1 Introduction
The emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its associated disease, coronavirus disease 2019 (COVID-19), has resulted in rapid viral dissemination, leading to the global pandemic. COVID-19 is highly contagious with high morbidity and mortality, particularly in special populations. Chronic kidney disease (CKD) and, in particular, maintenance hemodialysis are important independent risk factors for severe COVID-19 [
1,
2]. They outcompete other risk factors, such as age, diabetes, and cardiovascular disease. Patients receiving hemodialysis are susceptible to SARS-CoV-2 infections because they need to continue to attend their dialysis unit three times per week, and the mortality among these patients who develop COVID-19 is high [
1]. The data from Europe and Canada stated a COVID-19 lethality of 20%–30% in hemodialysis-dependent patients [
3,
4].
Vaccines against SARS-CoV-2 have greatly reduced mortality risks, but their efficacy against the Omicron variant of SARS-CoV-2 is reduced compared with that against Delta [
5]. In addition, the efficacy and immunological responses to vaccination obtained by healthy cohorts are unsuitable for hemodialysis cohorts, thereby limiting the widespread use of vaccines among hemodialysis patients. Given the situation in China, particularly in Shanghai, the COVID-19 vaccination rate of hemodialysis patients is low. Combining the high morbidity and mortality of hemodialysis patients with repeatedly emerging SARS-CoV-2 variants results in great challenges in treating infected hemodialysis patients. Thus, exploring antiviral treatments applicable to these patients is particularly important.
Nirmatrelvir/ritonavir (Paxlovid), developed by Pfizer, is a combination of two oral drugs. The first drug, nirmatrelvir, is a newly developed agent that blocks the SARS-CoV-2 3CL protease, which is important for viral replication; the second drug, ritonavir, is used to slow down nirmatrelvir metabolism [
6,
7]. The Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients (EPIC-HR) trial reported that Paxlovid treatment can decrease progression to severe COVID-19 and quickly reduce SARS-CoV-2 viral load [
8]. This finding raises new hope for COVID-19 recovery. Given the pharmacokinetics of nirmatrelvir, a dosage reduction is required in patients with moderate kidney dysfunction (estimated glomerular filtration rate: ≥30 mL/min/1.73 m
2 to < 60 mL/min/1.73 m
2). Moreover, nirmatrelvir is forbidden for hemodialysis patients. Antiviral therapy among hemodialysis patients has not been reported until now. Therefore, in the present study, we investigated the safety and efficacy of Paxlovid therapy for hemodialysis patients with SARS-CoV-2 infections.
2 Materials and methods
2.1 Study populations
The present study is a prospective, single-center, open-label, randomized, controlled trial that evaluated the safety and efficacy of Paxlovid among hemodialysis patients with SARS-CoV-2 infection. The cohort included SARS-CoV-2-infected adults with established renal failure treated with hemodialysis. Eligible patients were required to be at least 18 years old and to have a confirmed SARS-CoV-2 infection and a symptom onset of no more than 5 days before randomization with at least one sign or symptom of COVID-19 on the day of randomization [
8].
The key exclusion criteria are as follows: history of active liver disease, known HIV (viral load: > 400 copies/mL), suspected/confirmed active systemic infection, acute heart failure or respiratory failure caused by uremia-related complications or severe cardiovascular disease, life expectancy of less than 3 months, and known hypersensitivity to the composition of Paxlovid.
2.2 Study design and rationale for modified dose
In the current wave of the COVID-19 pandemic in Shanghai with the Omicron variant of SARS-CoV-2, all the infected hemodialysis patients were admitted to the designated hospital for hemodialysis therapy. After the informed consent form was signed, the baseline clinical data and chest computed tomography (CT) scans of the recruited patients were collected. The eligible patients were randomly divided into Paxlovid treatment group and control group via an interactive response technology system. The study persisted until the patients’ polymerase chain reaction (PCR) tests turned negative. The Paxlovid treatment patients received Paxlovid for 5 days combined with basic treatment after dialysis on the dialysis days; the control patients received basic treatment only. In the current study, the basic treatment of the patients included Chinese medicine, nutritional support, and oxygen inhalation. During the study, a real-time reverse transcription–PCR (RT-PCR) test was performed to detect SARS-CoV-2 nucleic acid every other day. The clinical data and chest CT information were collected on the 1st day of administration and the day of negative PCR test results. They were reexamined as needed.
The Paxlovid used in the present study is manufactured by Pfizer and consists of nirmatrelvir and ritonavir. Nirmatrelvir is currently formulated as 150 mg and dosed at 300 mg with 100 mg ritonavir twice a day for patients with normal kidney function and at 150 mg with 100 mg ritonavir twice a day in patients with an estimated glomerular filtration rate (eGFR) of 30–60 mL/min/1.73 m
2. The safety profile of nirmatrelvir is quite favorable, and the animal data do not indicate dose-dependent toxicity. Pierre et al. [
9] have recently reported that a modified dose of Paxlovid (300 mg with 100 mg ritonavir followed by 150 mg daily) is associated with symptom resolution with no serious adverse effects. Hence, with pharmacist support, we chose a dose of 150 mg nirmatrelvir with 100 mg ritonavir to reduce possible side effects further and investigate the effect of Paxlovid on infected hemodialysis patients in the current study.
2.3 Outcomes
The primary objective of the trial was to assess the efficacy of Paxlovid treatment in the prognosis of pneumonia using chest CT. The secondary outcome was the time of the negative PCR tests and viral load in the two groups.
The safety endpoints included adverse events that emerged during or after the Paxlovid treatment period. We observed Paxlovid-related symptoms, including nausea, vomiting, diarrhea, and headache. In addition, we monitored patients’ liver function using laboratory examination data. The investigators actively collected safety information throughout hospital admission.
2.4 Statistical analyses
For normally distributed quantitative variables, the distribution was summarized as the means and standard deviations; for nonnormally distributed quantitative variables, the distributions were summarized as medians and ranges. For continuous variables, the Student’s t-test or the Mann‒Whitney U test was used to compare the two groups. Categorical variables were expressed as frequencies and percentages, and the group proportions were compared with a Pearson χ2 test.
2.5 Ethics
The study was approved by the Clinical Trial Ethics Committee of the Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. All the participants provided written informed consent.
3 Results
3.1 General characteristics of the enrolled patients
From April 3, 2022, to May 30, 2022, 13 hemodialysis patients with Omicron infections were enrolled in the present study. The flowchart of the current study is shown in Fig.1. The treatment group included six patients who received Paxlovid plus basic treatment, whereas the control group included seven patients who received only basic treatment. The baseline clinical characteristics are shown in Tab.1. The treatment group included five female patients, whereas the control group had two female patients (P=0.11). The mean ages of the treatment and control patients were 65.5 ± 14.9 and 73.1 ± 8.3, respectively (P=0.39), whereas the mean hemodialysis times were 4.9 ± 3.7 years and 2.9 ± 1.7 years, respectively (P=0.27). Regarding laboratory parameters, the alanine aminotransferase (ALT) levels in the treatment patients were higher than those in the control patients (P=0.02). However, all the patients’ ALT levels were within the normal range. In addition, no significant differences were found in other detected laboratory parameters or the baseline level of SARS-CoV-2 RT-PCR between the two groups (Tab.1).
Tab.2 shows the detailed clinical information of all the enrolled patients. The information on uremia-related medications is shown in Table S1. In the treatment group (T1–T6), the days of Paxlovid therapy from the symptom onset were 1–3 days. All patients were mildly symptomatic on admission. The principal symptoms were cough (five patients in the treatment group and five patients in the control group) and fever (one patient in the treatment group and three patients in the control group). In addition, two patients had sputum production (C2 and C7), one patient had shortness of breath (T1), and one patient had diarrhea (T4). Regarding comorbidities, all the patients, except T6, had hypertension, and six patients had diabetes (T2–T3, C2, and C5–C7). In addition, one patient had asthma (T3), one patient had poliomyelitis (T6), one patient had coronary heart disease (C6), and one patient had atrial fibrillation (C7). We also showed the other treatments during hospital admission in Tab.2. None of the patients received corticosteroid treatment. T2, C1, and C6 had bacterial infections. Thus, these three patients received additional antibiotic treatment. In addition, T1, T3, C1, and C6 received γ-globulin treatment to improve immunity. The results in Tab.1 and Tab.2 indicated that the clinical information between the two groups had no significant bias.
3.2 Effects of Paxlovid therapy
3.2.1 Clinical parameters
First, we compared the clinical parameters of the patients when the PCR tests turned negative (Tab.3), and we did not find any significant difference between the two groups. In addition, we were particularly concerned about the patients’ parameters related to liver function. Differences in the levels of ALT (P=0.45) and aspartate aminotransferase (P=0.75) between the two groups were not statistically significant. These results reflected that Paxlovid therapy among hemodialysis patients in the present study had no significant side effects on liver function.
Second, we observed dynamic changes in the laboratory parameters of the patients between the 1st day of admission and the day of negative PCR test results (Fig.2). We did not find significant differences in the two groups between the two time points. Furthermore, we did not find an obvious change trend in white blood cells (WBCs), except in T2, who also had a bacterial infection (Fig.2). Regarding lymphocytes, we observed an increasing trend on the day of a negative PCR test result in the two groups (Fig.2). In addition, ALT was maintained at a normal level during the study (Fig.2). A decreasing trend of D-dimer was observed in Paxlovid treatment patients and an increasing tendency in control patients on the day of negative PCR test results.
Regarding the time to negative PCR results, the mean times to negative PCR results in treatment and control patients were 18 ± 2.6 days and 18.9 ± 2.5 days, respectively (P=0.82) (Tab.1). This finding indicated the tendency of early PCR negativity in Paxlovid treatment patients. Furthermore, we investigated the time distribution of negative PCR results in the two groups (Fig.3). Four patients (two treatment and two control patients) recovered to develop a negative PCR test within 15 days, five patients (three treatment and two control cases) recovered to develop a negative PCR test within 22 days, and four patients (one treatment and three control patients) recovered to develop a negative PCR test within 28 days, indicating that 83.3% of the treatment and 57.1% of the control patients’ PCR tests turned negative within 22 days. These results reflected that Paxlovid therapy tended to reduce the time to negative PCR test results. The RT-PCR tests of SARS-CoV-2 reflected the viral load. Thus, we explored the changes in viral load by measuring the ORF (Fig.3) and N (Fig.3) gene values. The CT values on D1, D8, and D15 of the treatment and control patients were observed (Fig.3 and Fig.3). The results showed that the CT values of the ORF and N genes in the treatment patients on D8 were higher than those in the control patients. This result indicated that Paxlovid therapy might accelerate the reduction in viral load on D8.
Paxlovid had no obvious effect on the course of the disease, but we observed a difference in viral load on D8 between the treatment and control patients. We hypothesized that Paxlovid might affect the laboratory parameters of patients on D8 compared with those on D1 (Fig.4). We did not find significant differences regarding the changes in leucocytes, neutrophils, and fibrinogen. In the Paxlovid treatment group, the levels of lymphocytes and eosinophils on D8 were significantly higher than those on D1 (P=0.03 and 0.02, respectively), but we did not find a significant difference in the control group. In addition, we observed a decreased level of D-dimer on D8 compared with that on D1 in the treatment patients. However, the D-dimer level in the control patients was increased on D8, and the differences were not statistically significant. However, the change in the D-dimer level from D1 to D8 between the treatment and control patients was statistically significant (P=0.001). We also observed the inflammatory index C-reactive protein (CRP) and found no difference between D1 and D8 in the treatment and control groups. As shown in Fig.4, the CRP level in the treatment patients was higher than that in the control patients, possibly because the patients in the treatment group had bacterial infections.
3.2.2 Chest CT imaging findings
According to preliminary clinical studies, the rapidly spreading Omicron variant is less dangerous than its predecessor, the Delta variant. A similar phenomenon was observed in our hemodialysis patients with Omicron infections. A blinded radiologist evaluated the CT imaging. All patients were mildly symptomatic on admission. Four patients in the control group showed abnormalities on CT imaging and developed moderate disease with the extension of infection time. Patchy ground-glass opacities were seen in the CT images of three control patients on D8 after enrollment and were absorbed on D15 after enrollment (Fig.5–5J). These opacities were also seen in the CT images of another control patient on D8 after enrollment and persisted for at least 1 week (Fig.5–5L). The patients in the Paxlovid treatment group showed no obvious changes in the CT images on admission or D8 and D15 after the first dose of Paxlovid (Fig.5–5F). The difference between the two groups was statistically significant (P < 0.05).
3.3 Adverse effects of Paxlovid therapy in hemodialysis patients
In the present study, we did not find any Paxlovid-related symptoms, such as nausea, vomiting, diarrhea, and headache. None of the patients had liver dysfunction. No serious adverse reactions or safety events were recorded during the Paxlovid treatment in hemodialysis patients.
4 Discussion
After the Alpha, Beta, Gamma, and Delta SARS-CoV-2 variants of concern, the Omicron variant became the main threat worldwide in November 2021 [
10]. In late February 2022, a wave of SARS-CoV-2 infection rapidly appeared in Shanghai, China. The phylogenetic analysis of the SARS-CoV-2 viral genomes indicated that all of the new viral genomes in Shanghai were clustered into a sublineage of the Omicron variant. According to the Shanghai Municipal Health Commission, more than 0.6 million cases were identified as Omicron infections, including many hemodialysis patients. No effective antiviral therapy for hemodialysis patients exists until now. Therefore, we aimed to explore Paxlovid therapy for hemodialysis patients with the Omicron variant of SARS-CoV-2 infection.
An interim analysis of the EPIC-HR trial confirmed that treating symptomatic COVID-19 with Paxlovid results in a risk of progression to severe COVID-19 that is 89% lower than the risk with placebo [
8]. Similarly, Ronza Najjar-Debbiny et al. reported that the risk reduction is 46% in patients who received Paxlovid treatment [
11]. Although the two studies had several differences, such as differences in the viruses, study designs, and settings, both concluded that Paxlovid plays an important role in the progression of COVID-19. According to the instructions, Paxlovid is not recommended for hemodialysis patients. Pierre [
9] has recently reported good tolerance to a modified dose of Paxlovid in hemodialysis patients. With the clinical pharmacist’s support, we used a modified Paxlovid dosage of 150 mg nirmatrelvir with 100 mg ritonavir orally once daily to identify the effect of Paxlovid on hemodialysis patients with minimal side effects.
In the present study, we enrolled hemodialysis patients with laboratory confirmation of a SARS-CoV-2 (Omicron variant) infection. None of the patients received the SARS-CoV-2 vaccine. In contrast to the above trials, none of the patients progressed to severe COVID-19, which could be explained by several reasons. First, all of the enrolled patients in the present study were infected by Omicron. According to a report, Omicron causes low rates of severe diseases [
12]. All the patients in our study were mild. Patients with mild SARS-CoV-2 infections merely show upper respiratory symptoms but not lower respiratory symptoms [
13–
15]. Second, the sample size of the present study was too small, which was one of the study’s major limitations.
In line with the results of the above two trials, our results showed that according to chest CT images, four patients in the control group progressed to moderate disease with the extension of infection time. We did not observe any development in the chest CT images of Paxlovid treatment patients (
P < 0.05) (Fig.5). We also tried to investigate whether Paxlovid could shorten the time to a negative PCR test result. The results of the current study (Tab.3) showed that the Paxlovid treatment patients had a tendency toward early negative PCR test results. However, no significant difference was observed between the two groups, probably because of the study’s small sample size. We found from the CT value of the ORF/N gene detected by PCR that the viral load on D8 in Paxlovid treatment patients was lower than that in control patients (Fig.3). In the EPIC-HR trial, the investigators reported that treatment with Paxlovid in COVID-19 illness can decrease progression to severe disease and quickly reduce the viral load. Patients with CKD, particularly those on dialysis, characteristically have delayed viral clearance after SARS-CoV-2 infection [
16,
17], and impaired kidney function was an independent predictor of time to viral clearance. Although viral load cannot be a reliable predictor of viral infectivity, a strong association exists between quantitative viral load data and the ability to recover SARS-CoV-2 in viral culture [
18]. Therefore, in the present study, we speculated that the viral load result indicating early viral clearance benefits disease improvement. However, an expanded sample size should be used to validate the results further.
Regarding the laboratory parameters, we observed in the Paxlovid treatment group that the absolute values of lymphocytes and eosinophils on D8 were significantly higher than those on D1 (
P < 0.05) (Fig.4). However, the difference was not statistically significant in the control group. Lymphocytes are an important monitoring index in virus-related diseases. According to reports, the lymphocyte counts in COVID-19 patients’ peripheral blood are markedly decreased [
13,
19,
20]. Damages to T lymphocytes may be an important factor leading to exacerbations of patients [
21], and the low absolute value of lymphocytes can be used as a reference index of new coronavirus infections in the clinic [
13]. Regarding eosinopenia, Zhang et al. analyzed the clinical characteristics of 140 patients infected with SARS-CoV-2 and reported that eosinopenia occurred in 52.9% of patients [
22]. Similarly, Du et al. reviewed the medical records of 85 fatal cases of COVID-19 and noted that 81% of the patients had eosinopenia [
23]. The eosinophil counts correlate positively with the lymphocyte counts in patients [
22]. In addition, the eosinophil levels always improve before negative PCR tests and chest CT imaging improvement, suggesting that the resolution of eosinopenia may be an indicator of improving clinical status [
24]. In the present study, we found similar results: the counts of lymphocytes and eosinophils increased significantly in Paxlovid treatment patients, and the mechanism should be further studied in future research.
In addition, D-dimer levels are increased in COVID-19, particularly in severe patients [
25], and the dynamic changes in D-dimer levels are positively correlated with the prognosis of COVID-19 [
26]. In the current study, we observed a tendency toward decreased levels of D-dimer on D8 in the Paxlovid treatment group and increased D-dimer levels on D8 in the control group. The differences were not statistically significant because of the small sample size. However, we believe that Paxlovid therapy in the present study may play an active role in improving the disease treatment.
Given that Paxlovid could reduce the progression of chest CT findings, accelerate the reduction in viral load, and improve lymphocytes and eosinophils, we tended to affirm its role in hemodialysis patients with microscopic infections. In particular, we focused on the likely adverse effects of Paxlovid on hemodialysis patients. Fortunately, no severe adverse effects, including clinical symptoms and laboratory parameters, were observed in the present study.
However, the present study had several limitations. First, as mentioned above, the sample size was too small, thereby limiting the study’s credibility. A large number of samples are required to investigate further the side effects and role of Paxlovid in hemodialysis patients with SARS-CoV-2 infections. Second, all the patients enrolled in the current study had mild COVID-19. In future studies, patients with moderate or severe COVID-19 will be enrolled to investigate the effect of Paxlovid further. In addition, we are unsure whether the dosage of Paxlovid in the current study works on all hemodialysis patients. Thus, the pharmacokinetics of Paxlovid in patients with severe kidney injury should be investigated.
In summary, no obvious adverse effects were observed in the Paxlovid treatment group, suggesting that Paxlovid can be used on hemodialysis patients at a modified dose. Paxlovid treatment showed a potential therapeutic effect in hemodialysis patients. However, the optimal dose and effectiveness evaluation must be investigated further in a large cohort. Our findings are important for the future treatment and management of hemodialysis patients with SARS-CoV-2 infections.
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