICOVIDEHA registry

<footnote>ªUniversity of Cologne, Faculty of Medicine, and University Hospital Cologne, Chair Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany</footnote>

<footnote>ᵇUniversity of Cologne, Faculty of Medicine, and University Hospital Cologne, Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), Cologne, Germany</footnote>

<footnote>ᶜGerman Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany</footnote>

<footnote n="4">⁴Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy</footnote>

<footnote n="5">⁵Portuguese Institute of Oncology, Lisbon, Portugal</footnote>

<footnote n="1">¹IRCCS Ospedale San Raffaele, Milan, Italy</footnote>

<footnote n="9">⁹Hospital Nuestra Señora de Sonsoles, Ávila, Spain</footnote>

<footnote>ᵇDepartment of Internal Medicine, ADRZ, Goes, the Netherlands</footnote>

<footnote n="1">¹Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark</footnote>

<footnote>La Paz University Hospital, Madrid, Spain</footnote>

<footnote>ᵇCIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain</footnote>

<footnote n="1">¹University Medical Center Groningen, Groningen, the Netherlands</footnote>

<footnote>mDepartment of Hematology, Research Unit, Hospital Universitario de Burgos, Burgos, Spain</footnote>

<footnote>nFacultad de Ciencias de la Salud, Universidad Isabel I, Burgos, Spain</footnote>

<footnote n="0">⁰Ematologia con Trapianto, Ospedale Dimiccoli Barletta, Barletta, Italy</footnote>

<footnote>Oncology Center, Mansoura University, Mansoura, Egypt</footnote>

<footnote>qDepartment of Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University of Innsbruck (MUI), Innsbruck, Austria</footnote>

<footnote n="1">¹Department of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium</footnote>

<footnote>Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany</footnote>

<footnote n="1">¹Hematology and Stem Cell Transplant Unit, Vito Fazzi, Lecce, Italy</footnote>

<footnote>Hospital Escuela de Agudos Dr. Ramón Madariaga, Posadas, Argentina</footnote>

<footnote>AZ KLINA, Brasschaat, Belgium</footnote>

<footnote>San Luigi Gonzaga Hospital - Orbassano, Orbassano, Italy</footnote>

<footnote n="9">⁹Hematology Unit, Fondazione Policlinico Universitario Agostino Gemelli - IRCCS, Rome, Italy</footnote>

<footnote>Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary</footnote>

<footnote n="2">²Department of Hematology, University Hospital Virgen Macarena - University Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS / CSIC), Universidad de Sevilla (Departamento de Medicina), Seville, Spain</footnote>

<footnote>*Corresponding author. University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne Excellence, Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.</footnote>

<footnote>**Corresponding author. University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne Excellence, Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.</footnote>

<footnote>E-mail addresses: jon.salmanton-garcia@uk-koeln.de (J. Salmanton-García), oliver.cornely@uk-koeln.de (O.A. Cornely).</footnote>

<footnote>bShared junior authorship.</footnote>

<footnote>b Shared senior authorship.</footnote>
aaUniversity Clinic of Hematology, Skopje, North Macedonia

abFundacion Jimenez Diaz University Hospital, Health Research Institute IIS-FJD, Madrid, Spain

acHospital University of Parma - Hematology and Bone Marrow Unit, Parma, Italy

adDepartment of Hematology, University Hospital Dubrava, Zagreb, Croatia

aeOspedale Policlinico San Martino, Genoa, Italy

afFondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

agDepartment of Hematology, Hospital Universitario de Burgos, Burgos, Spain

ahUniversity Clinical Center Serbia, Medical Faculty University Belgrade, Belgrade, Serbia

aiHematology and Stem Cell Transplantation Unit, AOUC Policlinico, Bari, Italy

ajDepartment of Internal Medicine - Hematology and Oncology, Masaryk University Hospital Brno, Brno, Czech Republic

akAzienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy

alIstituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland

amUOC Hematology, AORN Cardarelli, Naples, Italy

anCentre Hospitalier de Versailles, Le Chesnay, France

aoDepartment of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland

apUniversity Hospital Centre Rijeka, Rijeka, Croatia

aqCroatian Cooperative Group for Hematological Diseases (CROHEM), Croatia

afFaculty of Medicine and Faculty of Health Studies University of Rijeka, Rijeka, Croatia

agMedizinische Klinik II, Klinikum rechts der Isar, TU München, Munich, Germany

atHematology Unit, Center for Translational Medicine, Azienda USL Toscana NordOvest, Livorno, Italy

auComplejo Hospitalario de Navarra, Iruña-Pamplona, Spain

avUniversity Hospital Centre Zagreb, Zagreb, Croatia

awSchool of Medicine University of Zagreb, Zagreb, Croatia

axHospital Universitario Marqués de Valdecilla, Santander, Spain

ayAmsterdam UMC, Location VUmc, Amsterdam, the Netherlands

azAzienda Sanitaria Universitaria del Friuli Centrale, Udine, Italy

baLaikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

bbService d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Inserm UMRs 938, Paris, France

bcHematology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy

bdHead ICU and CRC, Centre Hospitalier Victor DUPOUY, Argenteuil, France

beAzienda Ospedaliera Sant'Anna e San Sebastiano, Caserta, Italy

bfFederal University of Rio de Janeiro, Rio de Janeiro, Brazil

bgDepartment of Hematology, Vall d'Hebron Hospital Universitari, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain

bhDepartment de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain

bNorthumbria Healthcare, Newcastle, United Kingdom

bHospital Universitario Infanta Leonor, Madrid, Spain

bkDepartmento de Medicina, Universidad Complutense de Madrid, Madrid, Spain

blHematology Unit, ASST-Spedali Civili, Brescia, Italy

bmDepartment of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden

bnDepartment of Hematology, University Hospital Virgen Macarena, Seville, Spain

bqI, Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

bpII, Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

bqUniversity of Cologne, Faculty of Medicine, and University Hospital Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany

brHematology Unit, Università Cattolica del Sacro Cuore, Rome, Italy

bsUniversity of Cologne, Faculty of Medicine, and University Hospital Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne, Germany

btUniversity of Cologne, Faculty of Medicine, and University Hospital Cologne, Clinical Trials Centre Cologne (ZKS Köln), Cologne, Germany

buUniversité Paris-Saclay, UVSQ, Inserm, Équipe "Exposome et Hérédité", CESP, Villejuif, France

## Summary

**Background** Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients.

**Methods** This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022.
Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan-Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir.

**Findings** A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448–4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619–8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093–0.732) and obesity (aOR 0.105, 95%CI 0.014–0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration.

**Interpretation** Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir.

**Funding** EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

**Copyright** © 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

**Keywords:** Nirmatrelvir; SARS-CoV-2; Haematology; Malignancy; COVID-19

## Research in context

### Evidence before this study

Nirmatrelvir/ritonavir is a new antiviral targeting the SARS-CoV-2 3CI protease. It is widely recommended for patients with mild symptoms to prevent severe episodes of COVID-19. A web search was performed on November 12th for articles in English, French, German, Italian, or Spanish using strings combining the terms "haemato", "hemato*", "nirmatrelvir*", "paxlovid" with "administration", "mortality", "outcome", and "treatment". No studies focusing specifically on nirmatrelvir/ritonavir administration in haematological patients were found. Single publications targeting the general population or immunosuppressed patients were retrieved, but provided no detailed information on patients with haematological malignancy.

### Added value of this study

To the best of our knowledge, this is the first publication describing the factors associated with nirmatrelvir/ritonavir administration and investigating factors associated with mortality in patients with haematological malignancy.

Our results show that nirmatrelvir/ritonavir was administered more frequently to patients with extrapulmonary symptoms and those who had received a 2nd vaccine booster dose against SARS-CoV-2. On the contrary, patients with chronic pulmonary disease or obesity were less likely to receive nirmatrelvir/ritonavir. Mortality was significantly lower than in patients with other directed treatments.

### Implications of all the available evidence

Clinical management of COVID-19 patients with baseline haematological malignancies remains challenging two years after onset of the pandemic. Although vaccines prevent hospitalization and reduce mortality rates, patients with haematological malignancy may not mount protective immune response. In this vulnerable immunosuppressed patient group nirmatrelvir/ritonavir treatment results in lower mortality rates as compared to other treatment approaches. Still not all patients qualifying for nirmatrelvir/ritonavir received that treatment. Reasons for underuse remain unclear at this point.

## Introduction

Since the coronavirus disease 2019 (COVID-19) pandemic was declared in March 2020,¹ unprecedented

efforts by all stakeholders led to effective treatment options that can ameliorate the disease. Vaccines have proved to be a most effective method preventing
hospitalisation and mortality.²,³ Immunocompromised patients, for instance those with haematological malignancy, have been at increased risk for severe courses of COVID-19 and fatal outcome. Because of impaired immune response to vaccination, they are still at high-risk and need other approaches than current vaccines.⁴⁻⁶

Such approaches have been implemented with the
antivirals molnupiravir,⁷ nirmatrelvir/ritonavir,⁸ and
remdesivir,⁹ and with the monoclonal antibodies tar-
geting viral antigens.¹⁰⁻¹⁴ The common goal of these
drugs is reducing rates of hospitalisation, severe dis-
ease, and death. Approved for administration in
2022,¹⁵,¹⁶ during the initial moments of the omicron
wave, nirmatrelvir/ritonavir is an oral protease inhibitor
administered in high-risk patients with mild symptoms
early in the course of COVID-19.¹⁵,¹⁶ Although the phase
3 development programme addressed high-risk pa-
tients, only few patients with cancer were enrolled.⁸
Current consensus guidelines recommend nirma-
trelvir/ritonavir in patients with haematological malig-
nancy,¹⁷ although there is a lack of available data on this
patient group.¹⁸

This EPICOVIDEHA study compares epidemiology
and outcome of patients with haematological malig-
nancy receiving nirmatrelvir/ritonavir treatment versus
those who did not.

Methods

All data included in this analysis were exported from the
EPICOVIDEHA registry. EPICOVIDEHA (NCT04733729)
is an online registry open for patients with haematologic
malignancy and SARS-CoV-2 infection. Cases from
various regions of the world are documented in an elec-
tronic case report form (eCRF) accessible via www.
clinicalsurveys.net (EFS Summer 2021, TIVIAN, Co-
logne, Germany). The eCRF comprises epidemiological
data, such as baseline pre-COVID-19 conditions, previous
clinical management of the haematologic malignancy,
anti-SARS-CoV-2 vaccination history, COVID-19 diagnosis
and management, and outcome. All patients are included
in a validation process for data coherence and complete-
ness performed by experts in haematologic malignancy
and infectious diseases.¹⁹ In this validation process, data
missing completely at random were reduced as possible,
contacting contributors were to solve pending queries.
Exclusions from the database only happened if a patient
was not fulfilling all the inclusion criteria (no haemato-
logical malignancy, not active within the last 5 years prior
to COVID-19, no adult, no laboratory-based COVID-19
diagnosis).

For the present analysis, patients needed to fulfil all
inclusion criteria to be eligible: active haematologic
malignancy within the last five years prior to COVID-19,
including patients at onset or watch and wait; age ≥18
years; SARS-CoV-2 infection confirmed by either

polymerase chain reaction (PCR) or antigen test; and
SARS-CoV-2 diagnosis between January 1st and
September 30th, 2022.

Selected patients were grouped according to treat-
ment specifically received for COVID-19. Thus, we
formed the following categories: patients treated with
nirmatrelvir/ritonavir ± other directed or non-directed
treatments, patients receiving other SARS-CoV-2
directed antivirals or monoclonal antibodies ± other
non-directed treatments, and finally patients receiving
neither directed antivirals or monoclonal antibodies, nor
corticosteroids or convalescent plasma.

Statistical analysis

Consecutive data from participating institutions were summarised with frequencies and percentages for categorical variables and with median, interquartile range (IQR) and absolute range for continuous variables. Proportion comparisons were performed using Fisher's exact or Pearson's chi (X) squared tests, respectively. Logistic regression was utilised to determine which independent variables were associated with subsequent nirmatrelvir/ritonavir administration. For comparison analyses, patients were matched with a propensity score based on a logistic regression. The model included the variables sex, age (±10 years), baseline haematological malignancy, haematological malignancy status at COVID-19 onset, and origin continent (Europe). In order to determine the power and robustness of the performed propensity score, variables used for the matching were confronted with a median difference (age), Phi coefficient (sex and origin continent [Europe]), or Cramér's V (baseline haematological malignancy and haematological malignancy status at COVID-19 onset), as appropriate (Supplementary Table S1). A log-rank test was used to compare the survival probability of the patients based on the treatment received for COVID-19, which was graphically represented with a Kaplan-Meier survival plot. Additionally, Cox regression was used to analyse which factor could be associated with mortality both in every patient and in nirmatrelvir/ritonavir recipients who had data on duration of follow up. Variables with a p value < 0.1 in the univariable models were considered for the respective multivariable model. P value < 0.05 was considered statistically significant.

Ethics statement

The central ethics committee is at Fondazione Policli-
nico Universitario Agostino Gemelli - IRCCS, Uni-
versità Cattolica del Sacro Cuore of Rome, Italy (Study
ID: 3226). Additionally, each participating institution
may also have a local approval for the research initiative
as appropriate. The anonymized data that do not
contain any personally identifiable information from
any sources implies that the informed consent is not
applicable.
## Role of the funding source

The funders had no role in the study design, the collection, analysis, and interpretation of data, writing of the report and the decision to submit for publication. JSG, FM, LP, and OAC had access to and verified all raw data sets and made the decision to submit the manuscript.

## Results

This EPICOVIDEHA data set comprises 1859 patients with haematological malignancy from 84 centres in 28 countries, who were diagnosed with COVID-19 between January and September 2022 (Fig. 1A).

### Overall cohort

Almost 60% of the patients were male (n = 1070, 57.6%), and often with no other comorbidities (n = 766, 41.2%) besides haematological malignancy. Non-Hodgkin lymphoma (n = 602, 32.5%) was the most frequent haematological malignancy, followed by multiple myeloma (n = 337, 18.1%). Only one in four documented patients (n = 501, 26.9%) had active malignancy when COVID-19 was diagnosed. Overall, 69.0% (n = 1282) had received antineoplastic treatment within the preceding three months, or hematopoietic stem-cell transplantation or chimeric antigen receptor T cell administration within the last six months before COVID-19 diagnosis. The overall vaccination rate was 76.9% (n = 1430). Of 1118/1859 (60.1%) patients receiving directed treatment for COVID-19, 117/1118 (10.5%) received nirmatrelvir/ritonavir, either as monotherapy (n = 93/117, 79.5%) or in combination with other recommended drugs (n = 24/117, 20.5%), while 1001/1118 (89.5%) patients received treatment schemes without nirmatrelvir/ritonavir. A total of 741/1859 (39.9%) patients did not receive SARS-CoV-2 directed treatment. In total, intensive care was delivered to 148 (8.0%) patients (Table 1, Table 2).

In univariable logistic regression, nirmatrelvir/ritonavir treatment was associated with a patient without history of chronic pulmonary disease (odds ratio [OR] 0.341, 95% confidence interval [CI] 0.136–0.852), without obesity (OR 0.110, 95% CI 0.015–0.796), with extrapulmonary (i.e., anosmia, fever, rhinitis, or sinusitis) symptoms at COVID-19 onset (OR 2.102, 95% CI 1.278–3.457), and receipt of a second booster/4th dose (OR 3.434, 95% CI 1.674–7.045). In the multivariable model, patients with extrapulmonary symptoms (aOR 2.509, 95% CI 1.448–4.347) and those having received a 4th vaccine dose (aOR 3.624, 95% CI 1.619–8.109) were more likely to be treated with nirmatrelvir/ritonavir, while patients with chronic pulmonary disease (adjusted OR [aOR] 0.261, 95% CI 0.093–0.732) and obesity (aOR 0.105, 95% CI 0.014–0.776) were not (Table 3).

After matching the patients from the three treatment groups by sex, age (±10 years), baseline haematological

malignancy, haematological malignancy status at COVID-19 onset, and origin continent (Europe), the day-30 mortality rate was 2.0% (n = 2/102) after nirmatrelvir/ritonavir administration, 10.8% (n = 11/102) after the administration of directed treatment options other than nirmatrelvir/ritonavir, and 5.9% (n = 6/102) in patients without treatment administration (p = 0.036, Table 4, Supplementary Table S2). Survival probability was significantly higher in patients treated with nirmatrelvir/ritonavir as compared to those with directed treatment options other than nirmatrelvir/ritonavir (p = 0.008, Fig. 2A and B).

Sensitivity analyses we performed to determine which factors were associated to mortality in all the matched patients. Thus, we could observe how, in the univariable analyses, administration of directed drugs other than nirmatrelvir/ritonavir was associated with an increased mortality (p = 0.046), as compared to nirmatrelvir/ritonavir. Nevertheless, the factor more greatly associated with mortality in the analysed patients, either in the univariable or in multivariable analyses was the hospital, especially to ICU (Supplementary Tables S3 and S4). Nirmatrelvir/ritonavir administration remained as a protective factor in the coupled multivariable analyses performed considering the COVID-19 treatment and the variables observed to have a p < 0.1 in the univariable models when including in couples COVID-19 treatment and age, comorbidities, neutrophils, status of the malignancy at COVID-19 onset and symptoms at COVID-19 onset, respectively (Supplementary Tables S5 and S6).

### Nirmatrelvir/ritonavir recipients

The majority of the 117 patients receiving nirmatrelvir/ritonavir was male (n = 61, 51.7%). Non-Hodgkin lymphoma (n = 37/117, 31.6%) and multiple myeloma (n = 25/117, 21.4%) were the baseline haematological malignancy in more than half of the patients, 24.8% (n = 29/117) of which had active malignancy at COVID-19 onset. Immuno-chemotherapy (n = 49/117, 41.9%), targeted therapy (n = 23/117, 19.7%) and conventional chemotherapy (n = 16/117, 13.7%) were the most common HM treatment strategies administered immediately before infection diagnosis. Only 3.4% (n = 4/117) of the patients received no haematological malignancy treatment any time before COVID-19, all due to a contemporaneous diagnosis of malignancy and infection (Table 1).

In the unmatched populations, the proportion of patients without any additional comorbidity at COVID-19 onset was higher in patients with nirmatrelvir/ritonavir (n = 53/117, 45.3%) than in those receiving other directed drugs (n = 371/1001, 37.1%, p = 0.007), with no difference between nirmatrelvir/ritonavir patients and those with no treatment/non-SARS-CoV-2 directed treatment (n = 342/741, 46.2%, p = 0.618). Among the patients with at least one comorbidity, chronic cardiopathy was the most frequent (n = 48/117, 41.0%), similar
<figure><img src="image_4.png" /><figcaption>**Fig. 1:** Geographical distribution of patients documented in 2022 in EPICOVIDEHA according to the treatment received for COVID-19.

A) Overall sample. This figure includes patients from institutions worldwide. Countries with patterns of more than one colour indicate that more than one type of treatment has been administered in the respective country. Blue indicates patients with nirmatrelvir/ritonavir ± other treatments: Italy (n = 59), Spain (n = 31), Belgium (n = 13), Germany (n = 7), France (n = 5), and Austria and Serbia (n = 1, each). Orange indicates patients with other SARS-CoV-2-directed drugs ± other treatments: Italy (n = 284), Spain (n = 162), Denmark (n = 73), Netherlands (n = 59), Germany (n = 51), Croatia (n = 36), Egypt (n = 33), Hungary (n = 32), Austria (n = 31); Belgium and France (n = 29, each), North Macedonia (n = 23), Serbia (n = 20), Czech Republic (n = 19), Greece (n = 18), Argentina, Poland, and Portugal (n = 16, each), Switzerland (n = 13), United Kingdom (n = 11), Sweden (n = 8), Turkey (n = 7), Brazil and Saudi Arabia (n = 6, each), and Bangladesh, Chile, and Hong Kong SAR (n = 1, each). Brown indicates patients with non-SARS-CoV-2-directed drugs: Spain (n = 192), Italy (n = 166), Netherlands (n = 105), Portugal (n = 80), Belgium (n = 35), Croatia (n = 26), France (n = 23), Argentina (n = 20), Austria (n = 15), Egypt (n = 14), Hungary (n = 11), Germany (n = 10), North Macedonia (n = 9), Switzerland (n = 7), Brazil (n = 6), Greece (n = 5), Turkey (n = 4), Serbia (n = 3), Denmark, Poland, and Sweden (n = 2, each), and Czech Republic, Saudi Arabia, Singapore, and United Kingdom (n = 1, each). B) Proportional ambulatory administration of nirmatrelvir/ritonavir. This figure includes patients from European institutions. The darker the blue, the higher proportion of patients receiving ambulatory nirmatrelvir/ritonavir: France (5/5) 100.0%, Italy (48/59) 81.4%, Spain (5/29) 17.2%, Belgium (1/13) 7.7%, and Austria (0/1), Germany (0/7), and Serbia (0/1) 0.0%, each.</figcaption></figure>
<table><thead><tr><th rowspan="2"></th><th colspan="2">Directed treatment other than N/R</th><th rowspan="2">p value N/R vs other directed treatment</th><th colspan="2">N/R</th><th rowspan="2">p value N/R vs no/other non-directed tx</th><th colspan="2">No treatment/non-SARS-CoV-2 directed treatment</th><th colspan="2">Overall</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th></tr></thead><tbody><tr><td>Sex</td><td></td><td></td><td>0.112</td><td></td><td></td><td>0.618</td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>400</td><td>40.0</td><td></td><td>56</td><td>47.9</td><td></td><td>333</td><td>44.9</td><td>789</td><td>42.4</td></tr><tr><td>Male</td><td>601</td><td>60.0</td><td></td><td>61</td><td>51.7</td><td></td><td>408</td><td>55.1</td><td>1070</td><td>57.6</td></tr><tr><td>Age</td><td>66 (53-75)<br/>[18-95]</td><td></td><td>0.858</td><td>66 (55-75)<br/>[22-88]</td><td></td><td>0.165</td><td>63 (51-74)<br/>[19-97]</td><td></td><td>65 (52-75)<br/>[18-97]</td><td></td></tr><tr><td>Comorbidities at COVID-19 onset</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No comorbidities</td><td>371</td><td>37.1</td><td>0.007</td><td>53</td><td>45.3</td><td>0.618</td><td>342</td><td>46.2</td><td>766</td><td>41.2</td></tr><tr><td>1 comorbidity</td><td>320</td><td>32.0</td><td></td><td>40</td><td>34.2</td><td></td><td>248</td><td>33.5</td><td>608</td><td>32.7</td></tr><tr><td>2 comorbidities</td><td>192</td><td>19.2</td><td></td><td>22</td><td>18.8</td><td></td><td>102</td><td>13.8</td><td>316</td><td>17.0</td></tr><tr><td>3 or more comorbidities</td><td>118</td><td>11.8</td><td></td><td>2</td><td>1.7</td><td></td><td>49</td><td>6.6</td><td>169</td><td>9.1</td></tr><tr><td>Chronic cardiopathy</td><td>405</td><td>40.5</td><td>0.921</td><td>48</td><td>41.0</td><td>0.176</td><td>255</td><td>34.4</td><td>708</td><td>38.1</td></tr><tr><td>Chronic pulmonary disease</td><td>116</td><td>11.6</td><td>0.017</td><td>5</td><td>4.3</td><td>0.077</td><td>70</td><td>9.4</td><td>191</td><td>10.3</td></tr><tr><td>Diabetes mellitus</td><td>130</td><td>13.0</td><td>0.187</td><td>10</td><td>8.5</td><td>0.623</td><td>77</td><td>10.4</td><td>217</td><td>11.7</td></tr><tr><td>Liver disease</td><td>44</td><td>4.4</td><td>0.469</td><td>3</td><td>2.6</td><td>0.789</td><td>28</td><td>3.8</td><td>75</td><td>4.0</td></tr><tr><td>Obesity</td><td>73</td><td>7.3</td><td>0.005</td><td>1</td><td>0.9</td><td>0.072</td><td>33</td><td>4.5</td><td>107</td><td>5.8</td></tr><tr><td>Renal impairment</td><td>67</td><td>6.7</td><td>0.039</td><td>2</td><td>1.7</td><td>0.298</td><td>31</td><td>4.2</td><td>100</td><td>5.4</td></tr><tr><td>Smoking history</td><td>136</td><td>13.6</td><td>0.387</td><td>12</td><td>10.3</td><td>0.472</td><td>60</td><td>8.1</td><td>208</td><td>11.2</td></tr><tr><td>Baseline malignancy at COVID-19 onset</td><td></td><td></td><td>0.432</td><td></td><td></td><td>0.635</td><td></td><td></td><td></td><td></td></tr><tr><td>Leukemia</td><td>393</td><td>39.3</td><td></td><td>49</td><td>41.9</td><td></td><td>282</td><td>38.1</td><td>724</td><td>38.9</td></tr><tr><td>Acute myeloid leukemia</td><td>152</td><td>15.2</td><td></td><td>17</td><td>14.5</td><td></td><td>62</td><td>8.4</td><td>231</td><td>12.4</td></tr><tr><td>Chronic myeloid leukemia</td><td>15</td><td>1.5</td><td></td><td>4</td><td>3.4</td><td></td><td>36</td><td>4.9</td><td>55</td><td>3.0</td></tr><tr><td>Acute lymphoid leukemia</td><td>58</td><td>5.8</td><td></td><td>8</td><td>6.8</td><td></td><td>35</td><td>4.7</td><td>101</td><td>5.4</td></tr><tr><td>Chronic lymphoid leukemia</td><td>107</td><td>10.7</td><td></td><td>5</td><td>4.3</td><td></td><td>97</td><td>13.1</td><td>209</td><td>11.2</td></tr><tr><td>Myelodysplastic syndrome</td><td>58</td><td>5.8</td><td></td><td>14</td><td>12.0</td><td></td><td>50</td><td>6.7</td><td>122</td><td>6.6</td></tr><tr><td>Hairy cell leukemia</td><td>3</td><td>0.3</td><td></td><td>1</td><td>0.9</td><td></td><td>2</td><td>0.3</td><td>6</td><td>0.3</td></tr><tr><td>Lymphoma</td><td>392</td><td>39.2</td><td></td><td>38</td><td>32.5</td><td></td><td>257</td><td>34.7</td><td>687</td><td>37.0</td></tr><tr><td>Hodgkin lymphoma</td><td>39</td><td>3.9</td><td></td><td>1</td><td>0.9</td><td></td><td>45</td><td>6.1</td><td>85</td><td>4.6</td></tr><tr><td>Non-Hodgkin lymphoma</td><td>353</td><td>35.3</td><td></td><td>37</td><td>31.6</td><td></td><td>212</td><td>28.6</td><td>602</td><td>32.4</td></tr><tr><td>PH negative myeloproliferative diseases</td><td>28</td><td>2.8</td><td></td><td>5</td><td>4.3</td><td></td><td>51</td><td>6.9</td><td>84</td><td>4.5</td></tr><tr><td>Essential thrombocythemia</td><td>2</td><td>0.2</td><td></td><td>0</td><td>0.0</td><td></td><td>19</td><td>2.6</td><td>21</td><td>1.1</td></tr><tr><td>Myelofibrosis</td><td>20</td><td>2.0</td><td></td><td>3</td><td>2.6</td><td></td><td>15</td><td>2.0</td><td>38</td><td>2.0</td></tr><tr><td>Polycythemia vera</td><td>4</td><td>0.4</td><td></td><td>1</td><td>0.9</td><td></td><td>14</td><td>1.9</td><td>19</td><td>1.0</td></tr><tr><td>Systemic mastocytosis</td><td>2</td><td>0.2</td><td></td><td>1</td><td>0.9</td><td></td><td>3</td><td>0.4</td><td>6</td><td>0.3</td></tr><tr><td>Plasma cell disorders</td><td>179</td><td>17.9</td><td></td><td>25</td><td>21.4</td><td></td><td>143</td><td>19.3</td><td>347</td><td>18.7</td></tr><tr><td>Multiple myeloma</td><td>175</td><td>17.5</td><td></td><td>25</td><td>21.4</td><td></td><td>137</td><td>18.5</td><td>337</td><td>18.1</td></tr><tr><td>Amyloid light-chain amyloidosis</td><td>4</td><td>0.4</td><td></td><td>0</td><td>0.0</td><td></td><td>6</td><td>0.8</td><td>10</td><td>0.5</td></tr><tr><td>Other hematological malignancies</td><td>9</td><td>0.9</td><td></td><td>0</td><td>0.0</td><td></td><td>10</td><td>1.3</td><td>19</td><td>1.0</td></tr><tr><td>Aplastic anemia</td><td>9</td><td>0.9</td><td></td><td>0</td><td>0.0</td><td></td><td>10</td><td>1.3</td><td>19</td><td>1.0</td></tr><tr><td>Status malignancy at COVID-19 onset</td><td></td><td></td><td>0.234</td><td></td><td></td><td>0.065</td><td></td><td></td><td></td><td></td></tr><tr><td>Controlled disease</td><td>473</td><td>47.3</td><td></td><td>64</td><td>54.7</td><td></td><td>397</td><td>53.6</td><td>934</td><td>50.2</td></tr><tr><td>Stable disease</td><td>188</td><td>18.8</td><td></td><td>19</td><td>16.2</td><td></td><td>175</td><td>23.6</td><td>382</td><td>20.5</td></tr><tr><td>Active disease</td><td>314</td><td>31.4</td><td></td><td>29</td><td>24.8</td><td></td><td>158</td><td>21.3</td><td>501</td><td>26.9</td></tr><tr><td>Unknown</td><td>26</td><td>2.6</td><td></td><td>5</td><td>4.3</td><td></td><td>11</td><td>1.5</td><td>42</td><td>2.3</td></tr><tr><td>Last haematological malignancy treatment immediately before COVID-19 onset</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No treatment</td><td>85</td><td>8.5</td><td></td><td>4</td><td>3.4</td><td></td><td>95</td><td>12.8</td><td>184</td><td>9.9</td></tr><tr><td>alloHSCT</td><td>65</td><td>6.5</td><td></td><td>6</td><td>5.1</td><td></td><td>32</td><td>4.3</td><td>103</td><td>5.5</td></tr><tr><td>In the last 6 months</td><td>32</td><td>3.2</td><td></td><td>1</td><td>0.9</td><td></td><td>14</td><td>1.9</td><td>47</td><td>2.5</td></tr><tr><td>>6 months</td><td>32</td><td>3.2</td><td></td><td>5</td><td>4.3</td><td></td><td>18</td><td>2.4</td><td>55</td><td>3.0</td></tr><tr><td>Unknown</td><td>1</td><td>0.1</td><td></td><td>0</td><td>0.0</td><td></td><td>0</td><td>0.0</td><td>1</td><td>0.1</td></tr></tbody></table>

(Table 1 continues on next page)
<table><thead><tr><th rowspan="2"></th><th colspan="2">Directed treatment other than N/R</th><th colspan="2">p value N/R vs other directed treatment</th><th colspan="2">N/R</th><th colspan="2">p value N/R vs no/other non-directed tx</th><th colspan="2">No treatment/non-SARS-CoV-2 directed treatment</th><th colspan="2">Overall</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th></tr></thead><tbody><tr><td colspan="14">(Continued from previous page)</td></tr><tr><td>autoHSCT</td><td>16</td><td>1.6</td><td>5</td><td>4.3</td><td>5</td><td>0.7</td><td>26</td><td>1.4</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last 6 months</td><td>13</td><td>1.3</td><td>3</td><td>2.6</td><td>4</td><td>0.5</td><td>20</td><td>1.1</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;6 months</td><td>3</td><td>0.3</td><td>2</td><td>1.7</td><td>1</td><td>0.1</td><td>6</td><td>0.3</td><td></td><td></td><td></td><td></td></tr><tr><td>CAR-T</td><td>11</td><td>1.1</td><td>1</td><td>0.9</td><td>3</td><td>0.4</td><td>15</td><td>0.8</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last 6 months</td><td>4</td><td>0.4</td><td>0</td><td>0.0</td><td>2</td><td>0.3</td><td>6</td><td>0.3</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;6 months</td><td>7</td><td>0.7</td><td>1</td><td>0.9</td><td>1</td><td>0.1</td><td>9</td><td>0.5</td><td></td><td></td><td></td><td></td></tr><tr><td>Conventional chemotherapy</td><td>300</td><td>30.0</td><td>26</td><td>22.2</td><td>209</td><td>28.2</td><td>535</td><td>28.8</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last month</td><td>129</td><td>12.9</td><td>10</td><td>8.5</td><td>82</td><td>11.1</td><td>221</td><td>11.9</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last 3 months</td><td>146</td><td>14.6</td><td>13</td><td>11.1</td><td>92</td><td>12.4</td><td>251</td><td>13.5</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;3 months</td><td>20</td><td>2.0</td><td>3</td><td>2.6</td><td>35</td><td>4.7</td><td>58</td><td>3.1</td><td></td><td></td><td></td><td></td></tr><tr><td>Unknown</td><td>5</td><td>0.5</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>5</td><td>0.3</td><td></td><td></td><td></td><td></td></tr><tr><td>Demethylating agents</td><td>57</td><td>5.7</td><td>7</td><td>6.0</td><td>41</td><td>5.5</td><td>105</td><td>5.6</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last month</td><td>43</td><td>4.3</td><td>5</td><td>4.3</td><td>34</td><td>4.6</td><td>82</td><td>4.4</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last 3 months</td><td>11</td><td>1.1</td><td>0</td><td>0.0</td><td>6</td><td>0.8</td><td>17</td><td>0.9</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;3 months</td><td>3</td><td>0.3</td><td>0</td><td>0.0</td><td>1</td><td>0.1</td><td>4</td><td>0.2</td><td></td><td></td><td></td><td></td></tr><tr><td>Unknown</td><td>0</td><td>0.0</td><td>2</td><td>1.7</td><td>0</td><td>0.0</td><td>2</td><td>0.1</td><td></td><td></td><td></td><td></td></tr><tr><td>Immuno-chemotherapy</td><td>351</td><td>35.1</td><td>49</td><td>41.9</td><td>238</td><td>32.1</td><td>638</td><td>34.3</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last month</td><td>229</td><td>22.9</td><td>34</td><td>29.1</td><td>156</td><td>21.1</td><td>419</td><td>22.5</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last 3 months</td><td>42</td><td>4.2</td><td>5</td><td>4.3</td><td>24</td><td>3.2</td><td>71</td><td>3.8</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;3 months</td><td>79</td><td>7.9</td><td>10</td><td>8.5</td><td>57</td><td>7.7</td><td>146</td><td>7.9</td><td></td><td></td><td></td><td></td></tr><tr><td>Unknown</td><td>1</td><td>0.1</td><td>0</td><td>0.0</td><td>1</td><td>0.1</td><td>2</td><td>0.1</td><td></td><td></td><td></td><td></td></tr><tr><td>Immunotherapy</td><td>46</td><td>4.6</td><td>1</td><td>0.9</td><td>34</td><td>4.6</td><td>81</td><td>4.4</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last month</td><td>25</td><td>2.5</td><td>1</td><td>0.9</td><td>17</td><td>2.3</td><td>43</td><td>2.3</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last 3 months</td><td>10</td><td>1.0</td><td>0</td><td>0.0</td><td>6</td><td>0.8</td><td>16</td><td>0.9</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;3 months</td><td>9</td><td>0.9</td><td>0</td><td>0.0</td><td>11</td><td>1.5</td><td>20</td><td>1.1</td><td></td><td></td><td></td><td></td></tr><tr><td>Unknown</td><td>2</td><td>0.2</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>2</td><td>0.1</td><td></td><td></td><td></td><td></td></tr><tr><td>Supportive measures</td><td>16</td><td>1.6</td><td>5</td><td>4.3</td><td>19</td><td>2.6</td><td>40</td><td>2.2</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last month</td><td>3</td><td>0.3</td><td>1</td><td>0.9</td><td>1</td><td>0.1</td><td>5</td><td>0.3</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last 3 months</td><td>2</td><td>0.2</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>2</td><td>0.1</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;3 months</td><td>1</td><td>0.1</td><td>0</td><td>0.0</td><td>0</td><td>0.0</td><td>1</td><td>0.1</td><td></td><td></td><td></td><td></td></tr><tr><td>Unknown</td><td>10</td><td>1.0</td><td>4</td><td>3.4</td><td>18</td><td>2.4</td><td>32</td><td>1.7</td><td></td><td></td><td></td><td></td></tr><tr><td>Targeted therapy</td><td>183</td><td>18.3</td><td>23</td><td>19.7</td><td>147</td><td>19.8</td><td>353</td><td>19.0</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last month</td><td>138</td><td>13.8</td><td>21</td><td>17.9</td><td>116</td><td>15.7</td><td>275</td><td>14.8</td><td></td><td></td><td></td><td></td></tr><tr><td>In the last 3 months</td><td>19</td><td>1.9</td><td>0</td><td>0.0</td><td>9</td><td>1.2</td><td>28</td><td>1.5</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;3 months</td><td>17</td><td>1.7</td><td>0</td><td>0.0</td><td>16</td><td>2.2</td><td>33</td><td>1.8</td><td></td><td></td><td></td><td></td></tr><tr><td>Unknown</td><td>9</td><td>0.9</td><td>2</td><td>1.7</td><td>6</td><td>0.8</td><td>17</td><td>0.9</td><td></td><td></td><td></td><td></td></tr><tr><td>Neutrophils at COVID-19 onset</td><td></td><td></td><td>0.704</td><td></td><td>0.708</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;501</td><td>91</td><td>9.1</td><td>8</td><td>6.8</td><td>29</td><td>3.9</td><td>128</td><td>6.9</td><td></td><td></td><td></td><td></td></tr><tr><td>501-999</td><td>58</td><td>5.8</td><td>6</td><td>5.1</td><td>33</td><td>4.5</td><td>97</td><td>5.2</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;999</td><td>758</td><td>75.7</td><td>91</td><td>77.8</td><td>459</td><td>61.9</td><td>1308</td><td>70.4</td><td></td><td></td><td></td><td></td></tr><tr><td>Lymphocytes at COVID-19 onset</td><td></td><td></td><td>0.044</td><td></td><td>0.180</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;201</td><td>124</td><td>12.4</td><td>9</td><td>7.7</td><td>22</td><td>3.0</td><td>155</td><td>8.3</td><td></td><td></td><td></td><td></td></tr><tr><td>201-499</td><td>166</td><td>16.6</td><td>12</td><td>10.3</td><td>57</td><td>7.7</td><td>235</td><td>12.6</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;499</td><td>618</td><td>61.7</td><td>84</td><td>71.8</td><td>436</td><td>58.8</td><td>1138</td><td>61.2</td><td></td><td></td><td></td><td></td></tr><tr><td colspan="14">SARS-CoV-2 vaccination status at COVID-19 onset</td></tr><tr><td>Overall days from last dose administration to COVID-19 onset</td><td>127 (73-203) [2-532]</td><td>&lt;0.001</td><td>174 (121-235) [14-482]</td><td>&lt;0.001</td><td>116 (70-191) [3-372]</td><td>126 (75-201) [2-532]</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Number of doses</td><td></td><td>0.003</td><td></td><td></td><td>0.040</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Not vaccinated</td><td>258</td><td>25.8</td><td>23</td><td>19.7</td><td>148</td><td>20.0</td><td>429</td><td>23.1</td><td></td><td></td><td></td><td></td></tr><tr><td>One dose</td><td>32</td><td>3.2</td><td>3</td><td>2.6</td><td>27</td><td>3.6</td><td>62</td><td>3.3</td><td></td><td></td><td></td><td></td></tr><tr><td>Days from last dose administration to COVID-19 onset</td><td>231 (123-275) [5-461]</td><td></td><td>110 (23-394) [23-394]</td><td></td><td>163 (108-247) [6-368]</td><td>195.5 (110-258) [5-461]</td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

(Table 1 continues on next page)
<table><thead><tr><th rowspan="2"></th><th colspan="2">Directed treatment other than N/R</th><th colspan="2">p value N/R vs other directed treatment</th><th colspan="2">p value N/R vs no/other non-directed tx</th><th colspan="2">No treatment/non-SARS-CoV-2 directed treatment</th><th colspan="2">Overall</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th></tr></thead><tbody><tr><td colspan="11">(Continued from previous page)</td></tr><tr><td>Two doses</td><td>208</td><td>20.8</td><td>15</td><td>12.8</td><td>165</td><td>22.3</td><td>388</td><td>20.9</td><td></td><td></td></tr><tr><td>Days from last dose administration to COVID-19 onset</td><td>233 (161-276) [8-425]</td><td></td><td>305 (166-365) [39-482]</td><td></td><td>198 (141-244) [7-355]</td><td></td><td>212 (153-267) [7-482]</td><td></td><td></td><td></td></tr><tr><td>Three doses</td><td>454</td><td>45.4</td><td>61</td><td>52.1</td><td>351</td><td>47.4</td><td>866</td><td>46.6</td><td></td><td></td></tr><tr><td>Days from last dose administration to COVID-19 onset</td><td>97 (57-134) [2-532]</td><td></td><td>155 (111-190) [14-286]</td><td></td><td>90 (56-123) [3-372]</td><td></td><td>98 (59-135) [2-532]</td><td></td><td></td><td></td></tr><tr><td>Four doses</td><td>49</td><td>4.9</td><td>15</td><td>12.8</td><td>50</td><td>6.7</td><td>114</td><td>6.1</td><td></td><td></td></tr><tr><td>Days from last dose administration to COVID-19 onset</td><td>188 (155-216) [94-297]</td><td></td><td>234 (197-260) [104-295]</td><td></td><td>197 (164.5-234) [84-293]</td><td></td><td>193 (161-234) [84-297]</td><td></td><td></td><td></td></tr><tr><td colspan="11">Type of last vaccine</td></tr><tr><td>mRNA</td><td>683</td><td>68.2</td><td>92</td><td>78.6</td><td>547</td><td>73.8</td><td>1322</td><td>71.1</td><td></td><td></td></tr><tr><td>BioNTech/Pfizer</td><td>548</td><td>54.7</td><td>75</td><td>64.1</td><td>408</td><td>55.1</td><td>1031</td><td>55.5</td><td></td><td></td></tr><tr><td>Moderna COVE</td><td>135</td><td>13.5</td><td>17</td><td>14.5</td><td>139</td><td>18.8</td><td>291</td><td>15.7</td><td></td><td></td></tr><tr><td>Vector-based</td><td>38</td><td>3.8</td><td>1</td><td>0.9</td><td>39</td><td>5.3</td><td>78</td><td>4.2</td><td></td><td></td></tr><tr><td>AstraZeneca Oxford</td><td>29</td><td>2.9</td><td>1</td><td>0.9</td><td>18</td><td>2.4</td><td>48</td><td>2.6</td><td></td><td></td></tr><tr><td>Sputnik</td><td>5</td><td>0.5</td><td>0</td><td>0.0</td><td>6</td><td>0.8</td><td>11</td><td>0.6</td><td></td><td></td></tr><tr><td>J&J - Janssen</td><td>4</td><td>0.4</td><td>0</td><td>0.0</td><td>15</td><td>2.0</td><td>19</td><td>1.0</td><td></td><td></td></tr><tr><td>Inactivated</td><td>18</td><td>1.8</td><td>1</td><td>0.9</td><td>5</td><td>0.7</td><td>24</td><td>1.3</td><td></td><td></td></tr><tr><td>CoronaVac | Sinovac</td><td>5</td><td>0.5</td><td>0</td><td>0.0</td><td>1</td><td>0.1</td><td>6</td><td>0.3</td><td></td><td></td></tr><tr><td>Sinopharm</td><td>13</td><td>1.3</td><td>1</td><td>0.9</td><td>4</td><td>0.5</td><td>18</td><td>1.0</td><td></td><td></td></tr></tbody></table>

This table includes patients from institutions worldwide. alloHSCT, allogeneic hematopoietic stem-cell transplantation; autoHSCT, autologous hematopoietic stem-cell transplantation; CAR-T, chimeric antigen receptor T cells; COVE, coronavirus efficacy; COVID-19, coronavirus 2019 disease; J&J, Johnson and Johnson; mRNA, messenger ribonucleic acid; N/R, nirmatrelvir/ritonavir; PH, Philadelphia; tx, treatment. Reasons for no vaccination in nirmatrelvir/ritonavir: unknown (n = 23, 100.0%). Reasons for no vaccination in other SARS-CoV-2-directed drugs: unknown (n = 216, 83.7%), patient refusal (n = 24, 9.3%), ongoing malignancy treatment (n = 14, 5.4%), and other reasons (n = 4, 1.6%). Reasons for no vaccination in non-SARS-CoV-2-directed drugs: unknown (n = 129, 87.2%), patient refusal (n = 14, 9.5%), ongoing malignancy treatment (n = 4, 2.7%), and other reasons (n = 1, 0.7%).

<caption>**Table 1:** Baseline characteristics of EPICOVIDEHA patients after licensing of nirmatrelvir/ritonavir.</caption>

proportion to other patients (other directed drugs n = 405/1001, p = 0.921; no targeted drugs n = 255/741, p = 0.176). As compared to patients receiving other directed drugs against SARS-CoV-2, patients receiving nirmatrelvir/ritonavir had a lower proportion of chronic pulmonary diseases (n = 5/117, 4.3% versus n = 116/1001, 11.6%, p = 0.017), obesity (n = 1/117, 0.9% versus n = 73/1001, 7.3%, p = 0.005) and renal impairment (n = 2/117, 1.7% versus n = 67/1001, 6.7%, p = 0.039). No significant differences were observed between patients with nirmatrelvir/ritonavir and those with no treatment/non-SARS-CoV-2 directed treatment. Up to 80.3% (n = 94/117) had received at least one anti-SARS-CoV-2 vaccine dose preceding infection onset, a higher frequency than the 74.2% (n = 743/1001) in patients with other directed drugs (p = 0.003). Compared to patients with no treatment/non-SARS-CoV-2 directed treatment, patients with nirmatrelvir/ritonavir had received more frequently four vaccine doses (n = 15/117, 12.8% versus n = 50/741, 6.7%, p = 0.040, Tables 1 and 2). After matching, statistically significant differences were observed between patients in lymphocyte

levels at COVID-19 onset (p < 0.001), number of vaccine doses (p = 0.047), and symptoms at COVID-19 onset (p = 0.001, Table 4, Supplementary Table S2).

COVID-19 was diagnosed after a median of 174 days (IQR 121–235) since last vaccination. Thirteen (11.1%) patients out of 117 remained asymptomatic during the entire COVID-19 episode, whereas 38/117 (32.5%) had mild symptoms, 60/117 (51.3%) progressed to severe disease, and 6/117 (5.1%) to a critical condition (Table 2).

In unmatched patients with directed drugs other than nirmatrelvir/ritonavir, there were similar percentages of asymptomatic (n = 145/1001, 14.5%) and severely sick patients (556/1001, 55.5%), but fewer mild infections (176/1001, 17.6%) and more critical evolutions (124/1001, 12.4%) (p < 0.001). Patients with no treatment or no SARS-CoV-2 directed drugs, had a higher rate of asymptomatic courses (n = 211/741, 28.5%), and lower rates of mild (n = 185/741, 25.0%), severe (n = 327/741, 44.1%) and critical infections (n = 18/741, 2.4%) than patients with nirmatrelvir/ritonavir (p < 0.001). After matching the patients by sex,
<table><thead><tr><th rowspan="2"></th><th colspan="2">Directed treatment other than N/R</th><th rowspan="2">p value N/R vs other directed treatment</th><th colspan="2">N/R</th><th rowspan="2">p value N/R vs no/other non-directed tx</th><th colspan="2">No treatment/non-SARS-CoV-2</th><th colspan="2">Overall</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th></tr></thead><tbody><tr><td>SARS-CoV-2 variant of concern</td><td></td><td></td><td>0.139</td><td></td><td></td><td>1.000</td><td></td><td></td><td></td><td></td></tr><tr><td>Wild type</td><td>1</td><td>0.1</td><td></td><td>0</td><td>0.0</td><td></td><td>1</td><td>0.1</td><td>2</td><td>0.1</td></tr><tr><td>Delta</td><td>7</td><td>0.7</td><td></td><td>0</td><td>0.0</td><td></td><td>1</td><td>0.1</td><td>8</td><td>0.4</td></tr><tr><td>Omicron</td><td>479</td><td>47.9</td><td></td><td>44</td><td>37.6</td><td></td><td>281</td><td>37.9</td><td>804</td><td>43.2</td></tr><tr><td>Not tested</td><td>514</td><td>51.3</td><td></td><td>73</td><td>62.4</td><td></td><td>458</td><td>61.8</td><td>1045</td><td>56.2</td></tr><tr><td>Symptoms at COVID-19 onset</td><td></td><td></td><td>0.001</td><td></td><td></td><td>&lt;0.001</td><td></td><td></td><td></td><td></td></tr><tr><td>Pulmonary</td><td>145</td><td>14.5</td><td></td><td>34</td><td>29.1</td><td></td><td>220</td><td>29.7</td><td>399</td><td>21.5</td></tr><tr><td>Pulmonary + extrapulmonary</td><td>176</td><td>17.6</td><td></td><td>32</td><td>27.4</td><td></td><td>121</td><td>16.3</td><td>329</td><td>17.7</td></tr><tr><td>Extrapulmonary</td><td>556</td><td>55.5</td><td></td><td>38</td><td>32.5</td><td></td><td>178</td><td>24.0</td><td>772</td><td>41.5</td></tr><tr><td>Screening</td><td>124</td><td>12.4</td><td></td><td>13</td><td>11.1</td><td></td><td>222</td><td>30.0</td><td>359</td><td>19.3</td></tr><tr><td>COVID-19 infection</td><td></td><td></td><td>&lt;0.001</td><td></td><td></td><td>&lt;0.001</td><td></td><td></td><td></td><td></td></tr><tr><td>Asymptomatic</td><td>145</td><td>14.5</td><td></td><td>13</td><td>11.1</td><td></td><td>211</td><td>28.5</td><td>369</td><td>19.8</td></tr><tr><td>Mild infection</td><td>176</td><td>17.6</td><td></td><td>38</td><td>32.5</td><td></td><td>185</td><td>25.0</td><td>399</td><td>21.5</td></tr><tr><td>Severe infection</td><td>556</td><td>55.5</td><td></td><td>60</td><td>51.3</td><td></td><td>327</td><td>44.1</td><td>943</td><td>50.7</td></tr><tr><td>Critical infection</td><td>124</td><td>12.4</td><td></td><td>6</td><td>5.1</td><td></td><td>18</td><td>2.4</td><td>148</td><td>8.0</td></tr><tr><td>Stay during COVID-19 episode</td><td></td><td></td><td>&lt;0.001</td><td></td><td></td><td>&lt;0.001</td><td></td><td></td><td></td><td></td></tr><tr><td>Home</td><td>264</td><td>26.4</td><td></td><td>59</td><td>50.4</td><td></td><td>554</td><td>74.8</td><td>877</td><td>47.2</td></tr><tr><td>Hospital</td><td>736</td><td>73.5</td><td></td><td>56</td><td>47.9</td><td></td><td>182</td><td>24.6</td><td>974</td><td>52.4</td></tr><tr><td>Overall days of hospital stay</td><td>12 (7-21) [1-135]</td><td></td><td>0.001</td><td>8 (1-15) [1-57]</td><td>0.975</td><td>7 (2-15) [1-118]</td><td>11 (6-20) [1-135]</td><td></td><td></td><td></td></tr><tr><td>ICU admission</td><td>124</td><td>12.4</td><td>0.021</td><td>6</td><td>5.1</td><td>0.124</td><td>18</td><td>2.4</td><td>148</td><td>8.0</td></tr><tr><td>Overall days in ICU</td><td>9 (5-14) [1-68]</td><td></td><td>0.609</td><td>7 (3-11) [2-32]</td><td></td><td>0.323</td><td>3 (2-11) [1-24]</td><td></td><td>9 (4-14) [1-68]</td><td></td></tr><tr><td>COVID-19 treatment</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Days under COVID-19 treatment</td><td>2 (1-4) [1-34]</td><td></td><td></td><td>4 (4-5) [1-24]</td><td></td><td></td><td>4 (1-4) [1-34]</td><td></td><td></td><td></td></tr><tr><td>Days under nirmatrelvir/ritonavir treatment</td><td></td><td></td><td></td><td>4 (4-5) [1-10]</td><td></td><td></td><td></td><td></td><td>4 (4-5) [1-10]</td><td></td></tr><tr><td>Days from COVID-19 onset to nirmatrelvir/ritonavir treatment</td><td></td><td></td><td></td><td>1 (0-3) [0-151]</td><td></td><td></td><td></td><td></td><td>1 (0-3) [0-151]</td><td></td></tr><tr><td>Type of treatment</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No treatment administered</td><td>0</td><td>0.0</td><td></td><td>0</td><td>0.0</td><td></td><td>741</td><td>100.0</td><td>741</td><td>39.9</td></tr><tr><td>Antiviral + monoclonal antibody</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>± corticosteroids ± plasma</td><td>141</td><td>14.1</td><td></td><td>0</td><td>0.0</td><td></td><td>0</td><td>0.0</td><td>141</td><td>7.6</td></tr><tr><td>Antiviral ± corticosteroids ± plasma</td><td>293</td><td>29.3</td><td></td><td>0</td><td>0.0</td><td></td><td>0</td><td>0.0</td><td>293</td><td>15.8</td></tr><tr><td>Corticosteroids</td><td>242</td><td>24.2</td><td></td><td>0</td><td>0.0</td><td></td><td>0</td><td>0.0</td><td>242</td><td>13.0</td></tr><tr><td>Monoclonal antibodies</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>± plasma ± corticosteroids</td><td>305</td><td>30.5</td><td></td><td>0</td><td>0.0</td><td></td><td>0</td><td>0.0</td><td>305</td><td>16.4</td></tr><tr><td>Nirmatrelvir combination therapy</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>± corticosteroids ± plasma</td><td>0</td><td>0.0</td><td></td><td>24</td><td>20.5</td><td></td><td>0</td><td>0.0</td><td>24</td><td>1.3</td></tr><tr><td>1st line</td><td>0</td><td>0.0</td><td></td><td>7</td><td>6.0</td><td></td><td>0</td><td>0.0</td><td>7</td><td>0.4</td></tr><tr><td>Other line</td><td>0</td><td>0.0</td><td></td><td>17</td><td>14.5</td><td></td><td>0</td><td>0.0</td><td>17</td><td>0.9</td></tr><tr><td>Nirmatrelvir monotherapy</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>± corticosteroids ± plasma</td><td>0</td><td>0.0</td><td></td><td>93</td><td>79.5</td><td></td><td>0</td><td>0.0</td><td>93</td><td>5.0</td></tr><tr><td>1st line</td><td>0</td><td>0.0</td><td></td><td>93</td><td>79.5</td><td></td><td>0</td><td>0.0</td><td>93</td><td>5.0</td></tr><tr><td>Plasma ± corticosteroids</td><td>20</td><td>2.0</td><td></td><td>0</td><td>0.0</td><td></td><td>0</td><td>0.0</td><td>20</td><td>1.1</td></tr><tr><td>Outcome</td><td></td><td></td><td>0.027</td><td></td><td></td><td>0.016</td><td></td><td></td><td></td><td></td></tr><tr><td>Days from COVID-19 onset to final day of follow up/death</td><td>26 (12-47) [0-219]</td><td></td><td></td><td>35 (16-64) [0-191]</td><td></td><td></td><td>27 (12-46) [0-214]</td><td></td><td>27 (13-48) [0-219]</td><td></td></tr><tr><td>Alive</td><td>853</td><td>85.2</td><td>0.023</td><td>109</td><td>93.2</td><td>0.666</td><td>701</td><td>94.6</td><td>1663</td><td>89.5</td></tr><tr><td>Dead</td><td>148</td><td>14.8</td><td></td><td>8</td><td>6.8</td><td></td><td>40</td><td>5.4</td><td>196</td><td>10.5</td></tr><tr><td>Days from COVID-19 onset to final day of follow up</td><td>29 (14-51) [0-219]</td><td></td><td></td><td>35 (15-63) [0-191]</td><td></td><td></td><td>28 (13-46) [0-214]</td><td></td><td>29 (14-50) [0-219]</td><td></td></tr><tr><td>Days from COVID-19 onset to death</td><td>16 (8-28) [0-109]</td><td></td><td></td><td>48.5 (28.5-83) [14-156]</td><td></td><td></td><td>12 (4-25) [0-127]</td><td></td><td>16 (7-30) [0-156]</td><td></td></tr></tbody></table>

(Table 2 continues on next page)
<table><caption>Table 2: Characteristics of COVID-19 episodes.</caption><thead><tr><th rowspan="2"></th><th colspan="2">Directed treatment other than N/R</th><th rowspan="2">p value N/R vs other directed treatment</th><th colspan="2">N/R</th><th rowspan="2">p value N/R vs no/other non-directed tx</th><th colspan="2">No treatment/non-SARS-CoV-2</th><th colspan="2">Overall</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>%</th><th>n</th></tr></thead><tbody><tr><td>(Continued from previous page)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Reason for death</td><td></td><td></td><td>0.177</td><td></td><td></td><td>0.588</td><td></td><td></td><td></td><td></td></tr><tr><td>COVID-19</td><td>84</td><td>8.4</td><td></td><td>2</td><td>1.7</td><td></td><td>17</td><td>2.3</td><td>103</td><td>5.5</td></tr><tr><td>COVID-19</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>+ hematological malignancy</td><td>46</td><td>4.6</td><td></td><td>4</td><td>3.4</td><td></td><td>11</td><td>1.5</td><td>61</td><td>3.3</td></tr><tr><td>Hematological maligancies</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>+/- other reasons</td><td>14</td><td>1.4</td><td></td><td>2</td><td>1.7</td><td></td><td>9</td><td>1.2</td><td>25</td><td>1.3</td></tr><tr><td>Other reasons</td><td>4</td><td>0.4</td><td></td><td>0</td><td>0.0</td><td></td><td>3</td><td>0.4</td><td>7</td><td>0.4</td></tr></tbody><tfoot><tr><td colspan="11">This table includes patients from institutions worldwide. COVID-19, coronavirus 2019 disease; ICU, intensive care unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.</td></tr></tfoot></table>

age (±10 years), baseline haematological malignancy, haematological malignancy status at COVID-19 onset, and origin continent (Europe), those with directed drugs other than nirmatrelvir/ritonavir remained with a higher prevalence of critical COVID-19 episodes (p < 0.001, Table 1, Table 2, Table 4, Supplementary Table S2).

Overall, nirmatrelvir/ritonavir was administered with similar frequencies to hospital in-patients (n = 59/117, 50.4%) and out-patients (n = 56/117, 47.9%). However, when analysing results by country, this significantly differed, being more common for outpatients in Italy (n = 48/59, 81.4%) versus (n = 11/59, 18.6%) in-patients rather than in Spain (24/29, 82.8% hospital versus n = 5/29, 17.2% home, p < 0.001, Fig. 1B). Of the 56/117 (47.9%) patients admitted to hospital, 6/117 (10.7%) required intensive care. In patients with other directed drugs, both hospitalization (n = 736/1001, 73.5%, p < 0.001) and intensive care (n = 124/1001, 12.4%, p = 0.02) were significantly more frequent. On the contrary, patients with no treatment/non-SARS-CoV-2 directed treatment were less frequently in-hospital (n = 182/741, 24.6%, p < 0.001), although similarly treated in intensive care (n = 18/741, 2.4%, p = 0.12, Table 2, Table 4, Supplementary Table S2).

Nirmatrelvir/ritonavir treatment commenced the day after COVID-19 diagnosis (median 1, IQR 0–3) and lasted a median of 4 days (IQR 4–5). Among the 24/117 (20.5%) patients receiving nirmatrelvir/ritonavir in combination with other drugs (9/24 with other antivirals, 7/24 with monoclonal antibodies and 8/24 with both) only 17/24 received it as salvage treatment (Table 2).

The overall mortality rate in nirmatrelvir/ritonavir recipients was 6.8% (n = 8/117), death was attributed to COVID-19 in 5.1% (n = 6/8) cases. In the Cox regression models, no factor stood out to be associated with mortality after administration of nirmatrelvir/ritonavir (Table 2, Table 5).

## Discussion

Of 1859 patients with haematological malignancy registered in EPICOVIDEHA since the licensing of nirmatrelvir/ritonavir, 117 (6.3%) received the drug to prevent complicated courses of COVID-19.⁸ Patients with extrapulmonary symptoms at COVID-19 onset and those who had received a 2nd booster dose of an mRNA vaccine were more likely to receive nirmatrelvir/ritonavir. Recipients of nirmatrelvir/ritonavir had a significantly lower mortality rate than patients with other treatment approaches. Additionally, we aimed to discover factors associated with mortality in patients receiving nirmatrelvir/ritonavir for the COVID-19 treatment, although none was observed as significant, potentially linked to the reduced sample size and overall mortality rate.

Patients with chronic pulmonary diseases and obesity were less likely to receive nirmatrelvir/ritonavir, although precisely these are patients at risk of developing more severe COVID-19,²⁰ and therefore being the most appropriate candidates for nirmatrelvir/ritonavir administration even in the absence of haematological malignancy.¹⁵⁻¹⁷ This apparent underuse of nirmatrelvir/ritonavir may have multiple reasons explaining such results: lack of stock in hospital pharmacies and clinical practices,²¹ unawareness on when and how to administer it, unidentified obstacles in prescription, or already described adverse events, such us dysgeusia, diarrhoea or emboli, or drug-drug interactions.⁸,²² The performance of a similar analyses once the drug has been longer available may show broader use and may provide results more in line with the drug recommendations. In parallel, the presence of only extrapulmonary symptoms at COVID-19 was associated with nirmatrelvir/ritonavir use, following the prescription recommendations regarding target patients: mild COVID-19 episodes with high-risk for SARS-CoV-2 progression.¹⁵⁻¹⁷ Those fully vaccinated including a 2nd booster dose were more likely to receive nirmatrelvir/ritonavir. Interpretations
<table><thead><tr><th rowspan="2"></th><th colspan="3">Univariable analysis</th><th colspan="3">Multivariable analysis</th></tr><tr><th>p value</th><th>OR</th><th>95% CI</th><th>p value</th><th>OR</th><th>95% CI</th></tr></thead><tbody><tr><td><strong>Sex</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td></tr><tr><td>Male</td><td>0.101</td><td>0.725</td><td>0.494</td><td>1.065</td><td></td><td></td></tr><tr><td><strong>Age</strong></td><td>0.521</td><td>1.004</td><td>0.992</td><td>1.016</td><td></td><td></td></tr><tr><td><strong>Comorbidities at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Chronic cardiopathy</td><td>0.906</td><td>1.024</td><td>0.694</td><td>1.511</td><td></td><td></td></tr><tr><td>Chronic pulmonary disease</td><td><strong>0.021</strong></td><td>0.341</td><td>0.136</td><td>0.852</td><td><strong>0.011</strong></td><td>0.261</td><td>0.093</td><td>0.732</td></tr><tr><td>Diabetes mellitus</td><td>0.173</td><td>0.626</td><td>0.319</td><td>1.228</td><td></td><td></td><td></td><td></td></tr><tr><td>Liver disease</td><td>0.356</td><td>0.572</td><td>0.175</td><td>1.873</td><td></td><td></td><td></td><td></td></tr><tr><td>Obesity</td><td><strong>0.029</strong></td><td>0.110</td><td>0.015</td><td>0.796</td><td><strong>0.027</strong></td><td>0.105</td><td>0.014</td><td>0.776</td></tr><tr><td>Renal failure</td><td>0.050</td><td>0.242</td><td>0.059</td><td>1.003</td><td>0.071</td><td>0.265</td><td>0.063</td><td>1.120</td></tr><tr><td>Smoking history</td><td>0.316</td><td>0.727</td><td>0.389</td><td>1.357</td><td></td><td></td><td></td><td></td></tr><tr><td>No comorbidity</td><td>0.261</td><td>1.250</td><td>0.847</td><td>1.845</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Neutrophils at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;501</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>501-999</td><td>0.774</td><td>1.177</td><td>0.388</td><td>3.565</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;999</td><td>0.418</td><td>1.366</td><td>0.642</td><td>2.905</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Lymphocytes at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;201</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>201-499</td><td>0.993</td><td>0.996</td><td>0.407</td><td>2.438</td><td>0.672</td><td>1.219</td><td>0.487</td><td>3.052</td></tr><tr><td>&gt;499</td><td>0.085</td><td>1.873</td><td>0.917</td><td>3.824</td><td>0.050</td><td>2.080</td><td>1.000</td><td>4.329</td></tr><tr><td><strong>Status malignancy at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Controlled disease</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Stable disease</td><td>0.289</td><td>0.747</td><td>0.436</td><td>1.281</td><td></td><td></td><td></td><td></td></tr><tr><td>Active disease</td><td>0.105</td><td>0.683</td><td>0.430</td><td>1.083</td><td></td><td></td><td></td><td></td></tr><tr><td>Unknown</td><td>0.487</td><td>1.421</td><td>0.527</td><td>3.833</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Baseline malignancy at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Leukaemia</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lymphoma</td><td>0.269</td><td>0.777</td><td>0.498</td><td>1.215</td><td></td><td></td><td></td><td></td></tr><tr><td>PH negative myeloproliferative diseases</td><td>0.480</td><td>1.432</td><td>0.529</td><td>3.881</td><td></td><td></td><td></td><td></td></tr><tr><td>Plasma cell disorders</td><td>0.665</td><td>1.120</td><td>0.671</td><td>1.871</td><td></td><td></td><td></td><td></td></tr><tr><td>Other haematological malignancies</td><td>0.999</td><td>0.000</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Symptoms at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Pulmonary</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Pulmonary + extrapulmonary</td><td>0.908</td><td>0.970</td><td>0.585</td><td>1.611</td><td>0.995</td><td>1.002</td><td>0.570</td><td>1.762</td></tr><tr><td>Extrapulmonary</td><td><strong>0.003</strong></td><td>2.102</td><td>1.278</td><td>3.457</td><td><strong>0.001</strong></td><td>2.509</td><td>1.448</td><td>4.347</td></tr><tr><td>Screening</td><td>0.357</td><td>0.732</td><td>0.376</td><td>1.423</td><td>0.740</td><td>0.888</td><td>0.441</td><td>1.789</td></tr><tr><td><strong>SARS-CoV-2 vaccination status at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Not vaccinated</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>One dose</td><td>0.937</td><td>1.052</td><td>0.299</td><td>3.700</td><td>0.654</td><td>0.706</td><td>0.154</td><td>3.233</td></tr><tr><td>Two doses</td><td>0.539</td><td>0.809</td><td>0.412</td><td>1.590</td><td>0.292</td><td>0.673</td><td>0.322</td><td>1.406</td></tr><tr><td>Three doses</td><td>0.110</td><td>1.507</td><td>0.911</td><td>2.493</td><td>0.081</td><td>1.618</td><td>0.942</td><td>2.780</td></tr><tr><td>Four doses</td><td><strong>&lt;0.001</strong></td><td>3.434</td><td>1.674</td><td>7.045</td><td><strong>0.002</strong></td><td>3.624</td><td>1.619</td><td>8.109</td></tr></tbody></table>

This table includes patients from institutions worldwide. CI, confidence interval; COVID-19, coronavirus 2019 disease; OR, odds ratio; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

<caption>**Table 3:** Factors associated with a potential nirmatrelvir/ritonavir administration.</caption>

range from pockets of patients with access to all management options being very well taken care of (patients receiving nirmatrelvir/ritonavir were concentrated in Western Europe, as opposed to a wider geographical spread of patients in the other groups), to effects of

different vaccination schemes alleviating COVID-19 course.⁴,⁶,²³

We observed an overall vaccination rate of 76.9%; 80.3% in patients receiving nirmatrelvir/ritonavir, 80.0% in those with no treatment/non-SARS-CoV-2
<table><thead><tr><th rowspan="2"></th><th colspan="2">Directed treatment other than N/R</th><th colspan="2">N/R</th><th colspan="2">No treatment/non-SARS-CoV-2 directed treatment</th><th rowspan="2">p value</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th></tr></thead><tbody><tr><td>Sex</td><td></td><td></td><td></td><td></td><td></td><td></td><td>1.000</td></tr><tr><td>Female</td><td>44</td><td>43.1%</td><td>44</td><td>43.1%</td><td>44</td><td>43.1%</td><td></td></tr><tr><td>Male</td><td>58</td><td>56.9%</td><td>58</td><td>56.9%</td><td>58</td><td>56.9%</td><td></td></tr><tr><td>Age</td><td>66 (57-74) [21-89]</td><td></td><td>67 (56-75) [22-88]</td><td></td><td>67 (58-75) [22-89]</td><td></td><td>0.913</td></tr><tr><td>Comorbidities at COVID-19 onset</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No comorbidities</td><td>39</td><td>38.2%</td><td>46</td><td>45.1%</td><td>36</td><td>35.3%</td><td>0.429</td></tr><tr><td>1 comorbidity</td><td>32</td><td>31.4%</td><td>33</td><td>32.4%</td><td>35</td><td>34.3%</td><td></td></tr><tr><td>2 comorbidities</td><td>22</td><td>21.6%</td><td>21</td><td>20.6%</td><td>24</td><td>23.5%</td><td></td></tr><tr><td>3 or more comorbidities</td><td>9</td><td>8.8%</td><td>2</td><td>2.0%</td><td>7</td><td>6.9%</td><td></td></tr><tr><td>Chronic cardiopathy</td><td>41</td><td>40.2%</td><td>42</td><td>41.2%</td><td>38</td><td>37.3%</td><td>0.874</td></tr><tr><td>Chronic pulmonary disease</td><td>15</td><td>14.7%</td><td>5</td><td>4.9%</td><td>12</td><td>11.8%</td><td>0.062</td></tr><tr><td>Diabetes mellitus</td><td>9</td><td>8.8%</td><td>10</td><td>9.8%</td><td>9</td><td>8.8%</td><td>1.000</td></tr><tr><td>Liver disease</td><td>8</td><td>7.8%</td><td>3</td><td>2.9%</td><td>7</td><td>6.9%</td><td>0.397</td></tr><tr><td>Obesity</td><td>5</td><td>4.9%</td><td>1</td><td>1.0%</td><td>5</td><td>4.9%</td><td>0.245</td></tr><tr><td>Renal impairment</td><td>9</td><td>8.8%</td><td>2</td><td>2.0%</td><td>5</td><td>4.9%</td><td>0.097</td></tr><tr><td>Smoking history</td><td>9</td><td>8.8%</td><td>10</td><td>9.8%</td><td>16</td><td>15.7%</td><td>0.281</td></tr><tr><td>Baseline malignancy at COVID-19 onset</td><td></td><td></td><td></td><td></td><td></td><td></td><td>1.000</td></tr><tr><td>Leukemia</td><td>43</td><td>42.2%</td><td>43</td><td>42.2%</td><td>43</td><td>42.2%</td><td></td></tr><tr><td>Acute myeloid leukemia</td><td>12</td><td>11.8%</td><td>15</td><td>14.7%</td><td>11</td><td>10.8%</td><td></td></tr><tr><td>Chronic myeloid leukemia</td><td>3</td><td>2.9%</td><td>3</td><td>2.9%</td><td>8</td><td>7.8%</td><td></td></tr><tr><td>Acute lymphoid leukemia</td><td>9</td><td>8.8%</td><td>8</td><td>7.8%</td><td>5</td><td>4.9%</td><td></td></tr><tr><td>Chronic lymphoid leukemia</td><td>9</td><td>8.8%</td><td>4</td><td>3.9%</td><td>9</td><td>8.8%</td><td></td></tr><tr><td>Myelodysplastic syndrome</td><td>10</td><td>9.8%</td><td>13</td><td>12.7%</td><td>10</td><td>9.8%</td><td></td></tr><tr><td>Hairy cell leukemia</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Lymphoma</td><td>34</td><td>33.3%</td><td>34</td><td>33.3%</td><td>34</td><td>33.3%</td><td></td></tr><tr><td>Hodgkin lymphoma</td><td>2</td><td>2.0%</td><td>1</td><td>1.0%</td><td>4</td><td>3.9%</td><td></td></tr><tr><td>Non-Hodgkin lymphoma</td><td>32</td><td>31.4%</td><td>33</td><td>32.4%</td><td>30</td><td>29.4%</td><td></td></tr><tr><td>PH negative myeloproliferative diseases</td><td>3</td><td>2.9%</td><td>2</td><td>2.0%</td><td>7</td><td>6.9%</td><td></td></tr><tr><td>Essential thrombocythemia</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Myelofibrosis</td><td>2</td><td>2.0%</td><td>2</td><td>2.0%</td><td>3</td><td>2.9%</td><td></td></tr><tr><td>Polycythemia vera</td><td>1</td><td>1.0%</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td></td></tr><tr><td>Systemic mastocytosis</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>3</td><td>2.9%</td><td></td></tr><tr><td>Plasma cell disorders</td><td>21</td><td>20.6%</td><td>21</td><td>20.6%</td><td>21</td><td>20.6%</td><td></td></tr><tr><td>Multiple myeloma</td><td>19</td><td>18.6%</td><td>21</td><td>20.6%</td><td>19</td><td>18.6%</td><td></td></tr><tr><td>Amyloid light-chain amyloidosis</td><td>2</td><td>2.0%</td><td>0</td><td>0.0%</td><td>2</td><td>2.0%</td><td></td></tr><tr><td>Other hematological malignancies</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Aplastic anemia</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Status malignancy at COVID-19 onset</td><td></td><td></td><td></td><td></td><td></td><td></td><td>1.000</td></tr><tr><td>Controlled disease</td><td>62</td><td>60.8%</td><td>62</td><td>60.8%</td><td>62</td><td>60.8%</td><td></td></tr><tr><td>Stable disease</td><td>13</td><td>12.7%</td><td>13</td><td>12.7%</td><td>13</td><td>12.7%</td><td></td></tr><tr><td>Active disease</td><td>27</td><td>26.5%</td><td>27</td><td>26.5%</td><td>27</td><td>26.5%</td><td></td></tr><tr><td>Last hematological malignancy treatment immediately before COVID-19 onset</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No treatment</td><td>12</td><td>11.8%</td><td>4</td><td>3.9%</td><td>11</td><td>10.8%</td><td></td></tr><tr><td>alloHSCT</td><td>10</td><td>9.8%</td><td>5</td><td>4.9%</td><td>5</td><td>4.9%</td><td></td></tr><tr><td>In the last 6 months</td><td>5</td><td>4.9%</td><td>1</td><td>1.0%</td><td>3</td><td>2.9%</td><td></td></tr><tr><td>>6 months</td><td>5</td><td>4.9%</td><td>4</td><td>3.9%</td><td>2</td><td>2.0%</td><td></td></tr><tr><td>Unknown</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>autoHSCT</td><td>2</td><td>2.0%</td><td>5</td><td>4.9%</td><td>1</td><td>1.0%</td><td></td></tr><tr><td>In the last 6 months</td><td>2</td><td>2.0%</td><td>3</td><td>2.9%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>>6 months</td><td>0</td><td>0.0%</td><td>2</td><td>2.0%</td><td>1</td><td>1.0%</td><td></td></tr></tbody></table>

(Table 4 continues on next page)
<table><thead><tr><th rowspan="2"></th><th colspan="2">Directed treatment other than N/R</th><th colspan="2">N/R</th><th colspan="2">No treatment/non-SARS-CoV-2 directed treatment</th><th rowspan="2">p value</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th></tr></thead><tbody><tr><td>(Continued from previous page)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>CAR-T</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>In the last 6 months</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>&gt;6 months</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Conventional chemotherapy</td><td>12</td><td>11.8%</td><td>14</td><td>13.7%</td><td>16</td><td>15.7%</td><td></td></tr><tr><td>In the last month</td><td>10</td><td>9.8%</td><td>8</td><td>7.8%</td><td>10</td><td>9.8%</td><td></td></tr><tr><td>In the last 3 months</td><td>2</td><td>2.0%</td><td>3</td><td>2.9%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>&gt;3 months</td><td>0</td><td>0.0%</td><td>3</td><td>2.9%</td><td>6</td><td>5.9%</td><td></td></tr><tr><td>Unknown</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Demethylating agents</td><td>10</td><td>9.8%</td><td>6</td><td>5.9%</td><td>6</td><td>5.9%</td><td></td></tr><tr><td>In the last month</td><td>8</td><td>7.8%</td><td>4</td><td>3.9%</td><td>6</td><td>5.9%</td><td></td></tr><tr><td>In the last 3 months</td><td>2</td><td>2.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>&gt;3 months</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Unknown</td><td>0</td><td>0.0%</td><td>2</td><td>2.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Immuno-chemotherapy</td><td>38</td><td>37.3%</td><td>43</td><td>42.2%</td><td>37</td><td>36.3%</td><td></td></tr><tr><td>In the last month</td><td>27</td><td>26.5%</td><td>29</td><td>28.4%</td><td>27</td><td>26.5%</td><td></td></tr><tr><td>In the last 3 months</td><td>5</td><td>4.9%</td><td>4</td><td>3.9%</td><td>5</td><td>4.9%</td><td></td></tr><tr><td>&gt;3 months</td><td>6</td><td>5.9%</td><td>10</td><td>9.8%</td><td>5</td><td>4.9%</td><td></td></tr><tr><td>Unknown</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Immunotherapy</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td>4</td><td>3.9%</td><td></td></tr><tr><td>In the last month</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td>3</td><td>2.9%</td><td></td></tr><tr><td>In the last 3 months</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td></td></tr><tr><td>&gt;3 months</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Unknown</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Supportive measures</td><td>0</td><td>0.0%</td><td>5</td><td>4.9%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>In the last month</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>In the last 3 months</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>&gt;3 months</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Unknown</td><td>0</td><td>0.0%</td><td>4</td><td>3.9%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Targeted therapy</td><td>17</td><td>16.7%</td><td>18</td><td>17.6%</td><td>24</td><td>23.5%</td><td></td></tr><tr><td>In the last month</td><td>15</td><td>14.7%</td><td>17</td><td>16.7%</td><td>22</td><td>21.6%</td><td></td></tr><tr><td>In the last 3 months</td><td>2</td><td>2.0%</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td></td></tr><tr><td>&gt;3 months</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td></td></tr><tr><td>Unknown</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Neutrophils at COVID-19 onset</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.866</td></tr><tr><td>&lt;501</td><td>4</td><td>3.9%</td><td>6</td><td>5.9%</td><td>3</td><td>2.9%</td><td></td></tr><tr><td>501-999</td><td>4</td><td>3.9%</td><td>5</td><td>4.9%</td><td>3</td><td>2.9%</td><td></td></tr><tr><td>&gt;999</td><td>88</td><td>86.3%</td><td>80</td><td>78.4%</td><td>76</td><td>74.5%</td><td></td></tr><tr><td>Lymphocytes at COVID-19 onset</td><td></td><td></td><td></td><td></td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>&lt;201</td><td>15</td><td>14.7%</td><td>8</td><td>7.8%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>201-499</td><td>21</td><td>20.6%</td><td>11</td><td>10.8%</td><td>9</td><td>8.8%</td><td></td></tr><tr><td>&gt;499</td><td>60</td><td>58.8%</td><td>72</td><td>70.6%</td><td>73</td><td>71.6%</td><td></td></tr><tr><td>SARS-CoV-2 vaccination status at COVID-19 onset</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall days from last dose administration to COVID-19 onset</td><td>112 (47-173) [2-425]</td><td></td><td>173 (121-235) [14-482]</td><td></td><td>104 (57-170) [6-368]</td><td></td><td>&lt;0.001</td></tr><tr><td>Number of doses</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.003</td></tr><tr><td>Not vaccinated</td><td>27</td><td>26.5%</td><td>20</td><td>19.6%</td><td>15</td><td>14.7%</td><td>0.047 S</td></tr><tr><td>One dose</td><td>2</td><td>2.0%</td><td>2</td><td>2.0%</td><td>4</td><td>3.9%</td><td></td></tr><tr><td>Days from last dose administration to COVID-19 onset</td><td>175 (112-237) [112-237]</td><td></td><td>67 (23-110) [23-110]</td><td></td><td>191 (55-323) [6-368]</td><td></td><td></td></tr><tr><td>Two doses</td><td>21</td><td>20.6%</td><td>14</td><td>13.7%</td><td>20</td><td>19.6%</td><td></td></tr><tr><td>Days from last dose administration to COVID-19 onset</td><td>235 (83-276) [20-425]</td><td>-482</td><td>304 (166-364) [39]</td><td></td><td>208 (135-238) [7-272]</td><td></td><td></td></tr><tr><td>Three doses</td><td>49</td><td>48.0%</td><td>52</td><td>51.0%</td><td>58</td><td>56.9%</td><td></td></tr><tr><td>Days from last dose administration to COVID-19 onset</td><td>81 (37-125) [2-250]</td><td></td><td>154 (110-189) [14-286]</td><td></td><td>84 (51-113) [10-260]</td><td></td><td></td></tr></tbody></table>

(Table 4 continues on next page)
<table><thead><tr><th rowspan="2"></th><th colspan="2">Directed treatment other than N/R</th><th colspan="2">N/R</th><th colspan="2">No treatment/non-SARS-CoV-2 directed treatment</th><th rowspan="2">p value</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th></tr></thead><tbody><tr><td>(Continued from previous page)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Four doses</td><td>3</td><td>2.9%</td><td>14</td><td>13.7%</td><td>5</td><td>4.9%</td><td></td></tr><tr><td>Days from last dose administration to COVID-19 onset</td><td>152 (125-161) [125-161]</td><td></td><td>231 (197-260) [104-295]</td><td></td><td>189 (158-193) [127-196]</td><td></td><td></td></tr><tr><td>Type of last vaccine</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>mRNA</td><td>74</td><td>72.5%</td><td>80</td><td>78.4%</td><td>81</td><td>79.4%</td><td></td></tr><tr><td>BioNTech/Pfizer</td><td>58</td><td>56.9%</td><td>65</td><td>63.7%</td><td>59</td><td>57.8%</td><td></td></tr><tr><td>Moderna COVE</td><td>16</td><td>15.7%</td><td>15</td><td>14.7%</td><td>22</td><td>21.6%</td><td></td></tr><tr><td>Vector-based</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td>5</td><td>4.9%</td><td></td></tr><tr><td>AstraZeneca Oxford</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td>4</td><td>3.9%</td><td></td></tr><tr><td>Sputnik</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>J&J - Janssen</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>1</td><td>1.0%</td><td></td></tr><tr><td>Inactivated</td><td>1</td><td>1.0%</td><td>1</td><td>1.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>CoronaVac | Sinovac</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Sinopharm</td><td>1</td><td>1.0%</td><td>1</td><td>1.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>SARS-CoV-2 variant of concern</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.147</td></tr><tr><td>Wild type</td><td>1</td><td>1.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Delta</td><td>1</td><td>1.0%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Omicron</td><td>50</td><td>49.0%</td><td>38</td><td>37.3%</td><td>40</td><td>39.2%</td><td></td></tr><tr><td>Not tested</td><td>50</td><td>49.0%</td><td>64</td><td>62.7%</td><td>62</td><td>60.8%</td><td></td></tr><tr><td>Symptoms at COVID-19 onset</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.001</td></tr><tr><td>Pulmonary</td><td>35</td><td>34.3%</td><td>28</td><td>27.5%</td><td>25</td><td>24.5%</td><td></td></tr><tr><td>Pulmonary + extrapulmonary</td><td>21</td><td>20.6%</td><td>30</td><td>29.4%</td><td>15</td><td>14.7%</td><td></td></tr><tr><td>Extrapulmonary</td><td>21</td><td>20.6%</td><td>34</td><td>33.3%</td><td>30</td><td>29.4%</td><td></td></tr><tr><td>Screening</td><td>25</td><td>24.5%</td><td>10</td><td>9.8%</td><td>32</td><td>31.4%</td><td></td></tr><tr><td>COVID-19 infection</td><td></td><td></td><td></td><td></td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>Asymptomatic</td><td>20</td><td>19.6%</td><td>10</td><td>9.8%</td><td>29</td><td>28.4%</td><td></td></tr><tr><td>Mild infection</td><td>22</td><td>21.6%</td><td>34</td><td>33.3%</td><td>32</td><td>31.4%</td><td></td></tr><tr><td>Severe infection</td><td>41</td><td>40.2%</td><td>52</td><td>51.0%</td><td>40</td><td>39.2%</td><td></td></tr><tr><td>Critical infection</td><td>19</td><td>18.6%</td><td>6</td><td>5.9%</td><td>1</td><td>1.0%</td><td></td></tr><tr><td>Stay during COVID-19 episode</td><td></td><td></td><td></td><td></td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>Home</td><td>29</td><td>28.4%</td><td>53</td><td>52.0%</td><td>72</td><td>70.6%</td><td></td></tr><tr><td>Hospital</td><td>73</td><td>71.6%</td><td>48</td><td>47.1%</td><td>29</td><td>28.4%</td><td></td></tr><tr><td>Overall days of hospital stay</td><td>14 (7-28) [1-135]</td><td></td><td>8 (1-15) [1-57]</td><td></td><td>6 (1-11) [1-52]</td><td></td><td>&lt;0.001</td></tr><tr><td>ICU admission</td><td>19</td><td>18.6%</td><td>6</td><td>5.9%</td><td>1</td><td>1.0%</td><td>&lt;0.001</td></tr><tr><td>Overall days in ICU</td><td>14 (9-20) [3-54]</td><td></td><td>7 (3-11) [2-32]</td><td></td><td>(-) [-]</td><td></td><td>0.160</td></tr><tr><td>COVID-19 treatment</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Days under COVID-19 treatment</td><td>2 (1-4) [1-10]</td><td></td><td>4 (4-5) [1-24]</td><td></td><td></td><td></td><td></td></tr><tr><td>Days under nirmatrelvir/lopinavir treatment</td><td></td><td></td><td>4 (4-5) [1-10]</td><td></td><td></td><td></td><td></td></tr><tr><td>Days from COVID-19 onset to nirmatrelvir/lopinavir treatment</td><td></td><td></td><td>1 (0-3) [0-151]</td><td></td><td></td><td></td><td></td></tr><tr><td>Type of treatment</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No treatment administered</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td>102</td><td>100.0%</td><td></td></tr><tr><td>Antiviral + monoclonal antibody ± corticosteroids ± plasma</td><td>20</td><td>19.6%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Antiviral ± corticosteroids ± plasma</td><td>31</td><td>30.4%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Corticosteroids</td><td>21</td><td>20.6%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Monoclonal antibodies ± plasma ± corticosteroids</td><td>27</td><td>26.5%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Nirmatrelvir combination therapy ± corticosteroids ± plasma</td><td>0</td><td>0.0%</td><td>23</td><td>22.5%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>1st line</td><td>0</td><td>0.0%</td><td>6</td><td>5.9%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Other line</td><td>0</td><td>0.0%</td><td>17</td><td>16.7%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Nirmatrelvir monotherapy ± corticosteroids ± plasma</td><td>0</td><td>0.0%</td><td>79</td><td>77.5%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>1st line</td><td>0</td><td>0.0%</td><td>79</td><td>77.5%</td><td>0</td><td>0.0%</td><td></td></tr><tr><td>Plasma ± corticosteroids</td><td>3</td><td>2.9%</td><td>0</td><td>0.0%</td><td>0</td><td>0.0%</td><td></td></tr></tbody></table>

(Table 4 continues on next page)
<table><thead><tr><th rowspan="2"></th><th colspan="2">Directed treatment other than N/R</th><th colspan="2">N/R</th><th colspan="2">No treatment/non-SARS-CoV-2 directed treatment</th><th rowspan="2">p value</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th></tr></thead><tbody><tr><td>(Continued from previous page)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Outcome</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Days from COVID-19 onset to final day of follow up/death</td><td>28 (10-30) [1-30]</td><td></td><td>30 (16-30) [0-30]</td><td></td><td>28 (12-30) [0-30]</td><td></td><td>0.197</td></tr><tr><td>Day 30 mortality rate</td><td>11</td><td>10.8%</td><td>2</td><td>2.0%</td><td>6</td><td>5.9%</td><td>0.036</td></tr><tr><td>Days from COVID-19 onset to alive</td><td>30 (14-30) [1-30]</td><td></td><td>30 (16-30) [0-30]</td><td></td><td>30 (13-30) [0-30]</td><td></td><td></td></tr><tr><td>Days from COVID-19 onset to death</td><td>10 (6-16) [1-28]</td><td></td><td>18 (14-22) [14-22]</td><td></td><td>13 (10-19) [7-21]</td><td></td><td></td></tr></tbody></table>

This table includes patients from European institutions. § Sensitivity analyses on vaccination coverage proportions after propensity score-based matched analyses are depicted in Supplementary Table S2. alloHSCT, allogeneic hematopoietic stem-cell transplantation; autoHSCT, autologous hematopoietic stem-cell transplantation; CAR-T, chimeric antigen receptor T cells; COVE, coronavirus efficacy; COVID-19, coronavirus 2019 disease; ICU, intensive care unit; J&J, Johnson and Johnson; mRNA, messenger ribonucleic acid; N/R, nirmatrelvir/ritonavir; PH, Philadelphia; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; tx, treatment.

<caption>**Table 4:** Characteristics of patients and COVID-19 episodes after matching by propensity score.</caption>

directed treatment, and 74.2% in patients with directed drugs other than nirmatrelvir/ritonavir. These vaccination rates are similar to those in the general population.²⁴ In line with previous experiences in immunosuppressed settings,²⁵ the absence of vaccination in our patients was related to an ongoing haematological malignancy treatment or to patient refusal. However, in the majority of them it was unknown the rationale. Specific studies analysing the vaccination coverage in patients with an increased risk for COVID-19-associated mortality could help to understand and overcome this situation, facilitating a close-to-full vaccination in haematological malignancy patients. With these data, one could elucidate that the variables included in the propensity score-based matching performed in our analysis (sex, age (±10 years), baseline haematological malignancy, haematological malignancy status at COVID-19 onset, and origin continent [Europe]) has made the treatment groups very homogeneous and comparable, not only in the matching variables, but also in the vaccination coverage. Additionally, the fact that all the patients were diagnosed in 2022 has facilitated a higher coverage. In order to see more detailed reasons, we may need to look patient to patient and thus, the heterogenicity of the results to be potentially obtained could have a very poor significance. Further analysis may need to focus on this aspect and we will definitely keep in mind in our prospective research.

Surprisingly, the patients in our sample received nirmatrelvir/ritonavir for a median of only four days, one day less than the manufacturer recommendations, which may hint towards general shortage of the drug.¹⁵,¹⁶ Other potential reasons may be drug-drug interactions,²⁶,²⁷ adverse effects²² or prompt recovery of symptoms. Additionally, storage and supply restrictions,²¹ which can potentially end in a distribution of available doses among more patients than recommended, and difficulties in the access to the compound,²⁸ might have interfered with the correct number of administration days.

A retrospective study from Israel analysed factors associated with mortality in patients with high-risk of COVID-19 progression after receiving nirmatrelvir/ritonavir.²⁹ Immunosuppressed patients showed increased mortality, adjusted by different comorbidities (i.e., cardiovascular disease, chronic kidney disease, chronic lung disease, diabetes mellitus, malignancy in the prior year, or neurological disease), but the authors did not differentiate haematologic malignancy from other causes of immunosuppression. Interestingly we did not identify factors associated with mortality. The high rate of vaccinated patients may have reduced death rates even in our immunosuppressed population. The 6.8% mortality rate in nirmatrelvir/ritonavir recipients, much lower than in previously reported populations without vaccination (31.2%)⁵ or including pre-nirmatrelvir/ritonavir cases⁴ (9.2%), jeopardises the performance of further mortality analyses.

Our study has some limitations. The retrospective design may intrinsically yield lower data quality, and the sample size is large by comparison to published studies, but still too small to allow additional subgroup comparisons. We do not capture the actual antineoplastic treatment days and doses limiting analyses of drug-drug interactions with ritonavir.²⁶ Finally, we have been unable to detect which factors are associated with mortality. Further analyses with a larger sample size collecting more variables, including laboratory values, might overcome these limitations.

In conclusion, patients with extrapulmonary symptoms at COVID-19 onset and a 2nd vaccine dose are more prone to receive nirmatrelvir/ritonavir as opposed to those with chronic pulmonary disease and obesity. Despite mortality in patients with nirmatrelvir/ritonavir is lower as compared to that in other treatment schemes, no statistical significance was observed. Thus, further analyses are needed to depict the factors associated to this observation.
A

<figure><img src="image_5.png" /></figure>

This figure includes patients from European institutions.

<table><thead><tr><th>Log-rank test p value</th><th>Directed treatment other than nirmatrelvir/ritonavir</th><th>Nirmatrelvir/ritonavir</th></tr></thead><tbody><tr><td>Nirmatrelvir/ritonavir</td><td>0.008</td><td></td></tr><tr><td>No treatment/non-SARS-CoV-2 directed treatment</td><td>0.208</td><td>0.120</td></tr></tbody></table>

B

<figure><img src="image_6.png" /></figure>

This figure includes patients from European institutions.

<table><caption>**Fig. 2:** Survival probability by COVID-19 treatment strategy. A) Summarised treatment strategies. This table includes patients from European institutions. B) Detailed treatment strategies. This table includes patients from European institutions.</caption><thead><tr><th>Log-rank test p value</th><th>No treatment/non-SARS-CoV-2 directed treatment</th><th>Antiviral ± monoclonal antibody ± corticosteroids ± plasma</th><th>Antiviral ± corticosteroids ± plasma</th><th>Plasma ± corticosteroids</th><th>Monoclonal antibodies ± plasma ± corticosteroids</th><th>Nirmatrelvir combination therapy ± corticosteroids ± plasma</th><th>Nirmatrelvir monotherapy ± corticosteroids ± plasma</th></tr></thead><tbody><tr><td>Antiviral ± monoclonal antibodies ± corticosteroids ± plasma</td><td>0.288</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Antiviral ± corticosteroids ± plasma</td><td>0.165</td><td>0.088</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Plasma ± corticosteroids</td><td><strong>0.021</strong></td><td><strong>0.039</strong></td><td>0.498</td><td></td><td></td><td></td><td></td></tr><tr><td>Monoclonal antibodies ± plasma ± corticosteroids</td><td>0.816</td><td>0.245</td><td>0.412</td><td>0.171</td><td></td><td></td><td></td></tr><tr><td>Nirmatrelvir combination therapy ± corticosteroids ± plasma</td><td>0.572</td><td>0.419</td><td>0.186</td><td>0.053</td><td>0.528</td><td></td><td></td></tr><tr><td>Nirmatrelvir monotherapy ± corticosteroids ± plasma</td><td>0.112</td><td>0.641</td><td><strong>0.006</strong></td><td><strong>&lt;0.001</strong></td><td>0.112</td><td>0.534</td><td></td></tr></tbody></table>
<table><thead><tr><th rowspan="2"></th><th colspan="4">Univariable analysis</th><th colspan="4">Multivariable analysis</th></tr><tr><th>p value</th><th>HR</th><th colspan="2">95% CI</th><th>p value</th><th>HR</th><th colspan="2">95% CI</th></tr><tr><th></th><th></th><th></th><th>Lower limit</th><th>Upper limit</th><th></th><th></th><th>Lower limit</th><th>Upper limit</th></tr></thead><tbody><tr><td><strong>Sex</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>-</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>0.234</td><td>2.644</td><td>0.533</td><td>13.116</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Age</strong></td><td>0.332</td><td>1.029</td><td>0.972</td><td>1.089</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Comorbidities at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Chronic cardiopathy</td><td>0.063</td><td>7.479</td><td>0.900</td><td>62.169</td><td>0.092</td><td>6.761</td><td>0.731</td><td>62.532</td></tr><tr><td>Chronic pulmonary disease</td><td>0.619</td><td>0.044</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>0.056</td><td>5.001</td><td>0.957</td><td>26.126</td><td>0.167</td><td>4.229</td><td>0.547</td><td>32.698</td></tr><tr><td>Liver disease</td><td>0.720</td><td>0.046</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Obesity</td><td>-</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Renal failure</td><td>0.799</td><td>0.048</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Smoking history</td><td>0.626</td><td>0.044</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>No comorbidity</td><td>0.122</td><td>0.191</td><td>0.023</td><td>1.555</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Neutrophils at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;501</td><td>-</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>501-999</td><td>0.642</td><td>0.512</td><td>0.030</td><td>8.614</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;999</td><td>0.172</td><td>0.210</td><td>0.022</td><td>1.970</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Lymphocytes at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;201</td><td>-</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>201-499</td><td>0.640</td><td>0.563</td><td>0.051</td><td>6.249</td><td></td><td></td><td></td><td></td></tr><tr><td>&gt;499</td><td>0.149</td><td>0.266</td><td>0.044</td><td>1.607</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Status malignancy at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Controlled disease</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Stable disease</td><td>0.980</td><td>0.000</td><td>0.000</td><td>-</td><td>0.950</td><td>0.000</td><td>0.000</td><td>-</td></tr><tr><td>Active disease</td><td>0.064</td><td>4.721</td><td>0.915</td><td>24.354</td><td>0.311</td><td>2.462</td><td>0.431</td><td>14.060</td></tr><tr><td>Unknown</td><td>0.993</td><td>0.000</td><td>0.000</td><td>-</td><td>0.995</td><td>0.000</td><td>0.000</td><td>-</td></tr><tr><td><strong>Baseline malignancy at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Leukaemia</td><td>-</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Lymphoma</td><td>0.837</td><td>0.863</td><td>0.213</td><td>3.492</td><td></td><td></td><td></td><td></td></tr><tr><td>PH negative myeloproliferative diseases</td><td>0.989</td><td>0.000</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Plasma cell disorders</td><td>0.971</td><td>0.000</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Symptoms at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Pulmonary</td><td>-</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Pulmonary + extrapulmonary</td><td>0.966</td><td>0.968</td><td>0.212</td><td>4.419</td><td></td><td></td><td></td><td></td></tr><tr><td>Extrapulmonary</td><td>0.305</td><td>0.299</td><td>0.030</td><td>3.001</td><td></td><td></td><td></td><td></td></tr><tr><td>Screening</td><td>0.988</td><td>0.000</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>SARS-CoV-2 vaccination status at COVID-19 onset</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Not vaccinated</td><td>-</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>One dose</td><td>0.940</td><td>-</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Two doses</td><td>0.920</td><td>-</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Three doses</td><td>0.924</td><td>-</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Four doses</td><td>0.980</td><td>1735.991</td><td>0.000</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>ICU admission</strong></td><td>0.106</td><td>3.614</td><td>0.760</td><td>17.178</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Nirmatrelvir/ritonavir line</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Other line</td><td>-</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>First line</td><td>0.997</td><td>1.003</td><td>0.188</td><td>5.349</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Days from COVID-19 onset to nirmatrelvir/ritonavir treatment</strong></td><td>0.771</td><td>1.003</td><td>0.980</td><td>1.027</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Stay during COVID-19 episode</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Home</td><td>-</td><td>-</td><td>-</td><td>-</td><td></td><td></td><td></td><td></td></tr><tr><td>Hospital</td><td>0.171</td><td>4.387</td><td>0.528</td><td>36.477</td><td></td><td></td><td></td><td></td></tr></tbody></table>

This table includes patients from European institutions. CI, confidence interval; COVID-19, coronavirus 2019 disease; HR, hazard ratio; ICU, intensive care unit; PH, Philadelphia; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

<caption>Table 5: Factors associated with mortality in patients with nirmatrelvir/ritonavir administration.</caption>
## Contributors

JSG, FM, LP and OAC contributed to study design and study supervision. JSG did the statistical plan and analysis. JSG and OAC interpreted the data and wrote the paper. All the authors recruited, and documented participants, critically read, reviewed, and agreed to publish the manuscript.

## Data sharing statement

Data are available upon reasonable request to the corresponding authors
Dr. Jon Salmanton-García (jon.salmanton-garcia@uk-koeln.de) or Prof.
Dr. Oliver A. Cornely (oliver.cornely@uk-koeln.de).

## Declaration of interests

The authors do not declare conflicts of interest related to the submitted manuscript. The funder of the study had no role in study design, data analysis, interpretation, or writing of the report. All authors had full access to the data and had final responsibility for the decision to submit for publication.

## Acknowledgments

The authors thank all participating institutions for their utmost contributions and support to the project during a pandemic situation. In addition, we would like to express our gratitude to Professor Francisco Javier Martin-Vallejo (Department of Statistics, Faculty of Medicine, University of Salamanca, Salamanca, Spain) for his guidance in performing the statistical analyses of this manuscript. EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

## Appendix A. Supplementary data

Supplementary data related to this article can be found at https://doi.org/10.1016/j.eclinm.2023.101939.

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