
==== Front
Ren Fail
Ren Fail
Renal Failure
0886-022X
1525-6049
Taylor & Francis

39282735
10.1080/0886022X.2024.2385724
2385724
Version of Record
Research Article
Transplantation
The effectiveness of nirmatrelvir/ritonavir regimen in hospitalized renal transplant patients with prolonged COVID-19 infection: a multicenter clinical experience
H. Zhang et al.
Zhang Huanxi a*
Wu Wenrui a*
Zheng Yitao b*
Fu Qian a
Chen Peisong c
Li Jianyi a
Wu Zixuan b
Gu Jincui d
Li Jun a
Liu Longshan aef
Wu Chenglin a
Long Sizhe g
Xu Bowen a
Ling Liuting a
Fu Yingxin b
Wang Changxi aef
a Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
b Kidney Transplant Department, Organ Transplant Center, Third People’s Hospital of Shenzhen, The Second Affiliated Hospital, Southern University of Science and Technology, National Clinical Research Center for Infectious Disease, Shenzhen, China
c Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
d Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
e Guangdong Provincial Key Laboratory on Organ Donation and Transplant Immunology, Guangzhou, China
f Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
g Center for Information Technology and Statistics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
* These authors contributed equally to this work.

Supplemental data for this article can be accessed online at https://doi.org/10.1080/0886022X.2024.2385724.

CONTACT Yingxin Fu fuyingxin@vip.163.com Kidney Transplantation Department, The Third People’s Hospital of Shenzhen, No. 29, Bulan Road, Longgang District, Shenzhen 518112, China;
Changxi Wang wangchx@mail.sysu.edu.cn Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Second Road, Yuexiu District, Guangzhou 510080, China
16 9 2024
2024
16 9 2024
46 2 238572424 1 2024
23 7 2024
24 7 2024
KnowledgeWorks Global Ltd.13 9 2024
published online in a building issue13 9 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

Objectives

Effectiveness of nirmatrelvir/ritonavir (NR) in kidney transplant recipients (KTRs) infected COVID-19 for more than 5 days has not been evaluated.

Methods

In this multicenter retrospective study, 85 KTRs with COVID-19 were enrolled, including 50 moderate, 21 severe, and 14 critical patients.

Results

The median time from onset to starting NR treatment was 14 (IQR, 11–19) days. Before NR treatment, 96.5% patients reduced use of antimetabolites. They also stopped using calcineurin inhibitors (CNI) 12–24 hours before NR treatment, with CNI concentrations well-controlled during NR treatment. The use of intravenous corticosteroids increased with COVID-19 severity. The median time to reach viral negative conversion was 5 (IQR, 4–8) days for all patients. For moderate and severe COVID-19 patients, they had a low rate of ICU admission (1.4%), exacerbation requiring upgraded oxygen therapy (5.6%), and dialysis (2.8%); no intubation and mechanical ventilation, and no deaths were observed. Patients with critical COVID-19 had a low mortality rate (7.1%).

Conclusions

A regimen including NR for clearing SARS-CoV-2 along with reducing immunosuppressants and using intravenous corticosteroids is associated with lower rates of exacerbation and mortality in KTRs who have moderate to critical SARS-CoV-2 infection and the virus still present after 5 days.

Keywords

Nirmatrelvir/ritonavir
SARS-CoV-2
COVID-19
kidney transplantation
efficacy
Science and Technology Planning Project of Guangzhou City 201903010058 202201011318 National Natural Science Foundation of China 10.13039/501100001809 81870511 82170770 Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology 2013A061401007 2017B030314018 2020B1212060026 Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation) 2015B050501002 2020A0505020003 Elite Talent Project of Guangdong Province R09002 Major Clinical Technology Project, Municipal Health Commission, Guangzhou, China 2023 P-ZD15 This study was supported by Science and Technology Planning Project of Guangzhou City (201903010058, 202201011318), National Natural Science Foundation of China (81870511, 82170770), Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (2013A061401007, 2017B030314018, 2020B1212060026), Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (2015B050501002, 2020A0505020003), Elite Talent Project of Guangdong Province (R09002), and Major Clinical Technology Project, Municipal Health Commission, Guangzhou, China (2023 P-ZD15).
==== Body
pmc1. Introduction

In December 2022, the Chinese government adjusted its COVID-19 epidemic prevention and control policy, resulting in an outbreak predominantly led by the Omicron subvariants BA.5.2 and BF.7. Renal transplant recipients, who have long-term exposure to immunosuppressive agents, are at high risk for severe SARS-CoV-2 infection, especially if they have not completed prior vaccination. Nirmatrelvir/ritonavir (NR) is an oral anti-viral agent that is effective in eliminating SARS-CoV-2 and preventing severe infection when used early (<5 days) after COVID-19 onset [1]. Previous studies have shown that using NR early after SARS-CoV-2 infection in renal transplant recipients reduces hospitalization and mortality rates [2–5]. However, most patients in this outbreak became infected without adequate drug preparation and failed to eliminate the virus with NR early after infection. Some of these patients had symptoms early after infection that were not severe, but with a long duration of illness, persistence of the virus, prolonged and recurrent symptoms, and some progressed to shortness of breath and decreased blood oxygen, which was found to be bilateral interstitial pneumonia after hospital visits. There is limited evidence on the efficacy of NR in these renal transplant recipients with moderate to critical SARS-CoV-2 infection, prolonged symptoms, and high virus load over 1–2 weeks after onset. The hypothesis is that using NR for virus clearance in renal transplant recipients after 5 days of infection can improve respiratory function, accelerate recovery, and reduce the risk of mechanical ventilation and death. This retrospective study aims to preliminarily assess the impact of NR on clinical outcomes in renal transplant patients with moderate to critical SARS-CoV-2 infection after 5 days of onset and whose viruses remain uncleared.

2. Patients and method

2.1. Study population and design

In this study, we analyzed adult kidney transplant recipients (KTRs) who were diagnosed with moderate to critical COVID-19, were hospitalized, and received the antiviral agent nirmatrelvir/ritonavir (NR). The study was conducted in the First Affiliated Hospital of Sun Yat-sen University (with 3956 hospital beds) and the Third People’s Hospital of Shenzhen (with 2416 hospital beds), between 1 November 2022 and 20 January 2023. None of the organs were procured from executed prisoners. All the organs were procured after informed consent or authorization for organ donation, by organ procurement organization. Participants had received their kidney transplant more than 2 months prior to hospitalization. Participants who had experienced graft failure at the time of hospitalization or who received NR treatment within 5 days after the onset of COVID-19 were excluded from the study. It was a retrospective study and written informed consent was waived. The study was approved by the institutional review board of the First Affiliated Hospital of Sun Yat-sen University.

2.2. COVID-19 diagnosis and evaluation

The diagnosis of COVID-19 was based on symptoms and positive results of SARS-CoV-2 nucleic acid or antigen tests. The day of onset was determined as either the first day of a positive test or the onset of symptoms. The SARS-CoV-2 ORF1ab and N gene were detected using real-time RT-PCR tests. The cycle threshold (Ct) value represented the number of replication cycles required for the detection of viral nucleic acid [6]. The severity of illness was evaluated based on definitions adopted from the National Institutes of Health [7]. Mild COVID-19 was defined as the presence of symptoms without evidence of lower respiratory disease. Moderate COVID-19 was diagnosed in patients with evidence of lower respiratory disease but with an oxygen saturation of 94% or higher on room air. Severe COVID-19 was diagnosed in patients with an oxygen saturation of less than 94%, a PaO2/FiO2 ratio of less than 300 mm Hg, a respiratory rate of more than 30 breaths per minute, or lung infiltrates of more than 50%. Critical COVID-19 was defined as respiratory failure, septic shock, or multiple organ dysfunction.

2.3. Treatment

The dose of NR was adjusted based on the patient’s renal allograft function, as measured by the estimated glomerular filtration rate (eGFR) [8]. For patients with eGFR above 60 mL/min/1.73m2, the regimen was 300 mg of nirmatrelvir combined with 100 mg of ritonavir twice a day for 5 days. For those with eGFR between 30 and 60 mL/min/1.73m2, the dose of nirmatrelvir was reduced to 150 mg [9]. And for patients with eGFR below 30 mL/min/1.73m2, the dose was reduced to 300 mg of nirmatrelvir combined with 100 mg of ritonavir once a day for the first day and 150 mg of nirmatrelvir combined with 100 mg of ritonavir once a day for 4 days [10]. The calcineurin inhibitor (CNI), including tacrolimus and cyclosporine, was stopped 12–24 hours before starting NR medication. The CNI plasma trough concentration was monitored and the dose was adjusted until it reached the target range [11, 12]. Other concomitant medications were reviewed and any that had strong drug–drug interactions with NR were discontinued or changed [8, 13–15]. Immunosuppressants were reduced or withdrawn based on the severity of illness, and corticosteroids were given intravenously for patients with recurrent high fever, high levels of CRP and IL-6, or hypoxia. Antibiotics, antifungals, anti-pneumocystis drugs, and other anti-viral drugs were used based on laboratory results and pathogenic evidence.

2.4. Outcome measurement

A negative COVID-19 result was defined as having Ct values of both ORF1ab and N genes above 35. The duration of time from the start of NR treatment to a negative test result and the percentage of patients who had a negative test result at every 7-day interval following NR treatment were recorded. The length of hospital stay from admission to discharge and the percentage of patients who were discharged from the hospital were also recorded. Other outcomes included the use of oxygen therapy, admission to the intensive care unit (ICU), all-cause mortality, graft rejection, and dialysis related to COVID-19 infection.

2.5. Statistical analysis

The continuous variables were expressed as median and interquartile range (IQR), and the categorical variables were presented as counts and percentages. Comparisons of continuous or categorical variables between patients with different levels of COVID-19 severity were conducted using Wilcoxon rank-sum tests or chi-squared tests, respectively. Shapiro–Wilk test was used for test of normality. All statistical tests were 2-sided and a p value less than 0.05 was considered statistically significant. Analyses were conducted using R version 4.2.2. Package base (4.2.2) and stats (4.2.2) were used for statistical inference analysis, compareGroups (4.7.0) was used for statistical descriptive analysis, and ggplot2 (3.5.0) was used for visualization.

3. Result

3.1. Baseline characteristics

In this study, 85 KTRs with COVID-19 were enrolled (Figure 1), of which 50 were moderate (58.8%), 21 were severe (24.7%) and 14 were critical (16.5%) (Table 1). There were no significant differences in baseline parameters between the groups expect the presence of hypertension, hepatitis and acute kidney injury (AKI) at admission, oxygen therapy, use of intravenous glucocorticoids, antibiotics and anti-Pneumocystis jiroveci pneumonia (PJP) agent. NR treatment was initiated a median of 14.0 (IQR, 11.0–19.0) days after the onset of COVID-19. Six patients (7.06%) required two rounds of NR treatment. A higher prevalence of hypertension (85.7%, p = 0.042) and hepatitis (35.7%, p = 0.011) was found in critical patients compared with those with mild or severe infection. At admission, 30.6% of patients had concurrent AKI, with a higher incidence in patients with more severe COVID-19 (p trend = 0.002). Before starting NR treatment, 82.4% patients discontinued their use of antimetabolites, and 14.1% reduced their doses by 50–66%. Patients with more severe COVID-19 were more likely to discontinue antimetabolites, with all critical patients stopped their use prior to starting NR medication. During NR treatment, the trough concentrations of CNI were well-controlled, with a median concentration of 3.7 (IQR, 2.3–5.2) ng/mL for tacrolimus, and 64.6 (IQR, 56.0–93.0) ng/mL for cyclosporine. The use of intravenous corticosteroids increased with the severity of COVID-19 (p < 0.001), with 54.0%, 81.0%, and 100% of moderate, severe, and critical patients receiving the treatment, respectively. A substantial number of patients were prescribed antibiotics (69.4%), antifungal drugs (7.06%), and anti-PJP medications (14.1%) due to co-infection. Antivirals were prescribed to 31.8% of the patients, with 21.2% receiving Azvudine for a median duration of 5.00 days (IQR, 3.00–7.75). However, SARS-CoV-2 clearance was not achieved before NR treatment. A trend was observed that patients with more severe COVID-19 were more likely to use drugs for co-infections, especially for antibiotics (p = 0.014) and anti-PJP drugs (p = 0.013).

Figure 1. The flowchart of inclusion and exclusion.

Table 1. Baseline characteristics of patients among different COVID-19 severity.

 	Total
(N = 85)	Moderate
(N = 50)	Severe
(N = 21)	Critical
(N = 14)	p Value	p Value
for trend	
Age (years)	51.0 [41.0;57.0]	50.0 [39.2;55.8]	53.0 [48.0;57.0]	51.0 [41.2;58.0]	0.308	0.192	
Gender: male	57 (67.1%)	30 (60.0%)	18 (85.7%)	9 (64.3%)	0.115	0.341	
BMI (kg/m2)	22.0 [20.2;24.2]	21.6 [19.7;23.3]	22.4 [20.4;25.3]	23.0 [21.3;24.2]	0.142	0.053	
Chronic disease	 	 	 	 	 	 	
 Hypertension	51 (60.0%)	25 (50.0%)	14 (66.7%)	12 (85.7%)	0.042	0.012	
 Diabetes mellitus	28 (32.9%)	15 (30.0%)	8 (38.1%)	5 (35.7%)	0.766	0.573	
 Coronary heart disease	6 (7.06%)	5 (10.0%)	1 (4.76%)	0 (0.00%)	0.603	0.172	
 Hepatitis	15 (17.6%)	10 (20.0%)	0 (0.00%)	5 (35.7%)	0.011	0.613	
Hospitalization with AKI	26 (30.6%)	10 (20.0%)	7 (33.3%)	9 (64.3%)	0.007	0.002	
Time from KT to COVID-19 onset (months)	40.7 [15.9;83.8]	33.7 [15.9;75.7]	50.1 [15.6;83.8]	47.8 [29.6;121]	0.48	0.264	
Time from COVID-19 onset to NR (days)	14.0 [11.0;19.0]	12.5 [10.0;19.8]	17.0 [13.0;20.0]	12.0 [11.0;16.8]	0.183	0.564	
Oxygen therapy prior to NR	 	 	 	 	<0.001	<0.001	
 No oxygen therapy	11 (12.9%)	11 (22.0%)	0 (0.00%)	0 (0.00%)	 	 	
 Oxygen by mask or nasal prongs	60 (70.6%)	39 (78.0%)	21 (100%)	0 (0.00%)	 	 	
 Oxygen by NIV or high flow	13 (15.3%)	0 (0.00%)	0 (0.00%)	13 (92.9%)	 	 	
 Intubation and mechanical ventilation	1 (1.18%)	0 (0.00%)	0 (0.00%)	1 (7.14%)	 	 	
SCr prior to NR (μmol/L)	142 [102;207]	136 [102;193]	156 [103;253]	144 [104;189]	0.681	0.692	
Total rounds of NR:	 	 	 	 	0.288	0.158	
 One	79 (92.9%)	48 (96.0%)	19 (90.5%)	12 (85.7%)	 	 	
 Two	6 (7.06%)	2 (4.00%)	2 (9.52%)	2 (14.3%)	 	 	
Modification of antimetabolite drugs prior to NR	 	 	 	 	0.294	0.062	
 No modification	3 (3.53%)	2 (4.00%)	1 (4.76%)	0 (0.00%)	 	 	
 Reduction	12 (14.1%)	10 (20.0%)	2 (9.52%)	0 (0.00%)	 	 	
 Withdrawal	70 (82.4%)	38 (76.0%)	18 (85.7%)	14 (100%)	 	 	
Tacrolimus concentration during NR	3.70 [2.30;5.18]	3.80 [2.55;4.75]	2.90 [2.15;5.00]	3.60 [1.00;6.30]	0.818	0.676	
Cyclosporine concentration during NR	64.6 [56.0;93.0]	63.9 [59.6;78.7]	81.5 [60.2;103]	65.0 [65.0;65.0]	0.875	0.701	
Concomitant drugs during NR	 	 	 	 	 	 	
 Intravenous glucocorticoids	58 (68.2%)	27 (54.0%)	17 (81.0%)	14 (100%)	0.001	<0.001	
 Antivirala	27 (31.8%)	12 (24.0%)	9 (42.9%)	6 (42.9%)	0.180	0.096	
 Antibiotic	59 (69.4%)	30 (60.0%)	16 (76.2%)	13 (92.9%)	0.050	0.014	
 Antifungal	6 (7.06%)	3 (6.00%)	1 (4.76%)	2 (14.3%)	0.501	0.392	
 Anti-PJP	12 (14.1%)	4 (8.00%)	3 (14.3%)	5 (35.7%)	0.035	0.013	
Note: continuous variables reported as median [IQR], categorical variables reported as n (%).

aAntiviral treatment including azvudine, ribavirin, molnupiravir, ganciclovir, and oseltamivir.

BMI: body mass index; AKI: acute kidney injury; KT: kidney transplantation; NR: nirmatrelvir/ritonavir; NIV: noninvasive ventilation; SCr: serum creatinine; PJP: Pneumocystis jiroveci pneumonia.

3.2. Viral negative conversion

The median Ct values of N and ORF1ab genes before NR treatment were 27.4 (IQR, 23.9–32.3) and 28.4 (IQR, 24.4–32.8) for all patients, respectively (Table 2). Patients with critical COVID-19 had the lowest Ct values of N gene (p = 0.027) and ORF1ab gene (p = 0.040). The Ct values of all patients increased significantly 7 days after NR treatment (p < 0.001) (Supplement Figure 1). The viral negative conversion (VNC) rate 7 days, 14 days and 28 days after NR treatment was 71.8%, 90.6% and 95.3% for all patients, respectively. The median time to reach VNC was 5.00 (IQR, 4.00–8.00) days for all patients. No significant differences were found in the time or rates of VNC among patients with different levels of COVID-19 severity.

Table 2. Viral negative conversion and Ct values of patients among different COVID-19 severity.

 	Total
(N = 85)	Moderate
(N = 50)	Severe
(N = 21)	Critical
(N = 14)	p Value	p Value
for trend	
N gene	 	 	 	 	 	 	
 Ct value on D0	27.4 [23.9;32.3]	27.2 [24.0;32.3]	31.2 [27.4;34.1]	24.4 [22.2;29.3]	0.027	0.919	
 Ct value on D7	40.0 [35.2;40.0]	40.0 [34.2;40.0]	40.0 [36.0;40.0]	40.0 [35.6;40.0]	0.858	0.587	
 Difference of Ct values (D7–D0)	8.56 [5.37;13.4]	9.25 [5.73;13.3]	6.09 [5.15;9.93]	11.5 [4.97;17.8]	0.121	0.828	
ORF1ab gene	 	 	 	 	 	 	
 Ct value on D0	28.4 [24.4;32.8]	28.4 [24.5;32.2]	31.4 [27.9;34.1]	24.0 [23.0;30.1]	0.040	0.809	
 Ct value on D7	40.0 [35.7;40.0]	40.0 [34.8;40.0]	40.0 [37.0;40.0]	40.0 [35.8;40.0]	0.853	0.583	
 Difference of Ct values (D7–D0)	8.30 [5.27;14.0]	8.96 [5.42;13.8]	6.61 [5.32;10.3]	13.0 [4.82;17.0]	0.224	0.955	
Viral negative conversion rate	 	 	 	 	 	 	
 Within 7 days	61 (71.8%)	39 (78.0%)	14 (66.7%)	8 (57.1%)	0.244	0.102	
 Within 14 days	77 (90.6%)	47 (94.0%)	18 (85.7%)	12 (85.7%)	0.381	0.244	
 Within 21 days	81 (95.3%)	49 (98.0%)	20 (95.2%)	12 (85.7%)	0.115	0.070	
 Within 28 days	81 (95.3%)	49 (98.0%)	20 (95.2%)	12 (85.7%)	0.115	0.070	
Time from NR to viral negative conversion (days)	5.00 [4.00;8.00]	5.00 [4.00;7.00]	6.00 [4.00;8.00]	6.50 [5.25;9.00]	0.356	0.201	
Note: continuous variables reported as median [IQR], categorical variables reported as n (%).

N: nucleocapsid protein; ORF1ab: open reading frame 1ab; NR: nirmatrelvir/ritonavir; D0: the day prior to NR medication; D7: 7 days after NR medication; Ct: cycle threshold.

3.3. Hospital discharge

Patients with moderate and severe COVID-19 had a higher rate of hospital discharge within 28 days (96.0% and 85.7%, respectively) compared to critical patients (57.1%, p < 0.001). The median time of hospitalization was 12.0 days (IQR, 8.0–18.0) for all patients, with critical patients staying longer in the hospital (25.0 days; IQR, 14.5–33.0) compared to moderate (11.0 days; IQR, 8.0–14.0, p < 0.001) and severe (11.0 days; IQR, 9.0–15.0, p = 0.007) patients.

3.4. Other outcomes

During the hospitalization, higher level of oxygen therapy was needed in patients with more severe COVID-19 (p < 0.001). For critical patients, 64.3% required noninvasive ventilation (NIV) or high-flow oxygen therapy and 35.7% required intubation with mechanical ventilation (Table 3). While only 2.00% of moderate and 14.3% of severe patients required NIV or high-flow oxygen therapy, and no moderate and severe patients required intubation and mechanical ventilation. Furthermore, patients with more severe COVID-19 required more upgrades of oxygen therapy (p = 0.002). Of all the 85 patients, 9.4% patients were transferred to ICU for further treatment, 5.9% needed dialysis, and 1.2% died. Higher rates of ICU admission (p < 0.001) and dialysis (p = 0.013) were observed in more severe COVID-19 patients. No rejection due to COVID-19 infection was observed. On hospital discharge, liver enzymes (ALT or AST) of 5.0% of all patients were higher than 3 times the upper limit of normal.

Table 3. Outcomes of patients among different COVID-19 severity.

 	Total
(N = 85)	Moderate
(N = 50)	Severe
(N = 21)	Critical
(N = 14)	p Value	p Value
for trend	
Highest level of oxygen therapy during hospitalization	 	 	 	 	<0.001	<0.001	
 No oxygen therapy	11 (12.9%)	11 (22.0%)	0 (0.00%)	0 (0.00%)	 	 	
 Oxygen by mask or nasal prongs	56 (65.9%)	38 (76.0%)	18 (85.7%)	0 (0.00%)	 	 	
 Oxygen by NIV or high flow	13 (15.3%)	1 (2.00%)	3 (14.3%)	9 (64.3%)	 	 	
 Intubation and mechanical ventilation	5 (5.88%)	0 (0.00%)	0 (0.00%)	5 (35.7%)	 	 	
Upgrade of oxygen therapya	8 (9.41%)	1 (2.00%)	3 (14.3%)	4 (28.6%)	0.007	0.002	
Dialysis	5 (5.88%)	1 (2.00%)	1 (4.76%)	3 (21.4%)	0.032	0.013	
Rejection	0 (0.00%)	0 (0.00%)	0 (0.00%)	0 (0.00%)	.	.	
ICU admission	8 (9.41%)	0 (0.00%)	1 (4.76%)	7 (50.0%)	<0.001	<0.001	
Mortality	1 (1.18%)	0 (0.00%)	0 (0.00%)	1 (7.14%)	0.165	0.060	
SCr on hospital discharge (μmol/L)	126 [101;189]	130 [102;187]	142 [98.5;227]	118 [104;127]	0.517	0.738	
ALT or AST > 3 times of ULN on hospital discharge	4 (5.00%)	1 (2.17%)	2 (10.0%)	1 (7.14%)	0.263	0.288	
Hospital discharge rate	 	 	 	 	 	 	
 Within 7 days	11 (12.9%)	11 (22.0%)	0 (0.00%)	0 (0.00%)	0.012	0.007	
 Within 14 days	57 (67.1%)	38 (76.0%)	15 (71.4%)	4 (28.6%)	0.005	0.003	
 Within 21 days	69 (81.2%)	47 (94.0%)	17 (81.0%)	5 (35.7%)	<0.001	<0.001	
 Within 28 days	74 (87.1%)	48 (96.0%)	18 (85.7%)	8 (57.1%)	0.001	<0.001	
Time of hospitalization (days)	12.0 [8.00;18.0]	11.0 [8.00;14.0]	11.0 [9.00;15.0]	25.0 [14.5;33.0]	<0.001	<0.001	
Note: continuous variables reported as median [IQR], categorical variables reported as n (%).

aLevels of oxygen therapy: No oxygen therapy < Oxygen by mask or nasal prongs < Oxygen by NIV or high flow < Intubation and mechanical ventilation. A change to a higher level of oxygen therapy was defined as an upgrade of oxygen therapy.

NIV: noninvasive ventilation; ICU: intensive care unit; ALT: alanine transaminase; AST: aspartate transaminase; ULN: upper limit of normal.

4. Discussion

Studies have shown that taking NR orally within 5 days of SARS-CoV-2 infection in kidney transplant patients reduces hospitalization and mortality rates [2–5]. However, there is limited research on the impact of taking NR more than 5 days after infection. Our study found that taking NR orally after reducing or withdrawing immunosuppressants with or without intravenous corticosteroids was effective in clearing the virus in hospitalized kidney transplant recipients, with a 100% negative conversion rate and median virus clearance time of 4 days (IQR 3–7 days). The results were consistent across patients with different levels of severity. Patients with moderate or severe illness had low rates of progression to invasive mechanical ventilation, and all patients had low mortality.

In the general population with COVID-19, the median duration of virus shedding was 20 days [16]. A study has found that taking NR within 5 days of onset accelerates nucleic acid negative conversion to a median of 10 days, but taking it beyond 5 days is similar to not taking it at all (median 15 vs 17 days) [6]. In renal transplant patients, the duration of virus shedding is longer, with studies finding it to be 28.4 ± 9.3 days and up to 65 days in some cases [17, 18]. Four out of 16 renal transplant patients in a study by L Benotmane et al. had viable virus shedding for over 3 weeks [19]. These findings highlight the need for NR in accelerating virus clearance in kidney transplant patients and our results confirm that using NR remains effective even more than 5 days after onset of symptoms.

SARS-CoV-2 virus has evolved into the current Omicron strain, which is less lethal but still poses a threat to patients who are hospitalized with COVID-19 [20]. During the Later Omicron epidemic (April to June 2022), the inpatient mortality rate was 4.86%, ICU admission rate 13.3%, noninvasive ventilation rate 10.5%, and invasive mechanical ventilation rate 6.1%. For the BA.5 strain epidemic in the US, the inpatient mortality rates were 1.1%, 2.8%, and 6% for ages 18–49, 50–64, and 65 and above, respectively [21]. Renal transplantation is considered a high-risk factor for severe COVID-19 due to the use of immunosuppressive drugs, underlying illnesses, and chronic kidney disease [22, 23]. However, studies have shown that transplantation was not associated with a significantly increased risk of severe disease and death compared to nontransplant patients [24]. The risk of death after SARS-CoV-2 infection in organ transplant recipients is related to the presence of high-risk factors [25]. The above findings were based on early strains of SARS-CoV-2. During the BA.1 and BA.2 epidemic, a cohort of organ transplant patients in Miami (67.5% kidney transplants) had an invasive mechanical ventilation rate of 15% and a mortality rate of 11.3% [26]. In Saudi Arabia, a cohort of 25 organ transplant patients (12 kidney transplants) had an ICU admission rate of 26.1% and a mortality rate of 21.7% [27]. No patients in these studies were treated with NR. During the Omicron epidemic, hospitalized organ transplant recipients appear to have a higher risk of death than the general hospitalized population. In our multicenter cohort using NR for postrenal transplant SARS-CoV-2 infection, inpatient mortality was very low (1.18%). Another cohort in China included 40 kidney transplant recipients (eGFR < 30 mL/min/1.73m2) with prolonged COVID-19 infection, who were also treated with NR treatment. The motility of this cohort with severe renal dysfunction was 5%, which was also much lower than patients without NR treatment but relatively higher than our cohort [28]. These results suggested that elimination virus with NR and reducing or withdrawing immunosuppression, with or without intravenous corticosteroids, is likely to improve clinical outcomes.

The known pathophysiological mechanisms following SARS-CoV-2 infection include two main components: first, viral replication, which induces host cell apoptosis and direct damage to respiratory epithelial cells; and second, release of cytokine storm, which activates the innate and adaptive immune systems and causes inflammatory and immune-related damage in the process of virus clearance [29]. During the early stage of infection, viral replication dominates, while later stages are dominated by inflammation. In renal transplant recipients, immunosuppressive drugs suppress the inflammatory response and prolong viral replication, leading to persistently high virus levels and persistent inflammatory response. Rapid viral clearance is therefore crucial in controlling inflammation and preventing exacerbation of the disease.

Some hospitalized renal transplant patients used Azvudine to clear the virus before the use of NR. Azvudine is an antiviral drug which acts as a reverse transcriptase inhibitor. Results from randomized controlled trials showed that in patients with mild to moderate COVID-19, the mean time to negative conversion was 2.6 days after Azvudine administration, significantly shorter than the control group [30]. In our cohort, Azvudine was used for a median of 5.0 days, with no significant change in Ct values. This suggests that for renal transplant recipients with moderate to severe SARS-CoV-2 infection, if the disease has exceeded 5 days, Azvudine may not be sufficient to achieve rapid viral clearance and more effective antiviral drugs may be needed. In addition to NR’s highly effective antiviral ability, remdesivir is also recommended for both adult and pediatric patients [31, 32], but access to it is limited and it must be administered intravenously, limiting its widespread use during the pandemic. Several new oral potent antiviral drugs have recently been launched globally, including simnotrelvir/ritonavir (SR) and VV116. Simnotrelvir in SR is a SARS-CoV-2 main protease inhibitor, as is nirmatrelvir in NR. A multicenter, randomized, double-blind, placebo-controlled phase II/III clinical trial evaluating the efficacy and safety of SR in the treatment of adult patients with mild to moderate COVID-19 infection has been completed, and the results suggest favorable efficacy. As a result, the Chinese FDA has granted conditional approval for its marketing [33]. VV116 is a deuterated remdesivir hydrobromide with oral bioavailability and potent activity against SARS-CoV-2. A phase 3 trial of VV116 was reported in the New England Journal of Medicine and the results showed that among adults with mild to moderate COVID-19 who were at risk for progression, VV116 was noninferior to NR with respect to the time to sustained clinical recovery, and had fewer safety concerns [34]. These drugs may contribute to efficient virus clearance and be useful for SARS-CoV-2 infected kidney transplant recipients in the future.

In summary, the study has a significant limitation as it lacks a control group, making it difficult to determine the exact effectiveness of NR in preventing disease progression and death related to COVID-19. Nevertheless, the results suggest that a regimen including NR for clearing SARS-CoV-2 virus along with reducing immunosuppressants and using intravenous corticosteroids is associated with lower rates of exacerbation and mortality in kidney transplant recipients who have moderate to critical SARS-CoV-2 infection and the virus still present after 5 days. Further controlled studies are needed to fully establish the effectiveness of NR.

Supplementary Material

Supplementary materials_V2.docx

Author contributions

Huanxi Zhang: Conceptualization, Methodology, Validation, Supervision, Writing – review & editing. Wenrui Wu: Methodology, Software, Data curation, Formal analysis, Visualization, Writing – original draft. Yitao Zheng: Data curation, Investigation, Validation, Formal analysis, Writing – original draft. Qian Fu: Data curation, Investigation, Validation. Peisong Chen: Data curation, Investigation, Resources. Jianyi Li: Data curation, Investigation. Zixuan Wu: Data curation, Investigation. Jincui Gu: Data curation, Validation. Jun Li: Data curation, Validation. Longshan Liu: Data curation, Validation. Chenglin Wu: Data curation, Validation. Sizhe Long: Data curation, Investigation. Bowen Xu: Resources. Liuting Ling: Resources. Yingxin Fu: Supervision, Project administration, Writing – review & editing. Changxi Wang: Supervision, Funding acquisition, Project administration, Resources, Writing – review & editing.

Disclosure statement

The abstract of this article, entitled The Potential Benefit of Rapid Virus Clearance in Hospitalized Renal Transplant Patients with Prolonged COVID-19 Infection: A Multi-Center Clinical Experience, has been published as conference poster abstract (https://doi.org/10.1016/j.ajt.2023.05.014, #ALB25) in the American Transplant Congress 2023 (in San Deigo, America).
==== Refs
References

1 Akinosoglou K, Schinas G, Gogos C. Oral antiviral treatment for COVID-19: a comprehensive review on nirmatrelvir/ritonavir. Viruses. 2022;14 (11 ):2540. doi: 10.3390/v14112540.36423149
2 Devresse A, Briol S, De Greef J, et al. Safety, efficacy, and relapse of nirmatrelvir-ritonavir in kidney transplant recipients infected with SARS-CoV-2. Kidney Int Rep. 2022;7 (11 ):2356–2363. doi: 10.1016/j.ekir.2022.08.026.36060621
3 Radcliffe C, Palacios CF, Azar MM, et al. Real‐world experience with available, outpatient COVID‐19 therapies in solid organ transplant recipients during the omicron surge. Am J Transpl. 2022;22 (10 ):2458–2463. Published online May 30, doi: 10.1111/ajt.17098.
4 Salerno DM, Jennings DL, Lange NW, et al. Early clinical experience with nirmatrelvir/ritonavir for the treatment of COVID-19 in solid organ transplant recipients. Am J Transpl. 2022;22 (8 ):2083–2088. doi: 10.1111/ajt.17027.
5 Hedvat J, Lange NW, Salerno DM, et al. COVID-19 therapeutics and outcomes among solid organ transplant recipients during the Omicron BA.1 era. Am J Transpl. 2022;22 (11 ):2682–2688. doi: 10.1111/ajt.17140.
6 Li H, Gao M, You H, et al. Association of nirmatrelvir/ritonavir treatment on upper respiratory severe acute respiratory syndrome coronavirus 2 reverse transcription-polymerase chain reaction (SARS-Cov-2 RT-PCR) negative conversion rates among high-risk patients with coronavirus disease 2019 (COVID-19). Clin Infect Dis. 2023;76 (3 ):e148–e154. doi: 10.1093/cid/ciac600.35870128
7 Management. COVID-19 treatment guidelines; [accessed 2023 Jan 28]. Available from: https://www.covid19treatmentguidelines.nih.gov/management/
8 Gerhart J, Cox DS, Singh RSP, et al. A comprehensive review of the clinical pharmacokinetics, pharmacodynamics, and drug interactions of nirmatrelvir/ritonavir. Clin Pharmacokinet. 2024;63 (1 ):27–42. doi: 10.1007/s40262-023-01339-y.38177893
9 Ritonavir-Boosted Nirmatrelvir (Paxlovid). COVID-19 treatment guidelines; [accessed 2023 Feb 9]. Available from: https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/ritonavir-boosted-nirmatrelvir–paxlovid-/
10 Hiremath S, McGuinty M, Argyropoulos C, et al. Prescribing nirmatrelvir/ritonavir for COVID-19 in advanced CKD. Clin J Am Soc Nephrol. 2022;17 (8 ):1247–1250. doi: 10.2215/CJN.05270522.35680135
11 Lange NW, Salerno DM, Jennings DL, et al. Nirmatrelvir/ritonavir use: managing clinically significant drug–drug interactions with transplant immunosuppressants. Am J Transpl. 2022;22 (7 ):1925–1926. doi: 10.1111/ajt.16955.
12 Shiohira H, Arakaki S, Uehara W, et al. Nirmatrelvir/ritonavir-induced elevation of blood tacrolimus levels in a patient in the maintenance phase post liver transplantation. J Infect Chemother. 2024;30 (1 ):77–80. doi: 10.1016/j.jiac.2023.09.006.37689137
13 Yalcin N, Demirkan K. Management of drug-related problems including drug–drug interactions caused by nirmatrelvir/ritonavir in paediatric patients with SARS-CoV-2. Arch Dis Child. 2023;108 (10 ):e16–e16. doi: 10.1136/archdischild-2022-324168.36180113
14 Yalcin N, Allegaert K. COVID-19 and antiepileptic drugs: an approach to guide practices when nirmatrelvir/ritonavir is co-prescribed. Eur J Clin Pharmacol. 2022;78 (10 ):1697–1701. doi: 10.1007/s00228-022-03370-7.35930055
15 Visscher R, Yalçın N, Bayraktar I, et al. Concomitant drug use of nirmatrelvir/ritonavir and CYP3A4-modulating antimicrobial agents: an approach for drug use. Eur J Hosp Pharm. 2024;31 (2 ):180–182. doi: 10.1136/ejhpharm-2023-003795.37105711
16 Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395 (10229 ):1054–1062. doi: 10.1016/S0140-6736(20)30566-3.32171076
17 Man Z, Jing Z, Huibo S, et al. Viral shedding prolongation in a kidney transplant patient with COVID-19 pneumonia. Am J Transpl. 2020;20 (9 ):2626–2627. doi: 10.1111/ajt.15996.
18 Zhu L, Gong N, Liu B, et al. Coronavirus disease 2019 pneumonia in immunosuppressed renal transplant recipients: a summary of 10 confirmed cases in Wuhan, China. Eur Urol. 2020;77 (6 ):748–754. doi: 10.1016/j.eururo.2020.03.039.32317180
19 Benotmane I, Risch S, Doderer-Lang C, et al. Long-term shedding of viable SARS-CoV-2 in kidney transplant recipients with COVID-19. Am J Transpl. 2021;21 (8 ):2871–2875. doi: 10.1111/ajt.16636.
20 Adjei S, Hong K, Molinari NAM, et al. Mortality risk among patients hospitalized primarily for COVID-19 during the omicron and delta variant pandemic periods—United States, April 2020-June 2022. MMWR Morb Mortal Wkly Rep. 2022;71 (37 ):1182–1189. doi: 10.15585/mmwr.mm7137a4.36107788
21 CDC. Coronavirus Disease 2019 (COVID-19). Centers for Disease Control and Prevention; 2020 [accessed 2023 Feb 9]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/science/data-review/populations.html
22 Goldman JD, Robinson PC, Uldrick TS, et al. COVID-19 in immunocompromised populations: implications for prognosis and repurposing of immunotherapies. J Immunother Cancer. 2021;9 (6 ):e002630. doi: 10.1136/jitc-2021-002630.34117116
23 Azzi Y, Parides M, Alani O, et al. COVID-19 infection in kidney transplant recipients at the epicenter of pandemics. Kidney Int. 2020;98 (6 ):1559–1567. doi: 10.1016/j.kint.2020.10.004.33069762
24 Opsomer R, Kuypers D. COVID-19 and solid organ transplantation: finding the right balance. Transpl Rev (Orlando). 2022;36 (3 ):100710. doi: 10.1016/j.trre.2022.100710.
25 Udomkarnjananun S, Kerr SJ, Townamchai N, et al. Mortality risk factors of COVID-19 infection in kidney transplantation recipients: a systematic review and meta-analysis of cohorts and clinical registries. Sci Rep. 2021;11 (1 ):20073. doi: 10.1038/s41598-021-99713-y.34625642
26 Anjan S, Khatri A, Viotti JB, et al. Is the omicron variant truly less virulent in solid organ transplant recipients? Transpl Infect Dis. 2022;24 (6 ):e13923. doi: 10.1111/tid.13923.35915957
27 Alshukairi AN, Aldabbagh Y, Adroub SA, et al. Outcome of transplant recipients infected with omicron BA.1 and BA.2: a single-center retrospective study in Saudi Arabia. J Epidemiol Glob Health. 2023;13 (1 ):47–54. doi: 10.1007/s44197-023-00084-6.36626091
28 Yang H, Yu X, Hou W, et al. Effectiveness and safety of nirmatrelvir-ritonavir in kidney transplant recipients with severe kidney dysfunction infected with COVID-19. Antimicrob Agents Chemother. 2024;68 (3 ):e0138423. doi: 10.1128/aac.01384-23.38289075
29 Parasher A. COVID-19: current understanding of its pathophysiology, clinical presentation and treatment. Postgrad Med J. 2021;97 (1147 ):312–320. doi: 10.1136/postgradmedj-2020-138577.32978337
30 Ren Z, Luo H, Yu Z, et al. A randomized, open-label, controlled clinical trial of azvudine tablets in the treatment of mild and common COVID-19, a pilot study. Adv Sci (Weinh). 2020;7 (19 ):e2001435. doi: 10.1002/advs.202001435.35403380
31 Yalçın N, Demirkan K. COVID-19 and remdesivir in pediatric patients: the invisible part of the iceberg. Pediatr Res. 2021;89 (6 ):1326–1327. doi: 10.1038/s41390-020-01109-7.32814341
32 Orth HM, Flasshove C, Berger M, et al. Early combination therapy of COVID-19 in high-risk patients. Infection. 2024;52 (3 ):877–889. doi: 10.1007/s15010-023-02125-5.38017344
33 National Medical Products Administration. [accessed 2023 Feb 9]. Available from: http://english.nmpa.gov.cn/
34 Cao Z, Gao W, Bao H, et al. VV116 versus nirmatrelvir-ritonavir for oral treatment of Covid-19. N Engl J Med. 2023;388 (5 ):406–417. doi: 10.1056/NEJMoa2208822.36577095
