Approaches and Challenges in the Current Management of Cytomegalovirus in Transplant Recipients: Highlighting the Role of Advanced Practice Providers (Nurse Practitioners and Physician Assistants)

Introduction

Cytomegalovirus (CMV) infection is a common post-transplant complication experienced by hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients [1–4]. CMV infection and/or disease can adversely affect patient outcomes by direct and indirect effects, including increased risk of organ rejection, graft failure, and bacterial and fungal secondary infections [3–8]. Clinical providers who care for HCT and SOT recipients are faced with frequent and sometimes challenging CMV infection episodes [9,10]. Therapy changes or multiple antiviral courses are often needed to manage CMV infections [9,10]. Toxicities of standard CMV antivirals are well-known and can lead to adverse events; neutropenia is associated with (val)ganciclovir therapies, and nephrotoxicity is associated with foscarnet and cidofovir therapies [11–15]. These adverse reactions, or the development of resistance, can lead to complex CMV episodes and add to the cumulative morbidity associated with multiple courses of anti-CMV therapies [9,10]. This has an adverse impact on both the individual patient and on healthcare costs [9,10]. For example, the burden of CMV management was highlighted in a retrospective, longitudinal study in the USA, where multiple-course anti-CMV therapies were given to 41.7% of HCT and 52.5% of SOT recipients treated for CMV infection. These multiple courses were associated with increased healthcare resource utilization and costs compared with a single course of an anti-CMV therapy [9]. In recent years, newer antiviral agents with reduced toxicity have shown promising results in transplant recipients for both the prevention of CMV infection with letermovir [16–20] and treatment of refractory CMV infection (with or without resistance) with maribavir [12,21]. However, since integration of clinical trial findings into clinical practice can be delayed, it is important to understand the limitations of traditionally employed therapies for CMV prevention and treatment. As such, this article is not intended to be a systematic review or comprehensive discussion of CMV, as other CMV practice reviews have been previously published [3,4,22–24]. Rather, the aim of this article is to outline the daily challenges in CMV management from an advanced practice provider’s (APP) standpoint, given the increased role of APPs and the paucity of literature in this regard. APPs are healthcare providers, distinct from a physician, who often undertake medical tasks typically associated with physicians and are involved in the day-to-day patient care. They have received advanced education, training, and certifications to be able to practice within this scope.

Herein, we evaluate the challenges of anti-CMV therapies traditionally used in the management of CMV infection in transplant recipients, how newer therapy options could have an impact on CMV management, and finally, how a multidisciplinary approach centered on APPs can improve CMV-associated outcomes for transplant recipients.

Prophylaxis and Pre-emptive Therapy, and Detection and Monitoring of CMV in Transplant Recipients

There are 2 strategies for the prevention of CMV infection/disease: prophylaxis and pre-emptive therapy (PET). Prophylaxis is when an anti-CMV therapy is given to patients (or a subset of patients) for a set period of time, regardless of whether or not CMV reactivation is present. PET involves regular (eg, weekly) monitoring of CMV viral loads and intervention with appropriate therapy when the viral load reaches a threshold value to prevent poor clinical outcomes; however, threshold values are not standardized across centers and can depend on the individual patient’s risk of developing CMV (eg, CMV serostatus and immunosuppression) [3,22,25].

Historically, many HCT programs have used PET protocols, while many SOT programs (especially in the USA and Europe) have used antiviral prophylaxis, particularly for donor-seropositive, recipient-seronegative (D+/R− SOT) recipients [2–4,25,26]. However, both paradigms are changing. For HCT recipients, this is primarily driven by the use of letermovir, an antiviral CMV therapy used for CMV prophylaxis [27] that is discussed in more detail below. For SOT recipients, changes to clinical practice may be driven by the outcomes of the phase 4 CAPSIL randomized trial involving valganciclovir (NCT01552369). The CAPSIL trial investigated prophylaxis versus PET in D+/R− liver transplant recipients and demonstrated improved CMV outcomes in the PET group compared with the prophylaxis group [28]. Furthermore, clinical practice might be further updated due to the recent letermovir approval (in June 2023) by the US Food and Drug Administration (FDA) for prophylaxis of CMV in kidney transplant recipients [29].

CMV detection and monitoring based on molecular quantification of CMV viral load is often used to diagnose CMV infection, inform treatment strategies, and monitor the patient’s response to therapy [3]. In PET protocols, sequential monitoring using a sensitive, early-detection test is key. Most frequently, this is accomplished by using quantitative polymerase chain reaction (qPCR) or the quantitative nucleic acid amplification test (qNAAT) [3]. In protocols using antiviral prophylaxis, sequential monitoring of CMV DNAemia via qPCR testing can detect delayed-onset CMV reactivation after prophylaxis, or breakthrough DNAemia during prophylaxis [3,4]. Furthermore, during treatment of an active CMV infection, sequential CMV DNAemia monitoring can determine whether the therapy is effective, or whether the patient is developing a resistant/refractory (R/R) CMV infection [3,4], as defined by Chemaly et al [8]. Resistant CMV refers to a CMV episode in which there is a genotypic mutation conferring resistance to 1 or more antiviral agents. Refractory CMV behaves clinically like resistant CMV (ie, ≥1 log increase in CMV viremia after 2 weeks on appropriately dosed therapy), but without a genotypic resistance mutation [8].

Clinical Features of CMV Infection and Disease in Transplant Recipients

Clinical manifestations of CMV infection fall into 3 categories: “asymptomatic CMV DNAemia” (formerly called “CMV viremia”), “CMV syndrome” (a symptomatic illness with cytopenias, defined only for SOT), and “CMV end-organ disease” (formerly called “tissue-invasive CMV disease”). Formal definitions of these categories for clinical trials have been published by Ljungman et al [7]. High CMV viral loads are associated with greater risk for development of symptomatic CMV disease, recurrences, and resistance [30,31]. For SOT, D+/R− recipients, in whom CMV is acquired from the donor without antecedent anti-CMV immunity in the recipient, are the patients at highest risk for symptomatic CMV, including DNAemia, CMV syndrome, and CMV end-organ disease [3,4,6]. For HCT, donor-seronegative/recipient-seropositive (D−/R+) serostatus confers higher risk [32], since the recipient’s newly reconstituted immune system from the donor has no pre-existing anti-CMV immunity to protect against the recipient’s latent CMV infection, which can lead to reactivation.

Historically, the 4 anti-CMV therapies used to manage CMV infection/disease in transplant recipients were valganciclovir, ganciclovir, cidofovir, and foscarnet [3], with valganciclovir and ganciclovir the most commonly used, and foscarnet and cidofovir reserved for second- or third-line therapy for R/R CMV due to their safety profiles [13,15].

The FDA approval of letermovir in 2017 (for prophylaxis in HCT) and maribavir in 2021 (for treatment of refractory CMV [with or without resistance]) changed the CMV antiviral landscape, offering patients the potential for effective anti-CMV therapies without the high rates of adverse events often associated with previous conventional therapies [15,33]. These 2 newer therapies will be discussed in detail below.

Challenges in Management: Neutropenia and Thrombocytopenia

Antiviral prophylaxis for CMV in SOT recipients, and PET for SOT and HCT recipients, have traditionally used (val)ganciclovir [3,22]; however, studies have found that valganciclovir is associated with adverse hematological events, including neutropenia [33] and leukopenia [34]. At some SOT centers, prophylaxis with valganciclovir has been extended, based on randomized clinical trials that showed significant reductions in CMV events with 200 versus 100 days of prophylaxis in D+/R− kidney transplant recipients (NCT00294515) [35], and 12 versus 3 months in D+ or R+ lung transplant recipients (NCT00227370) [36]. While some have advocated using a lower dose of valganciclovir for prophylaxis, a retrospective study of low (450 mg once daily for 90 days) and standard (900 mg once daily for 180 days) valganciclovir doses in D+/R− liver transplant recipients found a greater proportion of patients with CMV end-organ disease in the low-dose group, and 2 patients in the low-dose group developed ganciclovir resistance mutations [37]. Since the earliest descriptions of ganciclovir-resistant CMV in SOT recipients by Limaye et al [38], it has been noted that exposure to subtherapeutic levels of ganciclovir, especially in the setting of a high or rising viral load, is a risk factor for the development of resistance [39].

As previously mentioned, a major issue that occurs during therapy with (val)ganciclovir is cytopenias, most commonly leukopenia/neutropenia [33,34], and sometimes thrombocytopenia, although these are not the only drugs that can cause post-transplant cytopenias (mycophenolate mofetil is another cause of cytopenias [40]). The incidence of cytopenias may be higher in real-world use than what is observed in clinical trials [41]. In a study of 1682 kidney transplant recipients [42], 56 patients experienced neutropenic fever (which can be associated with increased risk of death-censored graft failure and acute rejection). At our center, in a retrospective study of 1076 kidney transplant recipients receiving valganciclovir-based prophylaxis from 2010–2014, 393 (36.5%) patients developed neutropenia (defined as an absolute neutrophil count of <1000 cells/mm3) at any time after transplant [43]. In our experience, neutropenia can develop rapidly and may be profound and protracted, even after treatment discontinuation. Additionally, neutropenia is a risk factor for secondary bacterial and fungal infections; this retrospective study showed that multiple types of infections (urinary tract infections, CMV, pneumonias, bloodstream infections) were significantly more common in the group who had had at least 1 episode of neutropenia versus the group who did not develop neutropenia (P<0.02 for all) [43].

For HCT, most centers have used PET because the risk of neutropenia from (val)ganciclovir is so high [2,25,44]. Boeckh et al reported that in a randomized trial investigating ganciclovir prophylaxis versus PET in HCT recipients, the reductions in CMV events were offset by mortality related to fungal infections in the setting of neutropenia in the ganciclovir group [45].

In terms of practical, day-to-day management in our center, transplant recipients on (val)ganciclovir must be assiduously monitored with complete blood counts and differentials performed at least every 2 weeks. This is especially important for HCT recipients who may be cytopenic prior to treatment. If neutropenia is severe, it may be necessary to adminster a colony-stimulating factor, such as filgrastim, to correct the neutropenia. However, filgrastim and similar agents can cause bone pain, fevers, and other adverse effects [46]. In addition, these are costly drugs that often require prior authorization from the patient’s insurance company [47]. This in turn may be time-consuming for a busy clinician to pursue (often an APP who is providing care for a large volume of patients), especially if neutropenia occurs immediately before a weekend. Furthermore, prior authorizations are frequently denied, necessating additional steps such as appeals and/or peer-to-peer calls [47].

Neutropenia may require modulation of immunosuppression, including dose reduction or stopping mycophenolate mofetil treatment [48]. Neutropenia may also require temporarily stopping (val)ganciclovir [49], which can be a problem if the patient has not yet cleared their CMV infection. Dose reduction of (val)ganciclovir for cytopenias is not recommended, since subtherapeutic levels of anti-CMV therapies can lead to resistance [25,50]. Dose alteration of (val)ganciclovir is, however, recommended in the setting of changing renal function; this setting also requires close monitoring of serum creatinine levels (and estimated glomerular filtration rate) [51]. In our center’s experience, if the patient’s renal function worsens, and the dose of (val)ganciclovir is not decreased promptly, increased toxicity may ensue. On the other hand, if the patient’s renal function improves, and the dose of (val)ganciclovir is not promptly increased, then the antiviral therapy may become less effective and lead to breakthrough CMV DNAemia, worsening symptomatic CMV, and/or resistance.

Another set of issues that confront HCT clinicians include when to initiate treatment (ie, at what level of CMV viral load) and what to do if the HCT recipient is neutropenic or borderline neutropenic, either at treatment initiation or during treatment. Green et al from the Fred Hutchinson Cancer Research Center published a risk-adapted viral load–based strategy where transplant recipients received PET if their plasma CMV viral load was ≥500 copies/mL, or ≥100 copies/mL if receiving ≥1 mg/kg of prednisone or anti–T-cell therapies, or if a ≥5-fold viral load increase from baseline was detected. This strategy successfully managed CMV with little progression to symptomatic disease [25]. Regarding management of CMV prior to engraftment, a single-center retrospective study from Johns Hopkins showed that clinicians usually waited until both the median viral load and absolute neutrophil count rose to 656 copies/mL and 760 cells/mm3, respectively, before initiating treatment with valganciclovir. Outcomes with this strategy were generally favorable, with only 6/73 patients developing CMV DNAemia of >5000 IU/mL, as determined by qNAAT [52].

All of this management, monitoring, and clinical decision-making puts heavy demands on busy clinicians, especially APPs, as well as on patients. In addition, the effort that is required to monitor cytopenias and obtain and administer filgrastim for patients receiving (val)ganciclovir may detract from clinical time needed for the care of other patients. For many years, there has been a need for antivirals with equivalent efficacy to (val)ganciclovir that do not cause cytopenias.

Challenges in Management: Nephrotoxicity and Other Adverse Effects

The second-line agents foscarnet and cidofovir carry significant risks of nephrotoxicity [13–15]. In a retrospective study of 39 transplant recipients (22 SOT, 17 HCT) who received foscarnet for treatment of CMV, renal dysfunction occurred in 51.3% (n=20) of patients by the end of treatment, and in 18.0% (n=7) of patients, renal dysfunction persisted for 6 months [13]. Multiple other studies have found similar results in both SOT and HCT recipients [14,53–55].

Foscarnet has other disadvantages, including but not limited to its availablility only as an intravenous (IV) formulation, which requires IV hydration prior to each dose [56]. In addition, foscarnet causes electrolyte depletion, and patients often require vigorous replacement of potassium and magnesium [13,54]. Occasionally, foscarnet causes painful genitourinary ulcerations [13]. For all these reasons its use is not preferred, as patients may spend most of their day receiving infusions of foscarnet, IV hydration, and electrolytes [13,54,56], which, in our experience, can prolong hospitalization and can make home administration risky, but for many years this was the main alternative to (val)ganciclovir for CMV treatment [9].

Cidofovir is also only available in IV formulation and has been shown to be nephrotoxic. It is long-acting (dosed once every week for 2 weeks, followed by an infusion every other week until viral clearance) and requires IV hydration and probenecid around each dose for protection of renal function [57,58]. In a retrospective study of 16 patients who received cidofovir for CMV treatment, 6 (37.5%) developed nephrotoxicity, and 4 (25.0%) patients developed uveitis, which is another severe adverse event caused by cidofovir treatment [15]. Because of these toxicities, cidofovir is also often used only when other anti-CMV therapies have failed [3].

Case Study: A Nurse Practitioner-Led Outpatient CMV Monitoring Program

Because of the inherent risks of the CMV management strategies outlined above, the role of APPs has become increasingly important, especially in the outpatient setting. One center adopted a post-prophylaxis CMV PCR monitoring protocol for D+/R− kidney and liver transplant recipients upon observing frequent CMV DNAemia occurrence after completion of valganciclovir prophylaxis. This protocol included valganciclovir prophylaxis for 6 months, followed by CMV qPCR monitoring every 2 weeks for months 7–9, and every month for months 10–12. However, patients were still developing delayed-onset CMV, leading to some patients requiring hospitalization. This was attributed to the non-uniform application of the CMV PCR monitoring protocol, which lead to the development of symptomatic CMV in certain patients, including some with high viral loads. Since the system was set for review of available laboratory values only, detection of missing patient laboratory tests was not accounted for. A quality improvement initiative was subsequently pursued, led by a transplant infectious disease (ID) physician and nurse practitioner (NP), who convened a multidisciplinary team and developed alerts in the electronic medical record (EMR) for reminders regarding monitoring and valganciclovir dosing. CMV outcomes before and after implementation of this quality improvement initiative were studied. Outcomes included adherence to the protocol, symptomatic CMV disease, and CMV-related hospitalizations. After implementation, adherence to the protocol improved from 69% to 83% (P<0.01) and CMV-related hospitalizations decreased by 50% [59].

Following on from these promising results, a multi-pronged approach was designed and implemented, which involved the transplant ID NP overseeing and educating transplant nurse coordinators and weekly review of the charts of all D+/R− patients within 1 year of transplant. All D+/R− patients would have an appointment with the transplant ID NP shortly after transplant and again at 6 months after transplant, to educate them about CMV and the importance of the monitoring program. The patients’ valganciclovir doses (whether prophylaxis or treatment), CMV qPCR results, any cytopenias, and changes in renal function were tabulated. Any missing laboratory tests resulted in communication with the transplant nurse coordinator and the transplant recipient until the laboratory tests were performed and the results received. The combined data from the monitoring of these patients was summarized each week in a document entitled “TWIC” (“This Week in CMV”), which is sent to several transplant ID physicians for review.

Moreover, to strengthen this monitoring system, the transplant ID NP worked with an expert in Epic Systems EMR technology to devise EMR alerts that notified providers whenever the valganciclovir dose was inappropriate for the patient’s current renal function and when laboratory results were missing.

This team approach has led to a sharp decrease in missed CMV qPCRs, prompt detection of CMV DNAemia, expedited treatment for patients who required it, and rapid management of neutropenia. The results of implementing this system demonstrated a significant reduction in hospitalizations for highly symptomatic CMV.

Furthermore, an NP-led Epic Systems EMR-based patient monitoring tool was evaluated in 263 D+/R− recipients who received a kidney or liver transplant between June 2017 and December 2019 (patient monitoring tool group). Data were compared against 82 D+/R− recipients who received a kidney or liver transplant between March 2016 and June 2017 and were not managed with this NP-led tool (control group). A lower proportion of patients in the NP-led program had CMV viral loads >20 000 IU/mL (11.0%) compared with those in the control group (25.6%; P=0.003) [60].

Although the incidence of low-level CMV viremia was similar between groups, there was a marked decline in hospital admission for CMV complications in the patient monitoring tool group versus the control group (7.7% vs 34.0%, respectively; P=0.001). These improvements illustrate the importance of employing APP-driven systems to reinforce implementation of protocols designed to reduce the complications of CMV. Having a protocol on file is not enough; instead, it was the design and introduction of an NP- and nurse-driven program, together with an EMR alert system, that led to the monitoring protocol being effectively implemented, to the benefit of high-risk patients [60].

Newer CMV Antivirals: Letermovir

EFFICACY AND SAFETY:

In the phase 3 randomized trial (NCT02137772) of CMV-seropositive HCT recipients treated with letermovir versus placebo, the investigators defined clinically significant CMV (csCMV) as any symptomatic CMV disease or any CMV viremia requiring treatment. The letermovir group was found to have significantly less csCMV versus the placebo group (37.5% vs 60.6%, respectively; P<0.001) [16]. A post hoc analysis found that all-cause mortality was similar at week 48 in the letermovir group in patients with or without csCMV [61]. However, in the placebo group, mortality at week 48 after HCT was higher in patients with csCMV compared with those without csCMV (31.0% vs 18.0%, respectively; P=0.02) [61]. Numerous post-marketing observational studies and systematic reviews have reported significant improvement in all-cause mortality at week 14 with prophylactic letermovir use [18,61,62].

Although letermovir has demonstrated efficacy as prophylactic treatment and has a favorable safety profile as it is not associated with cytopenias nor with nephrotoxicity [16], a recent study has reported that letermovir prophylaxis has not been adopted by all European HCT centers (ie, letermovir in 62/101 centers) [63]. One of the driving forces for lack of implementation in HCT centers could be the cost of letermovir and the frequent denial of prior authorizations/appeals by insurance companies [47].

The latest advancement involved an expanded indication for letermovir in preventing CMV among D+/R− kidney transplant recipients. This approval was based on the pivotal phase 3 randomized controlled trial comparing letermovir (480 mg daily, combined with acyclovir) to valganciclovir (900 mg daily, combined with acyclovir) in kidney transplant recipients, with the primary outcome being occurrences of CMV disease up to week 52 [29]. In this study of 601 participants, letermovir was found to be noninferior to valganciclovir for CMV disease prevention. Moreover, the incidence of leukopenia or neutropenia was significantly lower in the letermovir group versus the valganciclovir group (26% vs 64%, P<0.001), with fewer discontinuations because of adverse events in the letermovir group [29].

OFF-LABEL TREATMENT USES OF LETERMOVIR FOR CMV INFECTION AND SECONDARY PROPHYLAXIS:

Several studies have also investigated the off-label use of letermovir for the treatment of CMV infection in transplant recipients. For example, a multicenter retrospective study of 47 SOT/HCT recipients by Linder et al found that recipients who have a CMV viral load >1000 IU/mL are less likely to respond to letermovir upon initiation than those with viral loads <1000 IU/mL upon initiation [31]. As a result, it is our understanding that some clinicians initially prefer to reduce the CMV viral load using another agent such as (val)ganciclovir or foscarnet, then switch to letermovir once the viral load is <1000 IU/mL until completion of therapy (including secondary prophylaxis), to avoid the toxicities of standard anti-CMV therapies. Additionally, in a study of 28 lung transplant recipients with ganciclovir-resistant or refractory CMV infection, 5 (17.9%) were considered non-responders to letermovir treatment. Of these, 3 (60.0%) developed a UL56 mutation conferring resistance to letermovir [64]. As illustrated in a case report of a lung transplant recipient with ganciclovir-resistant CMV, high-level letermovir resistance can develop even after initial apparent control of CMV infection [65]. More studies are needed to determine the optimal role of letermovir in the treatment of active CMV infection.

Our experience shows that clinicians, including APPs, are also increasingly finding letermovir to be useful for secondary prophylaxis in patients at risk for further episodes of CMV reactivation and who have previously experienced neutropenia while on (val)ganciclovir. At centers using valganciclovir prophylaxis for SOT recipients, patients who have had their valganciclovir prophylaxis truncated because of neutropenia may benefit from substitution of letermovir. If letermovir is used in place of valganciclovir prophylaxis, valacyclovir or acyclovir should be co-administered for prophylaxis of herpes simplex and varicella zoster virus, as letermovir does not have any activity against those viruses [29].

Management of R/R CMV Infection and Disease in SOT and HCT Recipients: Challenges

Despite prophylaxis and PET strategies, CMV reactivation is still a common complication observed in transplant recipients [66,67]. A prospective observational analysis of 199 HCT recipients at Kyushu University Hospital found that 17 (8.5%) developed refractory CMV infection [66].

Persistent CMV DNAemia or symptomatic CMV disease, despite anti-CMV therapy at adequate doses, can be indicative of R/R CMV [68]. The development of R/R CMV can cause significant morbidity and mortality in transplant recipients as there is no standardized treatment for resistant CMV infection, and treatment options such as foscarnet or cidofovir are limited by their associated toxicities (as discussed above) and/or the development of further resistance [69,70]. The best treatment course is often determined by the individual patient’s circumstances and any known resistance genotype mutations [13,15,24].

CMV-specific T-cell therapies are being investigated for the management of CMV infection in both HCT and SOT recipients; however, randomized clinical trials will be needed to determine their efficacy and safety in comparison to conventional anti-CMV therapies in these transplant populations [71,72].

Newer CMV Antivirals: Maribavir

EFFICACY:

The efficacy of maribavir for the treatment of primary CMV infection/reactivation and R/R CMV in HCT and SOT recipients has been investigated in two phase 2 trials (NCT01611974 and EudraCT 2010-024247-32) [21,78]. Following on from the positive results obtained in these trials, the phase 3 SOLSTICE trial was initiated to investigate the efficacy of maribavir 400 mg twice daily for the treatment of refractory CMV infection (with or without resistance) in HCT and SOT recipients (NCT02931539) [12]. In this phase 3 trial, maribavir was superior to investigator-assigned therapy (IAT; valganciclovir, ganciclovir, foscarnet, or cidofovir) for confirmed CMV viremia clearance at the end of week 8 (55.7% vs 23.9% of patients, respectively; P<0.001) and confirmed CMV viremia clearance plus symptom control at the end of week 8, maintained through to week 16 (18.7% vs 10.3% of patients, respectively; P=0.01) [12].

SAFETY:

The safety profile of maribavir has been characterized in several clinical trials [12,21,78,79]. The rate of treatment-emergent adverse events (TEAEs) was similar between maribavir and IAT in the phase 3 SOLSTICE trial [12]. In this phase 3 trial, dysgeusia (a taste disorder which can persist beyond treatment) was the most frequently reported TEAE for maribavir (37.2% of patients vs 3.4% of patients for IAT); however, this was reported as mostly mild, rarely led to treatment discontinuation, and resolved either on treatment or shortly after the last dose of maribavir. Additionally, the rate of acute kidney injury was lower with maribavir versus foscarnet (8.5% vs 21.3%, respectively) and the rate of neutropenia was lower with maribavir versus (val)ganciclovir (9.4% vs 33.9%, respectively) [12].

DRUG–DRUG INTERACTIONS:

In the phase 3 SOLSTICE trial, the TEAE of immunosuppressant drug concentration level increase was more common in patients receiving maribavir than IAT [12]. This result was not surprising as maribavir has been shown to interact with P-glycoprotein, a transporter involved in the distribution and disposition of immunosuppressants [80]. However, immunosuppressive agents such as tacrolimus are commonly monitored and dose-adjusted according to sequential levels in clinical practice, so this drug–drug interaction is manageable.

DEVELOPMENT OF RESISTANCE:

As with other anti-CMV therapies, mutations conferring resistance to maribavir have been reported in the literature. For example, a substitution to UL27 L193F was observed in 1 transplant recipient in the phase 3 SOLSTICE trial, and was associated with a 2.6-fold reduction in maribavir susceptibility [77]. In an analysis of the two phase 2 trials, 73.9% (17/23) of transplant recipients with available UL97 genotyping data who developed recurrent CMV infection and did not respond to therapy after 14 days had known resistance mutations to maribavir (T409M or H411Y). The remaining 5 patients had an UL97 C480F mutation, which conferred high-grade maribavir resistance and low-grade ganciclovir resistance [81]. Recurrent CMV infection was also associated with the development of UL97 C480F mutations in 2 transplant recipients (1 kidney transplant recipient and 1 HCT recipient) after maribavir treatment in a small study by Santos Bravo et al [82]. It is yet to be determined how clinically significant maribavir mutations will be once it is in more widespread use.

Conclusions

Antiviral therapies traditionally used for CMV prophylaxis or treatment have major drawbacks in terms of toxicity, particularly neutropenia for (val)ganciclovir and nephrotoxicity for foscarnet and cidofovir. Neutropenia, in particular, predisposes patients to secondary infections and adverse consequences. Newer anti-CMV therapies including letermovir (approved for prophylaxis in HCT and D+/R− kidney transplant recipients) and maribavir (approved for treatment of refractory CMV [with or without resistance]) lack these toxicities, but real-world use patterns are still emerging. Protocols using anti-CMV antivirals must be implemented thoughtfully and with meticulous monitoring of quantitative CMV viral load, complete blood counts with differential, and estimated glomerular filtration rate. APPs, who increasingly have become the main clinicians managing transplant outpatients, are ideally positioned to design and implement programs that leverage EMR and close relationships with patients and nurse coordinators to achieve the best CMV outcomes for high-risk patients.