Nirmatrelvir/ritonavir treatment in SARS-CoV-2 positive kidney transplant recipients - a case series with four patients.

BACKGROUND: Despite vaccination coronavirus disease 2019 (COVID-19)-associated mortality caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains high in kidney transplant recipients. Nirmatrelvir is a protease inhibitor with activity against SARS-CoV-2. Nirmatrelvir reduces the risk for mortality and hospitalization, which is approved for treating adults at risk for severe disease. Nirmatrelvir is metabolized by the cytochrome P-450 (CYP) 3A4 isozyme CYP3A4 and is therefore co-administered with the irreversible CYP3A4 inhibitor ritonavir, which results in a drug interaction with tacrolimus. A limited number of patients with nirmatrelvir/ritonavir and tacrolimus therapy after kidney transplantation have been reported to date. It has been reported that tacrolimus was paused during the five-day nirmatrelvir/ritonavir therapy and subtherapeutic tacrolimus levels were observed after finishing nirmatrelvir/ritonavir in two patients. Therefore, optimization of tacrolimus dosing is urgently needed in transplant recipients receiving nirmatrelvir/ritonavir treatment. CASE PRESENTATION: Here, we present our first-hand experience with four patients receiving tacrolimus therapy following kidney transplantation and nirmatrelvir/ritonavir therapy due to COVID-19. Tacrolimus was paused during nirmatrelvir/ritonavir therapy in all patients, which resulted in stable therapeutic tacrolimus levels. Tacrolimus was continued directly after finishing nirmatrelvir/ritonavir to avoid subtherapeutic levels in the first patient treated. This patient received his usual tacrolimus maintenance dose, which resulted in toxic levels. Based on this observation, tacrolimus therapy was continued 24 h after finishing nirmatrelvir/ritonavir treatment at a reduced dose in the subsequent patients. In these patients, therapeutic to supratherapeutic tacrolimus levels were observed despite the therapeutic break and dose reduction. DISCUSSION AND CONCLUSIONS: Based on altered CYP3A4 metabolism, tacrolimus levels have to be closely monitored after treatment with nirmatrelvir/ritonavir. Our study suggests that tacrolimus treatment should be paused during nirmatrelvir/ritonavir medication and be continued 24 h after completing nirmatrelvir/ritonavir therapy at a reduced dose and under close monitoring. Based on the limited number of patients in this study, results must be interpreted with caution.

Tacrolimus Drug-Drug Interaction with Nirmatrelvir/Ritonavir (Paxlovid™) Managed with Phenytoin.

INTRODUCTION: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) pandemic has had a significant impact on communities and health systems. The Federal Drug Administration (FDA) authorized Pfizer's nirmatrelvir/ritonavir (Paxlovid™) through an EUA for the treatment of mild to moderate cases of COVID-19 at high risk for progression to severe disease. Patients with a history of transplant who test positive for COVID-19 are considered high risk because of their immunosuppression and are therefore candidates for nirmatrelvir/ritonavir. CASE REPORT: This is a case of a 67-year-old female with a past medical history of orthotopic heart transplant who received tacrolimus as part of her immunosuppressive regimen. She originally presented with complaints of dyspnea and cough for several days in the setting of COVID-19. The patient was started on nirmatrelvir/ritonavir due to her high risk for progression to severe disease. Four days after starting nirmatrelvir/ritonavir, she presented to the ED for slowed speech, fatigue, weakness, and loss of appetite. Upon admission she was found to have a supratherapeutic tacrolimus level of 176.4 ng/mL and an acute kidney injury. In this case, phenytoin was used as a CYP3A4 inducer to quickly decrease the tacrolimus level to within therapeutic range. CONCLUSION: This case highlights the strong and important drug-drug interaction between tacrolimus and nirmatrelvir/ritonavir leading to toxic levels of tacrolimus. It also demonstrates the utility and effectiveness of phenytoin as a "rescue" medication for tacrolimus toxicity.

Translation suppression underlies the restrained COVID-19 mRNA vaccine response in the high-risk immunocompromised group.

Background: Immunocompromised (IC) patients show diminished immune response to COVID-19 mRNA vaccines (Co-mV). To date, there is no 'empirical' evidence to link the perturbation of translation, a rate-limiting step for mRNA vaccine efficiency (VE), to the dampened response of Co-mV. Materials and methods: Impact of immunosuppressants (ISs), tacrolimus (T), mycophenolate (M), rapamycin/sirolimus (S), and their combinations on Pfizer Co-mV translation were determined by the Spike (Sp) protein expression following Co-mV transfection in HEK293 cells. In vivo impact of ISs on SARS-CoV-2 spike specific antigen (SpAg) and associated antibody levels (IgGSp) in serum were assessed in Balb/c mice after two doses (2D) of the Pfizer vaccine. Spike Ag and IgGSp levels were assessed in 259 IC patients and 50 healthy controls (HC) who received 2D of Pfizer or Moderna Co-mV as well as in 67 immunosuppressed solid organ transplant (SOT) patients and 843 non-transplanted (NT) subjects following three doses (3D) of Co-mV. Higher Co-mV concentrations and transient drug holidays were evaluated. Results: We observed significantly lower IgGSP response in IC patients (p<0.0001) compared to their matched controls in 2D and 3D Co-mV groups. IC patients on M or S showed a profound dampening of IgGSP response relative to those that were not on these drugs. M and S, when used individually or in combination, significantly attenuated the Co-mV-induced Sp expression, whereas T did not exert significant influence. Sirolimus combo pretreatment in vivo significantly attenuated the Co-mV induced IgMSp and IgGSp production, which correlated with a decreasing trend in the early levels (after day 1) of Co-mV induced Sp immunogen levels. Neither higher Co-mV concentrations (6µg) nor withholding S for 1-day could overcome the inhibition of Sp protein levels. Interestingly, 3-days S holiday or using T alone rescued Sp levels in vitro. Conclusions: This is the first study to demonstrate that ISs, sirolimus and mycophenolate inhibited Co-mV-induced Sp protein synthesis via translation repression. Selective use of tacrolimus or drug holiday of sirolimus can be a potential means to rescue translation-dependent Sp protein production. These findings lay a strong foundation for guiding future studies aimed at improving Co-mV responses in high-risk IC patients.

Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models.

Rationale: Human coronaviruses (HCoVs) seriously affect human health by causing respiratory diseases ranging from common colds to severe acute respiratory diseases. Immunophilins, including peptidyl-prolyl isomerases of the FK506-binding protein (FKBP) and the cyclophilin family, are promising targets for pharmaceutical inhibition of coronavirus replication, but cell-type specific effects have not been elucidated. FKBPs and cyclophilins bind the immunosuppressive drugs FK506 and cyclosporine A (CsA), respectively. Methods: Primary human bronchial epithelial cells (phBECs) were treated with CsA, Alisporivir (ALV), FK506, and FK506-derived non-immunosuppressive analogs and infected with HCoV-229E. RNA and protein were assessed by RT-qPCR and immunoblot analysis. Treatment with the same compounds was performed in hepatoma cells (Huh-7.5) infected with HCoV-229E expressing Renilla luciferase (HCoV-229E-RLuc) and the kidney cell line HEK293 transfected with a SARS-CoV-1 replicon expressing Renilla luciferase (SARS-CoV-1-RLuc), followed by quantification of luminescence as a measure of viral replication. Results: Both CsA and ALV robustly inhibited viral replication in all models; both compounds decreased HCoV-229E RNA in phBECs and reduced luminescence in HCoV-229E-RLuc-infected Huh7.5 and SARS-CoV-1-RLuc replicon-transfected HEK293. In contrast, FK506 showed inconsistent and less pronounced effects in phBECs while strongly affecting coronavirus replication in Huh-7.5 and HEK293. Two non-immunosuppressive FK506 analogs had no antiviral effect in any infection model. Conclusion: The immunophilin inhibitors CsA and ALV display robust anti-coronaviral properties in multiple infection models, including phBECs, reflecting a primary site of HCoV infection. In contrast, FK506 displayed cell-type specific effects, strongly affecting CoV replication in Huh7.5 and HEK293, but inconsistently and less pronounced in phBECs.

Coronavirus Disease 2019 Positivity Immediately After Lung Transplantation: A Case Report.

Management of COVID-19 in lung transplant recipients is challenging. We report a case of a 71-year-old male who underwent bilateral lung transplantation with an unexpected case of COVID-19. The patient had been fully vaccinated. The patient and donor tested negative for pretransplant COVID-19. On routine bronchoscopy on day 1 after transplant, the COVID-19 test was positive. Mycophenolic mofetil and the second dose of basiliximab were skipped, but tacrolimus and prednisone were continued. He was treated with casirivimab/imdevimab and remdesivir. He was discharged on day 14 and has had no episodes of acute rejection during the 3 months.

Transplantation Without Overimmunosuppression (TWO) study protocol: a phase 2b randomised controlled single-centre trial of regulatory T cell therapy to facilitate immunosuppression reduction in living donor kidney transplant recipients.

INTRODUCTION: Regulatory T cell (Treg) therapy has been demonstrated to facilitate long-term allograft survival in preclinical models of transplantation and may permit reduction of immunosuppression and its associated complications in the clinical setting. Phase 1 clinical trials have shown Treg therapy to be safe and feasible in clinical practice. Here we describe a protocol for the TWO study, a phase 2b randomised control trial of Treg therapy in living donor kidney transplant recipients that will confirm safety and explore efficacy of this novel treatment strategy. METHODS AND ANALYSIS: 60 patients will be randomised on a 1:1 basis to Treg therapy (TR001) or standard clinical care (control). Patients in the TR001 arm will receive an infusion of autologous polyclonal ex vivo expanded Tregs 5 days after transplantation instead of standard monoclonal antibody induction. Maintenance immunosuppression will be reduced over the course of the post-transplant period to low-dose tacrolimus monotherapy. Control participants will receive a standard basiliximab-based immunosuppression regimen with long-term tacrolimus and mycophenolate mofetil immunosuppression. The primary endpoint is biopsy proven acute rejection over 18 months; secondary endpoints include immunosuppression burden, chronic graft dysfunction and drug-related complications. ETHICS AND DISSEMINATION: Ethical approval has been provided by the National Health Service Health Research Authority South Central-Oxford A Research Ethics Committee (reference 18/SC/0054). The study also received authorisation from the UK Medicines and Healthcare products Regulatory Agency and is being run in accordance with the principles of Good Clinical Practice, in collaboration with the registered trials unit Oxford Clinical Trials Research Unit. Results from the TWO study will be published in peer-reviewed scientific/medical journals and presented at scientific/clinical symposia and congresses. TRIAL REGISTRATION NUMBER: ISRCTN: 11038572; Pre-results.

Early clinical experience with nirmatrelvir/ritonavir for the treatment of COVID-19 in solid organ transplant recipients.

Nirmatrelvir/ritonavir (NR) use has not yet been described in solid organ transplant recipients (SOTRs) with mild COVID-19. The objective was to evaluate outcomes among SOTR and describe the drug-drug interaction of NR. This is an IRB-approved, retrospective study of all adult SOTR on a calcineurin inhibitor (CNI) or mammalian target of rapamycin inhibitor who were prescribed NR between December 28, 2021 and January 6, 2022. A total of 25 adult SOTR were included (n = 21 tacrolimus, n = 4 cyclosporine, n = 3 everolimus, n = 1 sirolimus). All patients were instructed to follow the following standardized protocol during treatment with 5 days of NR: hold tacrolimus or mTOR inhibitor or reduce cyclosporine dose to 20% of baseline daily dose. Four patients (16%) were hospitalized by day 30; one for infectious diarrhea and three for symptoms related to COVID-19. No patients died within 30 days of receipt of NR. Median tacrolimus level pre- and post-NR were 7.4 ng/ml (IQR, 6.6-8.6) and 5.2 (IQR, 3.6-8.7), respectively. Four patients experienced a supratherapeutic tacrolimus concentration after restarting tacrolimus post-NR. Our results show the clinically significant interaction between NR and immunosuppressive agents can be reasonably managed with a standardized dosing protocol. Prescribers should carefully re-introduce CNI after the NR course is complete.

Tacrolimus Treatment for Post-COVID-19 Interstitial Lung Disease.

With expansion of the COVID-19 pandemic, reports of post-COVID-19 interstitial lung disease (ILD) have been emerging. However, there are few reports regarding treatment. Some reports indicate that corticosteroids are effective for post-COVID-19 ILD, but the use of long-term corticosteroid carries risks of side effects. We administered tacrolimus to an elderly patient with post-COVID-19 ILD who suffered a respiratory failure relapse during steroid tapering. The respiratory status improved with tacrolimus in the post-acute phase, but pulmonary fibrosis progressed in the late phase. Tacrolimus may be effective for treating post-COVID-19 ILD in the post-acute phase, but it does not halt progression of pulmonary fibrosis.

Calcineurin inhibitors and related medicines: a cohort study examining England's primary care prescription changes during the COVID-19 pandemic (January 2019 to March 2021).

PURPOSE: To examine the impact of the COVID-19 pandemic on calcineurin inhibitors and related prescriptions for community patients in England. METHODS: Data from all primary-care patients who had calcineurin inhibitors prescriptions, dispensed in the community in England were included. Descriptive statistics and interrupted time series analysis over 27 months (15 months before and 12 months after 1st lockdown) was evaluated. RESULTS: Descriptive statistics show that mean values have declined since the pandemic's onset. Over the 27 months: mean Tacrolimus 865,045 doses, standard deviation (SD) 76,147 doses, with 95% CI 834,923, 895,168, (min 567,508, max 1,010,900), ciclosporin 315,496 doses, SD 40,094, 95% CI 299,635, 331,356 (min 191,281, max 382,253) and sirolimus 21,384 doses, SD 2,610, 95% CI 20,352, 22,417 (min 13,022, max 26,156). Analysis of variance between the pre- and post- periods show significant variations in quantities of tacrolimus F 7.432, p = 0.012, ciclosporin F 33.147, p < 0.001 and sirolimus F 18.596, p < 0.001 (1df), mirrored in price analysis. The Interrupted Time Series (ARIMA Modelling) shows declining trends. After the pandemic's onset, a statistically significant downward trend in quantity for tacrolimus p = 0.008 is observed, with an estimated monthly decline of 14,524 doses, ciclosporin p = 0.185, with an estimated decline of 2,161 doses and sirolimus p = 0.002 with an estimated decline of 485 doses, along with declining prices. CONCLUSION: A decrease in prescription medicines use raises concerns for the care of (renal) transplant patients. Patients are encouraged to discuss their planned care with their doctor, secure supplies and remain adherent to their medication.

Case Report of COVID-19 Infection After Kidney Transplant Treated With Casirivimab-Imdevimab and Mycophenolate Mofetil Changed to Everolimus.

BACKGROUND: Casirivimab-imdevimab is a cocktail of 2 monoclonal antibodies designed to prevent infection by SARS-CoV-2, the virus that causes COVID-19. Casirivimab-imdevimab has been approved in Japan for treating mild to moderate COVID-19; however, to our knowledge, there are no reports of its use after kidney transplant from a live donor. Everolimus, an antineoplastic chemotherapy drug, is expected to be effective in inhibiting the spread of SARS-CoV-2 and preventing its replication, which may facilitate treatment. Here, we report a case of COVID-19 infection after kidney transplant that was initially treated with casirivimab-imdevimab and mycophenolate mofetil but was later changed to everolimus. CASE REPORT: A 47-year-old man underwent living donor kidney transplant from his mother in 2017. Immunosuppression therapy was underway through the administration of tacrolimus, mycophenolate mofetil, and methylprednisolone. In early September 2021, he was diagnosed as having COVID-19 and was hospitalized on day 3. On hospitalization, mycophenolate mofetil was discontinued and casirivimab-imdevimab and heparin were started. The patient started an everolimus regimen on day 5. The clinical course was successful without rejection. There was no exacerbation of COVID-19; the patient's serum creatinine levels and renal function had otherwise remained stable. CONCLUSIONS: We could safely treat a patient with casirivimab-imdevimab after kidney transplant. It is suggested that casirivimab-imdevimab can prevent COVID-19 from becoming severe and can be administered without worsening renal function. In addition, everolimus may have inhibited the spread of the virus and prevented it from replicating.

Acute Corneal Epithelial Rejection of LR-CLAL After SARS-CoV-2 Vaccination.

PURPOSE: The purpose of this study was to report a case of acute corneal epithelial rejection of living-related conjunctival limbal allograft (LR-CLAL) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. OBSERVATIONS: A 27-year-old woman developed acute epithelial rejection of LR-CLAL 2 weeks after receiving the SARS-CoV-2 vaccine. She received the LR-CLAL transplant 4 years and 7 months previously and had a stable clinical course with no history of rejection. She had an ABO blood group and human leukocyte antigen compatible donor, no systemic comorbidities, and no rejection risk factors. CONCLUSIONS: The novel SARS-CoV-2 vaccine upregulates the immune system to produce an adaptive immune response. The SARS-CoV-2 vaccine may potentially be associated with increased risk of rejection in those with ocular surface transplants.

The case of a liver-transplant recipient with severe acute respiratory syndrome coronavirus 2 infection who had a favorable outcome.

The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in 2019; thereafter, the COVID-19 outbreak became a health emergency of international concern. The impact of COVID-19 on liver-transplant recipients is unclear. Thus, it is currently unknown whether liver-transplant recipients are at a higher risk of developing complications related to COVID-19. Here, we report the case of liver-transplant recipients who were infected with SARS-CoV-2. A 20-year-old man who had undergone living-donor liver transplantation from his father at 5 years of age because of congenital biliary atresia was referred to our hospital for SARS-CoV-2 infection. Chest computed tomography did not show any abnormalities; however, laboratory results revealed liver dysfunction. He received tacrolimus as maintenance therapy that was continued at the same dose. He has not developed severe pulmonary disease and was discharged after 10 days of hospitalization. Limited data are available on post-transplant patients with COVID-19, and this case of a young patient without metabolic comorbidities did not show any association of severe COVID-19 under tacrolimus treatment. The progression of COVID-19 in liver-transplant recipients is complex, and COVID-19 risk should be evaluated in each patient until the establishment of optimal guidelines.

Coronavirus Disease 2019 in Kidney Transplant Recipients: Single-Center Experience and Case-Control Study.

BACKGROUND: Kidney transplant recipients (KTR) are considered high-risk for morbidity and mortality from coronavirus disease 2019 (COVID-19). However, some studies did not show worse outcomes compared to non-transplant patients and there is little data about immunosuppressant drug levels and secondary infections in KTR with COVID-19. Herein, we describe our single-center experience with COVID-19 in KTR. METHODS: We captured KTR diagnosed with COVID-19 between March 1, 2020 and May 18, 2020. After exclusion of KTR on hemodialysis and off immunosuppression, we compared the clinical course of COVID-19 between hospitalized KTR and non-transplant patients, matched by age and sex (controls). RESULTS: Eleven KTR were hospitalized and matched with 44 controls. One KTR and 4 controls died (case fatality rate: 9.1%). There were no significant differences in length of stay or clinical outcomes between KTR and controls. Tacrolimus or sirolimus levels were >10 ng/mL in 6 out of 9 KTR (67%). Bacterial infections were more frequent in KTR (36.3%), compared with controls (6.8%, P = .02). CONCLUSIONS: In our small case series, unlike earlier reports from the pandemic epicenters, the clinical outcomes of KTR with COVID-19 were comparable to those of non-transplant patients. Calcineurin or mammalian target of rapamycin inhibitor (mTOR) levels were high. Bacterial infections were more common in KTR, compared with controls.

Influence of patient characteristics and immunosuppressant management on mortality in kidney transplant recipients hospitalized with coronavirus disease 2019 (COVID-19).

The influence of patient characteristics and immunosuppression management on COVID-19 outcomes in kidney transplant recipients (KTRs) remains uncertain. We performed a single-center, retrospective review of all adult KTRs admitted to the hospital with confirmed COVID-19 between 03/15/2020 and 05/15/2020. Patients were followed from the date of admission up to 1 month following hospital discharge or study conclusion (06/15/2020). Baseline characteristics, laboratory parameters, and immunosuppression were compared between survivors and patients who died to identify predictors of mortality. 38 KTRs with a mean baseline eGFR of 52.5 ml/min/1.73 m2 were hospitalized during the review period. Maintenance immunosuppression included tacrolimus (84.2%), mycophenolate (89.5%), and corticosteroids (81.6%) in the majority of patients. Eleven patients (28.9%) died during the hospitalization. Older age (OR = 2.05; 1.04-4.04), peak D-dimer (OR = 1.20; 1.04-1.39), and peak white blood cell count (OR = 1.11; 1.02-1.21) were all associated with mortality among KTRs hospitalized for COVID-19. Increased mortality was also observed among KTRs with concomitant HIV infection (87.5% vs. 36.1%; p < .01). Conversely, immunosuppression intensity and degree of reduction following COVID-19 diagnosis were not associated with either survival or acute allograft rejection. Our findings potentially support a strategy of individualization of immunosuppression targets based on patient-specific risk factors, rather than universal immunosuppression reduction for KTRs at risk from COVID-19.