Ellam H

Montgomery EK

Pearce H

Sheerin N

English

Newcastle University E-Prints

A Novel Case of CMV Resistance toValganciclovir andMaribavir in a RenalTransplant PatientHelen Pearce1, Emma K. Montgomery2, Neil Sheerin2,3* and Helena Ellam41Newcastle Hospitals Trust, Newcastle upon Tyne, United Kingdom, 2Renal Services, Newcastle upon Tyne Hospitals NHSFoundation Trust, Newcastle upon Tyne, United Kingdom, 3Immunity and Inflammation Theme, Faculty of Medical Sciences,Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom, 4Department ofVirology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United KingdomKeywords: CMV infection, resistance, renal, transplant, maribavirDear Editors,Cytomegalovirus (CMV) is one of the most common viruses causing infectious complicationsafter kidney transplantation [1, 2]. Anti-viral prophylaxis and pre-emptive therapy are the mainstaysof CMV prevention. Maribavir is an oral benzimidazole riboside drug thought to have potent,selective multimodal anti-CMV activity, thus conferring protection against CMV strains resistant totraditional anti-viral drugs [3]. Whilst valganciclovir remains the first line oral anti-viral treatment inthe management of CMV, maribavir offers a promising oral alternative to previous second linenephrotoxic drugs, foscarnet and cidofovir [4]. Approved by the U.S. Food and Drug Administrationin November 2021, maribavir has been recommended by National Institute for Health and CareExcellence (NICE) for patients with resistance to at least one other first-line medication used in themanagement of CMV [4, 5]. Despite maribavir’s novel mode of action, we report a case of resistanceto both ganciclovir and maribavir in a patient following kidney transplantation.A 70-year-old male with end-stage kidney disease, underwent kidney transplantation on 27/11/22. The patient was high risk for CMV disease (donor CMV seropositive/recipient CMVseronegative). Histocompatibility report issued day 44 post-transplant and showed donor/recipient serologic equivalents of HLA-B, -C, -DRB1, -DQB1, and–DPB1 antigens werematched, aside from HLA-A (donor HLA type A*02/A*24, recipient HLA type A*68). Posttransplantation, the patient was initiated on CMV prophylaxis in the form of oral valganciclovir,450 mg three times weekly for 100 days, alongside his maintenance immunosuppressant regime(tacrolimus (Adoport) 5 mg BD, mycophenolate mofetil (MMF) 500 mg BD andprednisolone 5 mg OD).In the weeks following transplantation, the patient reported no symptoms suggestive of CMVdisease. However, day 53 post-transplant, a CMV viraemia was detected from a whole blood CMVassay (viral load 72,800 IU/mL, eGFR 28, lymphocyte count 0.73 109/L, tacrolimus level 13.9 ug/L)whilst the patient remained on prophylactic valganciclovir. Subsequently, the patient’s valganciclovirwas increased to treatment dose (450 mg OD), MMF was suspended, tacrolimus dose decreased to3 mg AM, 4 mg PM and prednisolone dose increased to 10 mg OD. Weekly CMV monitoring wasinstituted thereafter. Blood tests day 100 post-transplant showed the patients eGFR was stable at 34,the patient’s lymphocyte count was 1.14 109/L and tacrolimus level 8.8 ug/L. Since CMV viral titresremained high despite being on treatment-dose valganciclovir, a sample was sent for genotypicresistance testing on day 103 post-transplant (UL54 and UL97 regions sequenced by Sangersequencing). Results received on day 109 post-transplant identified the presence ofUL97 C603W mutation (a common mutation which confers resistance to ganciclovir) andvalganciclovir was subsequently stopped. The patient remained asymptomatic, however, on day116 post-transplant blood tests showed the patient’s alanine transaminase levels were elevated at160 IU/L, eGFR 28, lymphocyte count 0.99 109/L and tacrolimus level 12.8 ug/L. In the context of*CorrespondenceNeil Sheerin,neil.sheerin@newcastle.ac.ukReceived: 29 August 2023Accepted: 10 January 2024Published: 19 January 2024Citation:Pearce H, Montgomery EK, Sheerin Nand Ellam H (2024) A Novel Case ofCMV Resistance to Valganciclovir andMaribavir in a Renal Transplant Patient.Transpl Int 37:11985.doi: 10.3389/ti.2024.11985Transplant International | Published by Frontiers January 2024 | Volume 37 | Article 119851LETTER TO THE EDITORpublished: 19 January 2024doi: 10.3389/ti.2024.11985increasing viral titres, maribavir therapy (400mg BD) was initiated.It should be noted that maribavir strongly antagonises the action ofvalganciclovir, an effect thought to be precipitated by interference inthe phosphorylation process, therefore these two medications mustnot be used in conjunction with one another [6]. Furtheramendments were made to the patient’s immunosuppressantregime, specifically a reduction in tacrolimus dose to 3mg BD,day 116 post-transplant. In the initial phase following initiation ofmaribavir, the patient’s CMV viral load steadily decreased. Thepatient’s tacrolimus dose was further reduced to 2 mg BD inresponse to increasing trough levels, due to the knowninteraction between tacrolimus and maribavir. Blood tests day144 post-transplant showed the patient’s eGFR remained at 28,alanine transaminase levels decreased to 88 IU/L, lymphocyte countincreased to 2.23 109/L and tacrolimus level 10 ug/L.Day 165 post-transplant there was a significant rise in thepatient’s CMV viral load, despite full treatment compliance(Figure 1), and a sample was sent for repeat genotypicresistance testing (UL54, UL97, UL56 and UL89 regionssequenced by Sanger sequencing). This identified thedevelopment of two new mutations in addition to thepreviously identified C603W mutation in the UL97 region:T409M mutation in the UL97 region (which is known toconfer resistance to maribavir) and T503I mutation in theUL54 region (conferring resistance to ganciclovir andcidofovir). No drug resistance-associated mutations wereidentified in the UL56/UL89 regions. These results wereconfirmed by genotypic resistance testing at a secondlaboratory. Maribavir therapy was subsequently stopped onday 179 post-transplant. It should be noted that T409M is acommon mutation, well described in the literature, and confershigh level resistance to maribavir. Interestingly it often developsafter an initial suppression of a patient’s CMV viral load, as seenin this case [7]. In the week following termination of maribavir,the patient’s CMV viral load decreased, which could be indicativeof self-cleared infection. Further anti-viral treatment was notgiven and day 207 post-transplant, the following changes weremade to the patient’s immunosuppression regime: tacrolimus(Adoport) 2 mg BD, mycophenolate mofetil 500 mg remainedsuspended, prednisolone reduced to 10 mg/5 mg alternate days.The patient’s kidney transplant function remains satisfactory andliver function remains stable following termination of maribavir(Day 207 post-transplant: eGFR 38, alanine transaminase 48 IU/Land lymphocyte count 2.34 109/L and tacrolimus level 5.6 ug/L).In summary, to our knowledge, this is the first reported case ofresistance to both valganciclovir and maribavir outside of clinicaltrials in the UK. Although resistance to maribavir is described inthe SOLSTICE clinical trial [3, 8], our case highlights the need forclinicians to be vigilant when initiating treatment with maribavir.It should also be acknowledged that foscarnet may be a preferredoption over maribavir when treating refractory CMV diseaseswith high viral loads [9]. A low threshold for CMV resistancetesting is recommended if a patient’s CMV viral load increaseswhilst on treatment. Maribavir is known to increase exposure totacrolimus [10] and our case highlights the importance ofmonitoring concomitant immunosuppressant bloodconcentration at initiation, co-administration, anddiscontinuation of maribavir.DATA AVAILABILITY STATEMENTThe original contributions presented in the study are included inthe article/supplementary material, further inquiries can bedirected to the corresponding author.ETHICS STATEMENTWritten informed consent was obtained from the individual(s)for the publication of any potentially identifiable images or dataincluded in this article.FIGURE 1 | A graph to demonstrate change in CMV viral load, in-keeping with CMV resistance emergence.Transplant International | Published by Frontiers January 2024 | Volume 37 | Article 119852Pearce et al. Maribavir Resistance in Renal TransplantationAUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct, andintellectual contribution to the work and approved it forpublication.CONFLICT OF INTERESTThe authors declare that the research was conducted in theabsence of any commercial or financial relationships thatcould be construed as a potential conflict of interest.REFERENCES1. Gandhi MK, Khanna R. Human Cytomegalovirus: Clinical Aspects, ImmuneRegulation, and Emerging Treatments. Lancet Infect Dis (2004) 4(12):725–38.doi:10.1016/S1473-3099(04)01202-22. Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L,et al. The Third International Consensus Guidelines on the Management ofCytomegalovirus in Solid-Organ Transplantation. Transplantation (2018)102(6):900–31. doi:10.1097/TP.00000000000021913. Avery RK, Alain S, Alexander BD, Blumberg EA, Chemaly RF, Cordonnier C,et al. Maribavir for Refractory Cytomegalovirus Infections With or WithoutResistance Post-Transplant: Results From a Phase 3 Randomized ClinicalTrial. Clin Infect Dis (2022) 75(4):690–701. doi:10.1093/cid/ciab9884. Maertens J, Cordonnier C, Jaksch P, Poiré X, Uknis M, Wu J, et al. Maribavirfor Preemptive Treatment of Cytomegalovirus Reactivation. N Engl J Med(2019) 381:1136–47. doi:10.1056/NEJMoa17146565. NICE.TechnologyAppraisal TA860:Maribavir for Treating RefractoryCytomegalovirusInfection After Transplant (2023). Available from: https://www.nice.org.uk/guidance/ta860/chapter/1-Recommendations (Accessed January 18, 2023).6. Chou S, Ercolani RJ, Derakhchan K. Antiviral Activity of Maribavir inCombination With Other Drugs Active Against Human Cytomegalovirus.Antivir Res (2018) 157:128–33. doi:10.1016/j.antiviral.2018.07.0137. Chou S, Song K, Wu J, Bo T, Crumpacker C. Drug Resistance Mutations andAssociated Phenotypes Detected in Clinical Trials of Maribavir for Treatmentof Cytomegalovirus Infection. J Infect Dis (2022) 226(4):576–84. doi:10.1093/infdis/jiaa4628. Sunwen C, Alain S, Cervera C, Chemaly RF, Kotton CN, Lundgren J, et al.Drug Resistance Assessed in a Phase 3 Clinical Trial of Maribavir Therapy forRefractory or Resistant Cytomegalovirus Infection in Transplant Recipients.J Inf Dis (2023) 28:jiad293. doi:10.1093/infdis/jiad2939. Razonable RR. Oral Antiviral Drugs for Treatment of Cytomegalovirus inTransplant Recipients. Clin Microbiol Infect (2023) 29(9):1144–9. doi:10.1016/j.cmi.2023.03.02010. Pescovitz MD, Bloom R, Pirsch J, Johnson J, Gelone S, Villano SA. ARandomized, Double-Blind, Pharmacokinetic Study of Oral Maribavir WithTacrolimus in Stable Renal Transplant Recipients. Am J Transpl (2009) 9:2324–30. doi:10.1111/j.1600-6143.2009.02768.xCopyright © 2024 Pearce, Montgomery, Sheerin and Ellam. This is an open-accessarticle distributed under the terms of the Creative Commons Attribution License (CCBY). The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply withthese terms.Transplant International | Published by Frontiers January 2024 | Volume 37 | Article 119853Pearce et al. Maribavir Resistance in Renal Transplantation

A Novel Case of CMV Resistance to Valganciclovir and Maribavir in a Renal Transplant Patient

https://eprints.ncl.ac.uk/file_store/production/296831/933995C7-3DA8-4FC6-91B7-357E3E2274B1.pdf

A Novel Case of CMV Resistance to Valganciclovir and Maribavir in a Renal Transplant Patient

Abstract

Similar works

Full text

Available Versions

Newcastle University E-Prints