Therapeutic drug monitoring-guided treatment determination in a ganciclovir-unresponsive lung transplant recipient

doi:10.21203/rs.3.rs-4881975/v1

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Therapeutic drug monitoring-guided treatment determination in a ganciclovir-unresponsive lung transplant recipient

https://doi.org/10.21203/rs.3.rs-4881975/v1

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Ganciclovir and valganciclovir are used for cytomegalovirus infection after lung transplantation, but the emergence of resistant viruses complicates treatment. We experienced a lung transplant case where cytomegalovirus reactivation was observed under the valganciclovir prophylaxis. We utilized therapeutic drug monitoring for this case, and immediately suspected that the cytomegalovirus might be resistant to ganciclovir because the area under the curve of ganciclovir was sufficient for prophylaxis. Therefore, we determined to change the antiviral regimen to foscarnet and letermovir, which resulted in immediate cytomegalovirus clearance. This report demonstrated the utility of therapeutic drug monitoring of ganciclovir for suspecting the resistance to ganciclovir.

therapeutic drug monitoring

ganciclovir

cytomegalovirus

lung transplantation

regimen change

Human cytomegalovirus (CMV) infection after lung transplantation is one of the causes of graft loss and mortality [1]. Therefore, preventing CMV infection and reactivation after lung transplantation is crucial, especially in cases where the donor is CMV-positive and the recipient is CMV-negative (D+/R-). Ganciclovir (GCV) and its oral prodrug, valganciclovir (VGCV), are first-line antiviral agents for the treatment and prophylaxis of CMV after lung transplantation [2]. Dosages of GCV and VGCV are determined based on body weight and renal function. However, these may not be optimal in certain cases because of toxicities, such as severe myelosuppression or the emergence of GCV-resistant CMV [3-5]. Recently, therapeutic drug monitoring (TDM)-guided dosing of GCV and VGCV has been studied to achieve effective and tolerable treatment or prophylaxis [4, 5].

As alternatives to GCV, drugs such as cidofovir, foscarnet, letermovir, and maribavir have been developed and are expected to be used as treatments or prophylaxis for CMV in lung transplant recipients. Currently, there is little consensus on the second-line antiviral regimen for GCV-intolerant or GCV-resistant cases. Compared with cidofovir and foscarnet [6], letermovir causes milder adverse effects. However, letermovir resistance and treatment failure are concerns [7]. Additionally, letermovir has not yet been approved for the treatment or prophylaxis of CMV infection in lung transplant recipients.

GCV-resistant CMV can present significant challenges in treatment. It is crucial to make the timely adjustment of antiviral regimens for patient outcomes. The use of TDM for GCV has attracted attentions to warrant therapeutic efficacy and to minimise the risk of toxicity [4, 5, 8]. In this report, we utilized TDM not only to monitor the efficacy of GCV but also to determine regimen change by suspecting potential drug resistance.

We report a case of a woman in her twenties who underwent bilateral lung transplantation from a deceased donor for juvenile pulmonary emphysema. The CMV serostatus was D+/R-. Fig. 1 shows the clinical course of the patient. GCV injections (5 mg/kg q12h) were initiated on postoperative day (POD) 8. Although the CMV pp65 antigen (C7-HRP) test gave positive results (6/48000 cells) on POD 22, its expression decreased to 1/50400 cells on POD 29. The patient was switched from GCV to maintenance prophylaxis with oral VGCV (900 mg q24h) on POD 33 and discharged on POD 70. However, the C7-HRP test abruptly gave positive results on POD 94. The patient had diarrhoea and was readmitted, considering the risk of developing CMV enteritis. To confirm if VGCV prophylaxis was sufficient, we measured the area under the curve (AUC) of GCV in serum after orally administering 900 mg of VGCV on POD 108, which resulted as 67.0 µg×h/mL, as calculated by the linear trapezoidal method (Fig. 2). An AUC of 40-60 mg×h/mL has been proposed as the optimal range for prophylaxis [4, 5], leading us to suspect GCV resistance. GCV injection (5 mg/kg q12h) was reinitiated on POD 109; however, the treatment response was poor, as expected. Thus, the patient was switched from GCV to foscarnet (60 mg/kg q8h) on POD 122, soon after which the C7-HRP test gave negative results on POD 128, with no apparent adverse effects, including renal dysfunction. Diarrhoea was promptly resolved. We then added oral letermovir (480 mg q24h) to foscarnet on POD 131, followed by prophylaxis with oral letermovir only from POD 137. Subsequently, neither CMV DNA nor C7-HRP were detected. Peripheral localised oedema on the right ankle and alopecia were observed as adverse events; however, both were grade 1, as defined in the Common Terminology Criteria for Adverse Events Ver 5.0.

Here, GCV-unresponsive CMV antigenemia was observed under a sufficient prophylactic AUC of GCV, although antiviral resistance tests using genotypic sequencing were not conducted. TDM enables the rapid determination of the antiviral regimen in the absence of genotypic sequencing information. Recently, TDM-guided dosing of GCV has been studied [4, 5, 8]. AUCs are preferred over trough concentrations because trough concentrations alone inadequately reflect GCV exposure [4, 5, 9]. In cases with effective GCV clearance, as in this case, low trough concentrations would be observed despite a sufficient AUC. If low trough concentrations contributed to the CMVs acquiring drug resistance in this case, low and divided doses (e.g. VGCV of 450 mg q12h) were necessary to achieve high trough concentrations with comparable AUCs, although these deviated from the recommendations in the package insert. While administering GCV to high-risk patients, TDM could be crucial to prevent potential underdosing. Future studies are essential to establish the evidence for TDM.

We selected foscarnet and letermovir for treatment and prophylaxis, respectively. Letermovir was initiated only after we confirmed CMV clearance through foscarnet treatment, owing to concerns regarding the development of letermovir-resistant viruses [7]. Recently, the Food and Drug Administration (FDA) in the United States approved letermovir for prophylaxis of CMV disease in adult kidney transplant recipients at high risk (D+/R-), following the results of a randomised clinical trial [10]. Letermovir would also be useful for prophylaxis in lung transplant recipients refractory to GCV.

Here, we determined the antiviral regimen through TDM of GCV, which contributed to the successful patient outcome. Additionally, the usefulness of prophylaxis using letermovir for cases with suspected GCV-resistant CMV infection after lung transplantation was demonstrated.

Funding

This work was supported by the Grants-in-Aid for the Encouragement of Scientists (22H04309 and 23H05299).

Competing Interests

We declare that there are no conflicts of interest.

Author Contributions

KU and CS drafted the manuscript. YoK, YuK, DH, MT, SN, and TT revised the manuscript. AM, AO, and HD supervised treatment. MN conceptualised the regimen and critically revised the manuscript. All the authors contributed to the final version of this manuscript.

Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author, YoK, upon reasonable request.

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was generated by the Kyoto University Institutional Review Boards (R2933 and R3197). Written informed consent was obtained for publication of this case report.

Acknowledgement

We are grateful to the transplant surgeons, physicians, pharmacists, and nurses for their assistance with and care for the patients.

Beam E, Lesnick T, Kremers W, Kennedy CC, Razonable RR (2016) Cytomegalovirus disease is associated with higher all-cause mortality after lung transplantation despite extended antiviral prophylaxis. Clin Transplant 30(3):270-8. https://doi.org/10.1111/ctr.12686
Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A (2018) The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 102(6):900-31. https://doi.org/10.1097/TP.0000000000002191
Heliövaara E, Husain S, Martinu T, Singer LG, Cypel M, Humar A, Keshavjee S, Tikkanen J (2019) Drug-resistant cytomegalovirus infection after lung transplantation: Incidence, characteristics, and clinical outcomes. J Heart Lung Transplant 38(12):1268-74. https://doi.org/10.1016/j.healun.2019.09.005
Märtson AG, Edwina AE, Kim HY, Knoester M, Touw DJ, Sturkenboom MGG, Alffenaar JWC (2022) Therapeutic Drug Monitoring of Ganciclovir: Where Are We? Ther Drug Monit 44(1):138-47. https://doi.org/10.1097/FTD.0000000000000925
Märtson AG, Edwina AE, Burgerhof JGM, Berger SP, Joode A, DammanK, Verschuuren EAM, Blokzijl H, Bakker M, Span LF, van der Werf TS, Touw DJ, Sturkenboom MGG, Knoester M, Alffenaar JWC (2021) Ganciclovir therapeutic drug monitoring in transplant recipients. J Antimicrob Chemother 76(9):2356-63. https://doi.org/10.1093/jac/dkab195
Avery RK, Arav-Boger R, Marr KA, Kraus E, Shoham S, Lees L, Trollinger B, Shah P, Ambinder R, Neofytos D, Ostrander D, Forman M, Valsamakis A (2016) Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection. Transplantation 100(10):e74-80. https://doi.org/10.1097/TP.0000000000001418
Veit T, Munker D, Barton J, Milger K, Kauke T, Meiser B, Michel S, Zoller M, Nitschko H, Keppler OT, Behr J, Kneidinger N (2021) Letermovir in lung transplant recipients with cytomegalovirus infection: A retrospective observational study. Am J Transplant 21(10):3449-55. https://doi.org/10.1111/ajt.16718
Katada Y, Nakagawa S, Nagao M, Umemura K, Itohara K, Nishikawa A, Hashi S, Katsube Y, Hira D, Ohsumi A, Nakajima D, Date H, Terada T (2023) Trough ganciclovir concentration as predictor of leukopenia in lung transplant recipients receiving valganciclovir prophylaxis. Transpl Infect Dis e14141. https://doi.org/10.1111/tid.14141
Stockmann C, Roberts JK, Knackstedt ED, Spigarelli MG, Sherwin CM (2015) Clinical pharmacokinetics and pharmacodynamics of ganciclovir and valganciclovir in children with cytomegalovirus infection. Expert Opin Drug Metab Toxicol 11(2):205-19. https://doi.org/10.1517/17425255.2015.988139
Limaye AP, Budde K, Humar A, Vincenti F, Kuypers DRJ, Carroll RP, Stauffer N, Murata Y, Strizki JM, Teal VL, Gilbert CL, Haber BA (2023) Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial. JAMA 330(1):33-42. https://doi.org/10.1001/jama.2023.9106

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Therapeutic drug monitoring-guided treatment determination in a ganciclovir-unresponsive lung transplant recipient

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