Effectiveness and safety of nirmatrelvir-ritonavir in kidney transplant recipients with severe kidney dysfunction infected with COVID-19

ABSTRACT

Transplant patients face an elevated risk of coronavirus disease 2019 (COVID-19) morbidity and mortality and commonly encounter renal dysfunction. Nirmatrelvir is primarily excreted through the kidneys. The dosage of nirmatrelvir/ritonavir (NR) needs to be adjusted according to the degree of renal function impairment. Nevertheless, NR is not recommended for patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min) due to a dearth of associated research. In this study, we focus on kidney transplant patients and document and analyze the experiences of using NR in individuals with severe kidney dysfunction. This was a retrospective multicenter study that included transplant recipients hospitalized for COVID-19 in five major tertiary hospitals in China from December 2022 to June 2023. The outcomes consisted of the disease progression rate by day 28, individual disease progression events, safety outcomes, information on adverse events (AEs), and the blood drug concentrations of immunosuppressants. Data were presented with descriptive statistics. All analyses were performed using SPSS version 22. In total, 40 patients were included in the analysis. Considering the potential interaction between drugs, all patients temporarily discontinued their immunosuppressants during the NR treatment. None of the 32 moderate patients experienced disease progression. However, among the eight patients with critical COVID-19, unfortunately, two of them died. During the medication period, four patients experienced a total of six AEs associated with NR. None of them experienced AEs with a maximum grade of ≥3. Blood drug concentrations of immunosuppressants were monitored in 22 of 40 patients, and the blood drug concentrations of immunosuppressants did not show a significant increase, but some patients experienced lower blood drug concentrations. Our findings supported the use of NR therapy for the treatment of COVID-19 in transplant patients with severe renal insufficiency. A modified dose of NR was well-tolerated.

INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic, caused by SARS-CoV-2, has posed one of the most significant threats to public health in the 21st century, resulting in the deaths of more than 6.9 million people worldwide (1). Ensuring the widespread and timely distribution of effective antiviral drugs is a crucial component of the response.

Nirmatrelvir/ritonavir (NR) is an oral antiviral agent that has demonstrated its effectiveness in preventing the development of severe COVID-19 and is endorsed by the World Health Organization (WHO) guidelines for the treatment of mild-to-moderate COVID-19 (2). Nirmatrelvir is primarily excreted through the kidneys. The dosage of NR needs to be adjusted according to the degree of renal function impairment. Transplant patients, who face a significantly higher risk of COVID-19 morbidity and mortality due to factors like immunosuppression, limited vaccine response, and the presence of comorbid conditions, have an increased need for drug treatment.

However, transplant patients often experience renal dysfunction, with some already having severe renal impairment. It’s worth noting that the prescribing information for NR contraindicates its use in individuals with severe renal impairment [estimated glomerular filtration rate (eGFR) < 30 mL/min] due to a lack of corresponding research. This presents a dilemma, as the timely application of such medications is crucial for this specific high-risk population. Whether and how to use NR for these patients is of clinical significance. Unfortunately, there is currently a lack of relevant research on this topic. Studies focusing on patients with impaired kidney function, particularly those with an eGFR <30 mL/min, remain limited with small sample sizes (3, 4). Additionally, there are no studies on the application of NR in renal transplant patients with severe renal insufficiency. As a result, our study was designed with a specific focus on kidney transplant patients, addressing both effectiveness and safety aspects. The primary objective was to document the experience of using NR in patients with severe kidney dysfunction and provide valuable insights and guidance for other transplant professionals who may encounter similar cases in their clinical practice.

MATERIALS AND METHODS

Study design and data sources

This was a retrospective multicenter study that included transplant recipients hospitalized for COVID-19 in five major tertiary hospitals in China from December 2022 to June 2023. Our inclusion criteria were as follows: (i) meeting the diagnostic criteria for COVID-19, (ii) having received allogeneic transplantation with severe renal dysfunction (eGFR <30 mL/min), and (iii) receiving NR treatment. Ethical approval was granted by the ethics committees of the participating hospitals. Informed consent requirements were waived due to the retrospective nature of this study.

Data source

The necessary variables were collected from the hospital system and during follow-up visits. These included demographic data [age, gender, and body mass index (BMI)], clinical information (eGFR, comorbidities, number of transplants and time, COVID-19 severity, and clinical outcomes), medication-related details (maintenance immunosuppression, specific immunosuppressants, dosage, and duration), and other relevant data (vaccination against SARS-CoV-2).

Outcomes

Effectiveness outcomes

The primary effectiveness outcome in this study was the disease progression rate by day 28, defined as the percentage of individuals infected with the SARS-CoV-2 virus who either experienced death from any cause or progressed from a mild to moderate condition to a severe/critical one. Secondary outcomes encompassed individual disease progression events, including both death from any cause and progression from mild to moderate conditions to severe/critical ones.

Safety outcomes

Safety outcomes were evaluated based on adverse events (AEs) considered related to NR, AEs with a grade of ≥3, AEs resulting in hospital admission, AEs leading to intensive care unit (ICU) admission, and AEs resulting in death.

The blood drug concentrations for immunosuppressants

The French Society of Pharmacology and Therapeutics (SFPT) guidelines emphasize that therapeutic drug monitoring is crucial for managing inter-patient variability in immunosuppressant patients taking NR drugs (5). An approach to adjusting immunosuppressants was utilized to minimize the risk of drug interactions, as depicted in Fig. 1. We have documented fluctuations in the blood drug concentrations of immunosuppressants in patients while they were taking NR medications.

Fig 1.

Nirmatrelvir ritonavir workflow.

Statistical analysis

Descriptive statistics were utilized to summarize demographic and clinical characteristics. Continuous data were reported as mean ± standard deviation or medians with interquartile range (IQR) values, while categorical data were presented as counts along with their corresponding percentages (%). All analyses were performed using SPSS version 22.

RESULTS

Descriptive analysis

In total, 40 patients with severe kidney dysfunction were included in the analysis. The clinical characteristics of these cases are presented in Table 1. Among the participants, 50.00% were male, with a median age of 51 years (IQR: 41–61). Only 8.11% of the participants had been vaccinated against SARS-CoV-2, while over half of them had hypertension (55.00%) or diabetes (30.00%). All of them had undergone kidney transplants, with a median time from transplant of 8 years. The most commonly used immunosuppressive regimens were calcineurin inhibitor (CNI), antimetabolite, and steroids (90%). The severity of COVID-19 prior to NR use was moderate in 47.50% of cases, while 52.5% were classified as severe/critical. The time from symptom onset to NR treatment was 17 days. The mean withdrawal time of immunosuppressants with existing interactions was 1.44 ± 1.09 days before starting NR. The NR dosage used by these patients included 300/100 mg twice daily (bid) (20%), 150/100 mg bid (37.50%), 300/100 mg once daily (qd) (22.50%), and 150/100 mg qd (20%). Most patients underwent a 5-day course of NR treatment; however, in the case of three patients who tested positive for nucleic acid after the initial treatment period, a second round of treatment was administered. The maximum duration of treatment reached 10 days. The mean recovery time of immunosuppressants after completion of NP treatment was 5.20 ± 4.94 days.

TABLE 1.

Baseline characteristics of solid organ transplant recipients using NR^c

Characteristic	Total (N = 40)
Gender, male, n (%)	20 (50.00)
Age, median (IQR)	51 (41–61)
Age ≥ 60 years, n (%)	13 (32.50)
BMI, median (IQR) (n = 38)	22 (19–23)
Vaccination against SARS-CoV-2, n (%) (n = 37)	3 (8.11)
eGFR	21.62 (19.00–26.00)
Comorbidities, n (%)
Hypertension	22 (55.00)
Diabetes	12 (30.00)
Obesity (n = 38)	2 (5.26)
Coronary heart disease	1 (2.50)
Smoke	2 (5.00)
Chronic lung disease	0 (0.00)
Malignancy	1 (2.50)
First kidney transplant, n (%)	38 (95.00)
Time from transplant in years, median (IQR)	8 (2–15)
Recent transplanta, n (%)	5 (12.50)
Maintenance immunosuppression, n (%)
CNI, antimetabolite, and steroids	36 (90.00)
CNI, mTOR inhibitor, antimetabolite, and steroids	1 (2.50)
mTOR inhibitor, antimetabolite, and steroids	1 (2.50)
Others	2 (5.00)
Specific immunosuppressants
Tacrolimus	32 (80.00)
Cyclosporine	7 (17.50)
Sirolimus	2 (5.00)
Mycophenolate	36 (90.00)
Severity of COVID-19 prior to NR useb, n (%)
Mild	0 (0.00)
Moderate	19 (47.50)
Severe	13 (32.50)
Critical	8 (20.00)
Time from symptom onset to treatment, days, median (IQR)	17 (9–24)
The mean withdrawal time of immunosuppressants before starting NR (day)	1.44 ± 1.09
NR duration, n (%)
<5 days	1 (2.50)
5 days	36 (90.00)
>5 days	3 (7.50)
NR dosage, n (%)
300 + 100 mg bid	8 (20.00)
150 + 100 mg bid	15 (37.50)
300 + 100 mg qd	9 (22.50)
150 + 100 mg qd	8 (20.00)
The mean recovery time of immunosuppressants after completion of NP treatment (day)	5.20 ± 4.94

^a Recent transplants refer to transplants performed within 6 months.

^b The severity of COVID-19 is based on WHO diagnostic criteria.

^c n, number; mTOR, mechanistic target of rapamycin.

Effectiveness outcomes

Among the 40 hospitalized patients, 32 had moderate COVID-19 before taking NR medication, while 8 patients had critical COVID-19. Within 28 days, none of the 32 moderate patients experienced disease progression. However, among the eight patients with critical COVID-19, unfortunately, two of them died. The dosages for these deceased patients were 150 + 100 mg bid.

Adverse events

During the medication period, four patients experienced a total of six AEs associated with NR, including two cases of hypertension (5%), one case of hyperglycemia (2.5%), one case of albumin decline (2.5%), one case of abnormal liver function (2.5%), and one case of stomach discomfort (2.5%). The average eGFR of the above patients was 21.25 ± 5.50. None of them experienced AEs with a maximum grade of ≥3, which did not require hospitalization or result in death (see Table 2). Analysis revealed that among patients experiencing adverse reactions, higher NR medication doses seemed to be associated with a greater number of AEs. Specifically, two patients who received a dosage of 300 + 100 mg bid experienced adverse reactions, while patients who were prescribed a dosage of 150/100 mg qd did not experience any AEs.

TABLE 2.

Type, prevalence, and outcomes of AEs

Characteristic		Total (N = 40)
Patients with AEs, n (%)		4 (10.00)
Patients with AEs > 1, n (%)		2 (5.00)
Type of AEs, n (%)	Hypertension	2 (5.00)
	Hyperglycemia	1 (2.50)
	Albumin decline	1 (2.50)
	Abnormal liver function	1 (2.50)
	Stomach discomfort	1 (2.50)
NR dosage of patients with AEs, n (%)	300 + 100 mg bid	2 (5.00)
	150 + 100 mg bid	1 (2.50)
	300 + 100 mg qd	1 (2.50)
AEs with a maximum grade of ≥3a		0 (0.00)
Admission, yes, n (%)		0 (0.00)
Admission to ICU, n (%)		0 (0.00)
Death, yes, n (%)		0 (0.00)

^a Severity grades were defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. For events not listed in the NCI CTCAE, version 5.0, severity was determined according to prespecified criteria listed in the protocol.

Blood drug concentration monitoring

Blood drug concentrations of immunosuppressants were monitored in 22 of 40 patients. During the use of NR medication, the blood drug concentrations of immunosuppressants did not show a significant increase, but some patients experienced lower blood drug concentrations (Tac is shown in Fig. 2, while CsA and Sir are shown in Fig. S1 at https://doi.org/10.6084/m9.figshare.24970719.v1). The blood concentration of Tac in a patient increased from 12.7 to 19.2 ng/mL on the second day of using NR drugs. However, no related adverse reactions were observed.

Fig 2.

Blood concentrations of tacrolimus in various regimens (a: 150mg+100mg bid; b: 300mg+100mg bid; c: 300mg+100mg qd; d: 150mg+100mg qd). The range of therapeutic concentrations varies based on the post-transplantation time for patients, generally falling between 5 and 12 ng/mL. For some patients, adjustments to this range may be made based on individual circumstances.

DISCUSSION

In this study, we presented the outcomes of administering NR to renal transplant patients with severe renal insufficiency who were infected with COVID-19. Our observations revealed a favorable clinical response and a positive safety profile associated with NR usage. Moreover, in the subset of 22 out of 40 patients who underwent blood drug concentration monitoring, the blood concentrations of immunosuppressant drugs did not exhibit a significant increase when combined with NR.

In real-world studies, the impact of the COVID-19 pandemic on patients with advanced kidney disease has been evident. Without any therapeutic interventions, the prognosis for transplant recipients is exceedingly poor (6). Previous studies have demonstrated that NR medication provides a favorable protective effect for transplant recipients infected with COVID-19 (7). However, its application in transplant recipients with severe kidney dysfunction has not been reported in clinical efficacy studies. Previous research has focused on the use of this medication for severe kidney dysfunction. For instance, Hiremath et al. (3) conducted an analysis of dialysis patients who developed COVID-19 and were treated with a modified dose of the NR regimen. The results showed that 96% of patients were able to complete the course of NR, and none of the patients who received this medication died of COVID-19 during the 30-day follow-up period. Additionally, Chan et al. (4), in their study of 59 participants with Stage 5 chronic kidney disease who were on dialysis, found a significant decrease in viral load on days 5, 15, and 30 after treatment with NR (P < 0.001 for all). However, there is also a study that included 18 hemodialysis patients with COVID-19 infection, which found that the medication group did not show a significant advantage in the time of viral elimination compared to hemodialysis patients without NR (8).

In our study, none of the 32 moderate COVID-19 patients experienced disease progression within 28 days. However, in critically ill COVID-19 patients, two individuals experienced disease progression and died. This outcome may be related to the delayed administration of NR medication, as both of these patients were critically ill COVID-19 patients with a treatment initiation delay of more than 5 days.

In our study, the time from symptom onset to NR treatment was 17 days, which is excessively long, considering that the effectiveness of NR has been demonstrated when initiated up to 5 days upon symptom onset. There are two main reasons for the relatively delayed administration of antiviral medications, including NR, in patients. First, the increasing number of infections from December 2022 to June 2023, due to adjustments in China government’s epidemic prevention and control policies, resulted in a shortage of antiviral treatment drugs such as NR, preventing patients from receiving timely medication. Second, with the reduced virulence of the new strains of the coronavirus and a lower incidence of severe cases, many patients opted for symptomatic treatment. They waited until they developed more severe symptoms or their condition became uncontrollable before seeking medical attention. This contributed to the time from symptom onset to NR treatment exceeding 5 days.

The safety of NR medication in the NR population is also a matter of concern, consistent with previous research findings (9). Based on previous research, adverse reactions to NR drugs include disease recurrence, dysgeusia, diarrhea, hypertension, abnormal liver function, stomach discomfort, and other factors (10, 11). In our study, the observed adverse reactions were consistent with adverse effects associated with NR drugs. NR exhibited an acceptable safety profile in our study, with all observed adverse effects being below Grade 3, and none of them required hospitalization or resulted in death.

Studies have suggested that concentrations of nirmatrelvir are higher in patients with renal impairment and the exposure to the drug increases with the severity of renal impairment (12). Therefore, it is advisable to adjust the dose for patients with impaired renal function. However, there is currently no consistent method for making this adjustment for severe renal insufficiency. In a study conducted by Lu et al. (8), two different regimens of nirmatrelvir were compared: 150 or 300 mg once a day (with an additional 75 or 150 mg provided after hemodialysis), along with ritonavir 100 mg bid for 5 days in hemodialysis patients. This study suggested that using two doses of nirmatrelvir appeared to be excessive for these patients. Another pharmacokinetics (PK) study, which used a dose of 150/100 mg bid, indicated that in patients with end-stage renal disease, plasma concentrations of nirmatrelvir remained at higher levels. However, no accumulation of nirmatrelvir was observed, and plasma levels declined rapidly within a few days after the end of treatment (13). The currently recommended protocol primarily focuses on an initial dose of 300/100 mg once daily on day 1, followed by 150/100 mg once daily on days 2–5. Several studies have utilized this scheme and reported better clinical outcomes with good tolerance and manifested low mortality rate and viral load that decreased significantly (3, 4). This protocol has been used in previous studies for patients with an eGFR of less than 30 mL/min, irrespective of whether they undergo dialysis (3, 4). In our multicenter study, which included four different drug regimens, our results indicate that higher doses of nirmatrelvir were associated with a higher incidence of AEs. Specifically, two patients who received a dosage of 300/100 mg bid experienced adverse reactions, whereas patients who were prescribed a dosage of 150/100 mg once daily did not experience any AEs. These findings are consistent with those mentioned above.

Ritonavir is a potent inhibitor of CYP3A and may elevate the serum concentrations of drugs metabolized by CYP3A (14). Consequently, there is a noteworthy drug interaction between NR and immunosuppressants (15): ritonavir can cause a substantial increase in tacrolimus exposure (7, 16, 17). When taking NR, maintenance immunosuppressants need to be adjusted due to interactions. According to the SFPT guidelines (5), the dosage adjustment regimen for tacrolimus involves administering 1/8 of the usual daily dose (DD) on day 1, followed by discontinuation. Then, administer 1/2 of the DD on day 6, 3/4 of the DD on day 7, and resume the usual DD on day 8. For cyclosporine’s regimen, it includes administering 1/5 of the usual DD every day of NR treatment, followed by 1/2 of the DD on day 6, 3/4 of the DD on day 7, and resuming the usual DD on day 8. Regarding sirolimus and everolimus, administer 1/8 of the usual DD on day 1, day 3, and day 5. The usual DD can be restarted on day 7. In our study, a substantial increase in the plasma concentration of immunosuppressants was not observed, which may be related to our strict management. However, it is important to emphasize the need for vigilant monitoring of plasma concentrations during treatment. This vigilance is crucial because inadequate immunosuppression is associated with long-term risks, such as the development of donor-specific antibodies and antibody-mediated rejection, which greatly increase the likelihood of declining kidney function. Conversely, extended periods of excessive immunosuppression pose a risk of drug-related AEs (18). In conclusion, for renal transplant patients with severe renal dysfunction, it is crucial to adopt the premise of appropriate dose adjustments for NR drugs, reasonable adjustments for immunosuppressants, and regular monitoring of blood drug concentrations when using NR drugs.

Our study represented a preliminary investigation on the effectiveness and safety of NR therapy in kidney transplant patients with severe renal insufficiency in real-world settings, with the aim of contributing evidence to this field. However, the present study does have certain limitations. Firstly, the occurrence of kidney transplant patients with severe renal insufficiency was relatively infrequent. Even in a multicenter study, the number of patients included in our research remains limited. Secondly, this retrospective study was observational in nature. Due to the constraints of patient sample availability, we were unable to establish a control group. Consequently, we could only describe the effectiveness and safety without the ability to control for bias and confounding variables. Nonetheless, it’s important to highlight that our study held the distinction of being the first to investigate the safety profile and effectiveness of NR use in kidney transplant patients with severe renal insufficiency. It is essential to acknowledge that further research involving larger, high-quality samples is required to confirm and expand upon our findings.

Conclusion

Our findings supported the use of NR therapy for the treatment of COVID-19 in transplant patients with severe renal insufficiency. A modified dose of NR was well-tolerated. Further research is necessary to confirm and build upon our findings.

ETHICAL APPROVAL

Ethical approval was obtained from the respective ethics committees of the participating hospitals.

DATA AVAILABILITY

The data is availability in https://doi.org/10.6084/m9.figshare.24988149.v1.