Azvudine-Centered Comprehensive Therapeutic Strategy for the Treatment of COVID-19 Infection in Kidney Transplant Recipients in the Developing World: An Observational Pilot Study

doi:10.21203/rs.3.rs-5173483/v1

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Azvudine-Centered Comprehensive Therapeutic Strategy for the Treatment of COVID-19 Infection in Kidney Transplant Recipients in the Developing World: An Observational Pilot Study

https://doi.org/10.21203/rs.3.rs-5173483/v1

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Purpose

Coronavirus disease 2019 (COVID-19) remains a serious challenge for kidney transplant recipients due to their immunocompromised status. Azvudine may be effective in treating COVID-19 in these patients, but its overall efficacy remains unclear.

Methods

Twenty kidney transplant COVID-19 patients at Peking University First Hospital received Azvudine-centered treatment from December 2022 to January 2023. Patients were diagnosed via COVID-19 nucleic acid testing. Demographics and treatment outcomes were collected.

Results

The median duration of Azvudine therapy was 9.6 days (7–14 days), and the median conversion time from positive to negative was 13.22 days (5–33 days). Transplanted renal function improved significantly (estimated glomerular filtration rate increased by 27.29 ml/min/1.73m², t = 9.755, p < 0.0001; serum creatinine decreased by 57.72 µmol/L, t = 10.45 p < 0.0001). All patients experienced internal environment imbalance during treatment. Half had co-infections, with Mycoplasma pneumonia being the most common (7/20, 35%). The average cost of Azvudine was 220.44 RMB (94.56-342.78 RMB). After a 1-year follow-up, 70% (14/20) of patients maintained normal transplanted kidney function. No Azvudine-related complications were observed, indicating the therapy's initial safety.

Conclusion

This single-center study suggests that Azvudine-centered therapy may be effective and safe for COVID-19 in kidney transplant recipients. Azvudine could be a cost-effective alternative for those with poor access to first-line anti-COVID-19 agents.

Health sciences/Nephrology/Kidney diseases

Health sciences/Health care

Health sciences/Health care/Public health

Azvudine

COVID-19

kidney transplantation

Coronavirus disease 2019 (COVID-19) is still widely prevalent worldwide, and the prognosis of COVID-19 has improved significantly with the rapid development of comprehensive control tools such as vaccines, monoclonal antibodies, and antiviral drugs [1–3]. Nevertheless, COVID-19 remains a serious challenge for immunocompromised populations, and these patients are more susceptible to serious complications such as acute respiratory distress syndrome and multi-organ failure [4].

Kidney transplant recipients have a higher mortality rate from COVID-19 infection, not only because they are in a state of chronic immunosuppression, but also because they often have severe comorbidities such as hypertension, cardiovascular disease, kidney disease, and diabetes. The results of a study of transplant recipients from seven European countries showed an attributable mortality rate of 19.9% in kidney transplant recipients diagnosed with COVID-19, which was much higher than in the control group [5]. Another multicenter study in 12 centers in the U.S., Italy, and Spain showed that kidney transplant recipients have a higher mortality rate, with an initial mortality rate of 32% for kidney transplant recipients [6].

Azvudine (FNC) is the first dual-target nucleoside analogue that inhibits viral replication by mimicking a natural nucleoside that enters the host cell, embeds in viral DNA or RNA causing the termination of viral DNA or RNA strand synthesis, and inhibits viral DNA polymerase and RNA polymerase activity [7]. Four Phase III clinical trials of Azvudine for the treatment of COVID-19 were conducted between 2020 and 2022 and showed that Azvudine reduces the time to nucleic acid-negative conversion, viral load, and time to clinical improvement in patients with moderate COVID-19 [8].

With the release of the issuance of the Notice on Further Optimizing and Implementing the Prevention and Control Measures for the COVID-19 by the National Health Commission of China on December 7, 2022, a dramatic rise of COVID-19 infections will occur based on China’s large population. According to the data from the Chinese Center for Disease Control and Prevention, the reported population-wide cases of COVID-19 peaked on December 25, 2022 [9]. In the context of large-scale population-based infections where some patients have difficulty accessing conventional first-line medications such as Paxivoid, it is critical to explore suitable alternatives available to kidney transplant recipients for the treatment of COVID-19.

On account of its cost-effectiveness, Azvudine may be promoted for use in the treatment of COVID-19 in developing countries. Here we proposed an Azvudine-centered comprehensive therapeutic strategy for kidney transplant recipients with COVID-19 and reported the results of a preliminary study.

Twenty kidney transplant COVID-19 patients admitted to the Peking University First Hospital receiving Azvudine-centered comprehensive therapeutic strategy from December 2022 to January 2023 after the adjustment of the COVID-19 prevention policy were consecutively included in the study. Inclusion criteria: a) all the patients had received kidney transplantation, b) all the patients had clinical symptoms such as fever, breath-holding, cough, malaise, and generalized aches and pains, c) all the patients with a confirmed diagnosis of COVID-19 pneumonia were diagnosed by pathogenetic tests such as a positive throat swab COVID-19 nucleic acid testing, d) CT imaging findings met the standard of viral pneumonia. Exclusion criteria: a) age < 18 years, b) other antiviral drugs (e.g., Paxlovid) were used in addition to Azvudine, c) prior infection with COVID-19. The successive enrollment of patients based on the timeline is shown in Supplementary Fig. 1.

Demographics and treatment outcomes were prospectively collected for all patients. P values less than 0.05 represent statistical significance.

This study was approved by the Biomedical Research Ethics Committee of Peking University First Hospital (2023Research 244-001) and followed the World Medical Association Declaration of Helsinki as revised in 2013 [10].

2.1 Azvudine anti-COVID-19 strategy

All patients are started on oral Azvudine for COVID-19 on admission, even though some patients may have had COVID-19 for some time prior to hospitalisation. Azvudine can be used as soon as a definite COVID-19 diagnosis is made, and patients can still benefit from it even though the onset of the disease is prolonged. Depending on the patient's transplanted kidney creatinine level, the first day dose of Azvudine is 2–3 mg, followed by a maintenance dose of 3–5 mg. The course of treatment is 7–14 days until the nucleic acid test result for COVID-19 is negative. Since Azvudine may make patients nauseous and vomit, it is recommended that patients take it daily at bedtime.

2.2 Immunological balance

Azvudine does not have a major impact on patients' immunosuppressive blood levels. Patients discontinue cell cycle inhibitors (mycophenolate mofetil, MMF) early in the infection and reduce calcineurin inhibitors (CNIs) as appropriate. Patients' CNI blood levels are reduced to stable levels (tacrolimus is maintained below 5 ng/mL and cyclosporine is maintained around 100 ng/mL). The patient's glucocorticoid dose is increased to antagonise inflammation better and reduce fever. Patients may be given oral prednisone acetate (20mg/d or 10mg every 8h) and, if necessary, intravenous dexamethasone 5mg (1–2 times/day). Gradual and moderate resumption of previous immunosuppressive regimens during recovery from infection. We do not routinely infuse gammaglobulin to boost patients' immunity in this treatment strategy.

2.3 Homeostasis of the internal environment

Most kidney transplant recipients with COVID-19 develop ionic disturbances that require prompt attention to the patient's serum sodium, potassium, magnesium, and calcium ions. Stability of the patient's internal environment is maintained by adding various ions to Ringer's solution. The acid-base balance of the patient's internal environment also requires dynamic monitoring. Some patients develop acidosis and require intravenous sodium bicarbonate.

2.4 Treatment of co-infections with other pathogens

A vast majority of patients will be co-infected with other pathogens such as Mycoplasma pneumoniae, cytomegalovirus, Legionella pneumophila, and Pneumocystis jiroveci. Moxifloxacin is routinely used for the treatment of Mycoplasma pneumoniae infections and Legionella pneumophila infections (400 mg/d, course: 14 d), while those who do not respond to moxifloxacin should be switched to azithromycin (500 mg/d, course: 3–5 d of continuous use, 2–3 d of withdrawal). Ganciclovir is added to those with co-infection of cytomegalovirus (CMV) for a period of 3 to 6 months until CMV IgM antibodies become negative. In combination with Pneumocystis jiroveci infection, sulfonamides are added for half a month until conversion.

2.5 Supporting symptomatic treatment

Active supportive symptomatic treatment is used to improve the patient's symptoms and general condition. Most patients are in a state of chronic depletion during the course of the disease, which can be improved by supplementation with human albumin and plasma transfusions. Patients are given oxygen to maintain their index oxygen saturation ≥ 95%. The patient's urine output was maintained at (2,500 ± 500) ml/d. Paracetamol is also used to reduce fever and methoxyphenamine has been used to relieve coughs. The patient's graft kidney function is closely monitored and haemodialysis is used when necessary. This treatment strategy is used in general wards. If the patient develops respiratory failure, he or she is promptly transferred to the intensive care unit ward for further treatment, using ventilator-assisted ventilation if necessary.

3.1 General conditions

The patients’ characteristics are shown in Table 1. Totally, twenty renal transplant patients were included in our studies. 16 patients receive FK506 + MMF + Prednisone as immunosuppressive scheme after renal transplantation. And 4 patients receive cyclosporin A as immunosuppressive therapy after transplantation. Among included patients, hypertension was the most common comorbidity affecting 9 patients, followed by 4 who had diabetes mellitus, and 2 had a history cardiopathy.

Table 1

Characteristics of included patients.
Characteristics	Patients with blood creatinine > 141 µmol/L	Patients with blood creatinine ≤ 141 µmol/L	P-value
Gender,n(%)			/
Male	2(33)	8(57)
Female	4(67)	6(43)
Age(yr), median(range)	43(30–53)	53.5(37–73)	0.0528
Comorbidity,n(%)			/
Hypertension	2(100%)	7(50)
Hyperglycemia	0	4(29)
Cardiopathy	0	2(14)
Hepatitis B	0	1(7)
Medication duration(day), median(range)	9.5(8–11)	10(6–22)	0.8238
Immunosuppresive schemes,n(%)			/
FK + M + P	5(83)	11(79)
Cyclosporin A	1(17)	3(21)
Symptoms,n(%)			/
High fever	5(83)	13(93)
Fatigue	5(83)	5(36)
White sputum	3(50)	10(71)
Yellow sputum	2(33)	3(21)
Chest tightness	1(17)	2(14)
Hyposmia	1(17)	1(7)
Hypogeusia	0	1(7)
Nausea	1(17)	1(7)
Conversion time(day), median(range)	11(7–33)	12(5–25)	0.7197

The most common symptoms after COVID-19 in renal transplant patients is high fever (18,90%), followed by white sputum (13, 65%), fatigue (10, 50%), yellow sputum (5, 25%), chest tightness (3, 15%), hyposmia (2, 10%), nausea (2, 10%), hypogeusia (1, 5%). The median duration of Azvudine-centered therapy is 9.6 days (7–14 days), and the median conversion time of COVID-19 from positive to negative is 13.22 days (5-33days, including days of COVID-19 infection prior to admission for treatment).

3.2 Imaging manifestations

The patients' computed tomography (CT) imaging showed multiple foci of ground glass density and solid foci with scattered solid micronodules in both lungs (Fig. 1A). The foci were mostly located in the lateral bilaterally lower lungs with subpleural bands, accompanied by bronchial thickening. The patients were mostly free of pleural effusion and lung cavities. Some patients had severe pulmonary solid lesions. After treatment, the extent of the patient's solid lung lesions was significantly reduced or even disappeared (Fig. 1B).

3.3 Laboratory findings

The results of laboratory examination were collected for these twenty renal transplant COVID-19 patients. Changes in serum creatinine (Cr) and estimated glomerular filtration rate (eGFR) over the course of the patient's disease are shown in Fig. 2A. The ratio of neutrophils to lymphocytes during the course of the disease is shown in Fig. 2B. And the overall change in trend is shown in Fig. 2C.

Before antiCOVID-19 treatment, 5 patients’ serum creatinine > 141 µmol/L with 4 patients’ serum creatinine > 186 µmol/L. With the administration of Azvudine, patients’ blood creatinine showed a continuously decline during the course of treatment. What’s more, patients’ blood test after 10 days of administration showed a significantly increased eGFR (eGFR increased 27.29 ml/min/1.73m², t = 9.755, p < 0.0001) and decreased creatinine (serum creatine decreased 57.72 µmol/L, t = 10.45 p < 0.0001) compared to baseline.

Besides, the count of white blood cell varied among different patients, which showed increased, decreased or even normal percentage of white blood cell (WBC). Most patients showed a decreased lymphocyte count and percentage when COVID-19 progressed. 7 patients showed a decreased lymphocyte with absolute count of lymphocyte < 0.8×10⁹; Totally, 10 recipients showed decreased lymphocyte percentage (< 20%). Forty percent of patients showed lymphocyte proportion < 10% with 3 patients < 5%. With the administration of Azvudine and improvement of patients’ general condition, a tendency of increased proportion of lymphocyte was shown.

Electrolyte disorders were common for included recipients. Among all twenty patients, 5 patients suffered from hypokalemia (serum potassium < 3.5 mmol/L), 10 patients suffered from hyponatremia (serum sodium < 135 mmol/L), 18 patients suffered from hypocalcemia (serum calcium < 2.2 mmol/L), 19 patients suffered from hypomagnesemia (serum magnesium < 0.75 mmol/L).

3.4 Co-infections other than COVID-19

Totally, 10 patients had co-infection by other pathogens. 7 patients were infected by Mycoplasma pneumonia, 5 patients were infected by JC virus, 5 patients were infected by Legionella pneumophila, and 4 patients were infected by CMV.

3.5 Cost of Azvudine

The cost of Azvudine treatment (drug only) was calculated in our study. The average treatment dose of Azvudine was 37.3 mg (16–58 mg). And the average drug only cost of Azvudine was 220.44 Renminbi (94.56-342.78 RMB). The specific costs per patient were shown in Supplementary Table 1.

3.6 Follow-up results and long-term safety

The results of 1 year follow-up showed that most patients maintained a comparable renal function to the time they finished antiCOVID-19 treatment (Fig. 3). 14 patients remained a normal transplanted kidney function (14/20, 70%). 6 patients were tested out for poor renal function with blood creatinine > 141 µmol/L (Among them, 4 patients had blood creatinine > 186 µmol/L). Comparison analysis showed that patients with blood creatinine > 141 µmol/L and patients with blood creatinine ≤ 141 µmol/L didn’t have significant differences in age, medication duration and conversion time (Supplementary Table 2). Moreover, no patients need readmission for re-infection of COVID-19. All patients did not experience Azvudine-related complications.

During the past few years, the pandemic of COVID-19 has caused destructive strike to human health, especially to those with immunosuppressive status. Kidney transplant recipients, as one common population that need to take immunosuppressive medication, suffered from COVID-19 and have more serious symptoms and higher mortality rate due to their immunosuppressive status. Azvudine, as the first dual-target nucleoside analogue to interfere severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) multiplication, has been proved to be effective in treating COVID-19. However, whether Azvudine can still be effective in renal transplant COVID-19 patients is still unknown due to special immunosuppressive status of these patients. Here, we proposed an Azvudine-centered therapy for treating renal transplant COVID-19 patients and reported the preliminary results in 20 kidney transplant COVID-19 recipients.

Some studies had proved the efficacy and safety of Azvudine in treating COVID-19 patients. Zhigang Ren and his colleagues proved the preliminary clinical results that Azvudine could shorten the time of nucleic acid negativity conversion by an average 4.5 days after treatment with Azvudine compared with standard antiviral treatment [7]. Similarly, Yuming Sun and his colleagues conducted a single-center, retrospective cohort study and proved that Azvudine could lower the crude incidence rate of composite disease progression[11]. In our study, we firstly proved that Azvudine may be effective in treating kidney transplanted recipients. Our results showed that after the administration of Azvudine, all patients got symptom relieved with a mean nucleic acid negativity conversion time of 13.22 days. Compared to the results of Zhigang Ren, out results showed a delayed mean nucleic acid conversion time that may be caused by immunosuppressed status in kidney transplantation recipients.

Transplanted kidney function is the main focus during the whole process of Azvudine-centered antiCOVID-19 therapy. Our results showed that patients renal function indicators (eGFR and serum creatinine) significantly improved after mean administration days. Paxlovid is commonly used agents for COVID-19 treatment[12]. However, drug-drug interaction has been reported for those preference drugs, which needs renal dose adjustment when applying [13]. As far as we concerned, this is the first study that showed the effectiveness of Azvudine in treating COVID-19 in kidney transplant recipients. In our study, Azvudine showed a well tolerance with immunosuppressants and the 1-year follow-up results showed a well-preserved transplanted kidney function after Azvudine administration. Because nirmatrelvir booster (ritonavir) is a strong cytochrome P450 3A4 inhibitor and a P-glycoprotein inhibitor, it may increase blood concentrations of immunosuppressants and increase the potential for serious drug toxicity. Unlike Paxlovid, Azvudine is the first dual-target nucleoside analogue to interfere SARS-CoV-2 multiplication. Due to different pharmacological effects between Paxlovid and Azvudine, Azvudine showed better tolerance with immunosuppressants. Besides, activated Azvudine will concentrate in thymus [14], which can promote the expression of interleukin (IL)-4, IL-10, IL-13 and suppress the expression of IL-1β, interferon (INF)-γ, tumor necrosis factor (TNF)-α and IL-6. Azvudine suppressed cytokines are critical for COVID-19 related cytokine storm. And Azvudine promoted cytokines can booster the function of T cells, which will accelerate the clearance of COVID-19. Susan Hartzell and his colleges observed significantly fewer total lymphocytes in 19 subjects[15]. Our results were similar to previously reported ones. According to our results, the count and percentage of lymphocyte decreased with the progression of COVID-19 and increased after the administration of Azvudine. Therefore, we suggested that lymphocyte count and proportion may be a predictor for kidney transplantation recipients’ condition after COVID-19 infection.

Electrolytes balance can reflect patients’ kidney function and is also important for patients’ cardiac function. Our results showed that hypomagnesemia (19/20, 95%), hypocalcemia (18/20, 90%), metabolic alkalosis (13/20, 65%), metabolic acidosis (10/20, 50%), hyponatremia (10/20, 50%), hypokalemia (5/20, 25%) are common electrolytic imbalance that may happen in renal transplant COVID-19 patients. The phenomenon that most patients suffered from electrolytic imbalance after COVID-19 infection suggested that although blood creatine and eGFR improved with Azvudine administration, but transplanted kidney tubular function may be injured by COVID-19. What’s more, imbalance of potassium, calcium and magnesium suggested that patients’ cardiac function should be tightly monitored during Azvudine-centered therapy.

Compared to Paxlovid and other antiCOVID-19 agents, one of the biggest advantages of Azvudine is the better cost-effectiveness. According to the study of Dan Liu and her colleagues [16], they found that Paxlovid was not cost-effective in most patients using a Markov model by cost-effectiveness analysis. In our study, the maximum drug only cost of Azvudine was 342.78 RMB. And the cost of Paxlovid for full-course treatment is 1800RMB (drug only), which is five times higher than the maximum cost of using Azvudine in our research and four times higher than theoretical maximum cost of Azvudine according to our scheme (first day dose of 3mg, followed by a matintenace dose of 5mg for 14days). The advantage of lower cost of using Azvudine may improve the availability of COVID-19 treatment in developing areas for poor population.

Our study has several limitations. Firstly, the absence of a control group in our research design significantly undermines the reliability of the efficacy assessment for the intervention group. This limitation arose due to the circumstances at the time, as the Chinese government had recently adjusted COVID-19 epidemic prevention policies, resulting in a surge of new infections and a temporary shortage of first-line treatment drugs, which precluded the inclusion of a positive control group. Secondly, the small sample size of our study may introduce sampling errors, potentially leading to false-positive results. To address these issues, further investigation into the efficacy and safety of the Azvudine-centered anti-COVID-19 treatment is warranted through larger-scale and more rigorously designed randomized controlled trials.

To be concluded, we first figured out the effectiveness and safety of Azvudine-centered therapy for COVID-19 in kidney transplant recipients. Our study indicated that in areas with poor availability to recommended first-line antiCOVID-19 agents Azvudine may be an effective alternative for treating COVID-19 in this special immunosuppressed population.

COVID-19: Coronavirus disease 2019

FNC: Azvudine

MMF: mycophenolate mofetil

CNI: calcineurin inhibitor

CMV: cytomegalovirus

CT: computed tomography

Cr, creatinine

eGFR, estimated glomerular filtration rate

WBC: white blood cell

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2

IL: interleukin

INF: interferon

TNF: tumor necrosis factor

RMB: Renminbi

CT :computed tomography

Ethical approval statement

Consent to participate

This is an observational study, and written informed consents were obtained from all the enrolled patients for publication of this study in accordance with local regulations and policies.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Clinical trial number:
Not applicable.

Acknowledgements

Not applicable.

Declaration of generative AI and AI-assisted technologies in the writing process.

During the preparation of this work the authors used GPT-4 in order to improve the readability and language of the manuscript. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

Funding

This study was supported by National High Level Hospital Clinical Research Funding (Scientific and Technological Achievements Transformation Incubation Guidance Funding Project of Peking University First Hospital, 2022CX10).

Competing interests

The authors declare that they have no competing interests.

Author contributions

All authors were engaged in the treatment of the patients. X.X developed the Azvudine-centered comprehensive therapeutic strategy and guided the clinical diagnosis and treatment. X.L and W.L participated in clinical data analysis and manuscript writing. D.L, X.J, Z.Z, C.X, M.Z and C.S collected relevant clinical data. Critical revision of the manuscript for important intellectual content was produced by X.X, G.X, W.H and J.L. Supervision was performed by W.H and J.L.

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No competing interests reported.

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You are reading this latest preprint version

Azvudine-Centered Comprehensive Therapeutic Strategy for the Treatment of COVID-19 Infection in Kidney Transplant Recipients in the Developing World: An Observational Pilot Study

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

1. Introduction

2. Patients and Methods

2.1 Azvudine anti-COVID-19 strategy

2.2 Immunological balance

2.3 Homeostasis of the internal environment

2.4 Treatment of co-infections with other pathogens

2.5 Supporting symptomatic treatment

3. Results

3.1 General conditions

3.2 Imaging manifestations

3.3 Laboratory findings

3.4 Co-infections other than COVID-19

3.5 Cost of Azvudine

3.6 Follow-up results and long-term safety

4. Discussion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1