EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Refractory and resistant cytomegalovirus infections remain significant challenges in solid-organ transplant recipients. In this context, maribavir is a valuable therapeutic option for management of cytomegalovirus infection. Although the clinical efficacy and safety of maribavir are well established, the optimal approach for assessment of viremic response, which is defined as the clearance of viremia, still requires further clarification. Notably, some patients treated with maribavir do not achieve full viremia clearance, despite clinical improvement and a significant reduction in viral load. In this report, we shared our exploration of the potential for a new paradigm for management of the viremic response during maribavir therapy. Our experience suggested that the goal to achieve complete viremia clearance may not always be necessary if clinical resolution and stable viremic responses (ie, viral load <1000 IU/mL) are achieved. In such cases, discontinuation of therapy with close monitoring may be a viable option.

Key words : Maribavir therapy, Transplantation, Viremia

Refractory/resistant cytomegalovirus (CMV) infec-tion in solid-organ transplant (SOT) recipients represents a substantial challenge in the post-transplant period, as it is associated with both high morbidity and mortality.¹

Refractory CMV infection is defined as CMV viremia that either increases or persists despite at least 2 weeks of appropriate antiviral therapy,² whereas resistant CMV infection refers to the presence of a viral mutation that confers reduced sensitivity to at least 1 anti-CMV agent.² It is estimated that 3% to 10% of CMV infections in SOT patients are refractory or resistant to first-line antiviral treatments,³ with an associated mortality risk of approximately 31%.^4,5

The advent of maribavir has provided new hope in this setting, due to its activity against CMV, including strains resistant or refractory to other antiviral agents.^6,7 However, although maribavir has demonstrated safety and efficacy in terms of clinical response, its role in viremia clearance remains to be fully elucidated. The SOLSTICE trial, for instance, showed that only a subset of patients treated with maribavir achieved viremia clearance after 8 weeks of therapy, with only 55.7% of patients reaching this outcome.⁸

In light of these results, and considering the clinical recovery achieved and the substantial decrease in viral load in many patients, the question arises: should the definition of viremic response be reassessed? Specifically, is it essential to achieve complete viremia clearance, or should a new paradigm of viremic response be considered during antiviral therapy with maribavir? This consideration stems also from the potential risk of inducing resistance if antiviral therapy is continued in an attempt to achieve viremia suppression. In this context, we present our experience with maribavir, focusing on its effect on viremic response and clinical outcomes in SOT recipients.

We report the cases of a 24-year-old male kidney transplant recipient and a 39-year-old female kidney transplant recipient, both of whom developed refractory CMV infection and were treated with maribavir 400 mg twice daily. Both recipients had received a kidney transplant from a deceased donor. The characteristics of these 2 patients are presented in Table 1.

Both patients developed CMV infection during the first 3 months after transplant, specifically at 48 days and 55 days after transplant, respectively, while on preemptive therapy. As a result, both patients were initially treated with an intravenous dose of ganciclovir 5 mg/kg twice daily, adjusted according to the estimated glomerular filtration rate (eGFR) for each patient. Simultaneously, their immunosup-pression regimens were reassessed, and the dosages of the antimetabolite mycophenolate sodium were reduced.

Both patients developed CMV infection refractory to first-line treatment as demonstrated by lack of response at 15 days and 16 days of ganciclovir treatment, respectively. In fact, in both cases, viremia increased by more than a full logarithm increment, and clinical and laboratory manifestations consistent with CMV disease emerged. Specifically, the first patient experienced fever and thrombocytopenia, whereas the second patient developed fever, asthenia, thrombocytopenia, and hypertransamina-semia (Table 1). Unfortunately, resistance tests were not conducted in either case.

Given the refractory nature of the infection, both patients were switched to antiviral therapy with an oral dose of maribavir 400 mg twice daily. In patient 1, maribavir was initially combined with foscarnet (60 mg/kg intravenous every 8 h, adjusted for eGFR) for the first 3 days, followed by maribavir alone. However, for patient 2, foscarnet could not be administered due to an insufficient eGFR (<22 mL/min), so maribavir was combined with anti-CMV immunoglobulins (1 mg/kg/d intravenous) for the first 3 days, followed by maribavir alone.

During antiviral treatment, viral load was monitored every 96 hours along with regular blood chemistry checks.

No adverse events were observed, and both patients tolerated the therapy well with a favorable safety profile. In both cases, a clinical-laboratory response was noted, with clinical resolution of symptoms and recovery of thrombocytopenia, along with normalization of liver cytolysis tests.

Virologically, both patients showed a reduction of at least a full logarithm increment in viral load within the first 96 hours of treatment (Figure 1, Figure 2). A progressive decline in viral load continued during therapy, although viremia clearance was not achieved in either case (Figure 1, Figure 2). Viremia clearance was defined as a plasma CMV DNA level below the lower limit of quantification (<100 IU/mL) in 2 consecutive postbaseline samples, separated by at least 1 day (Roche Diagnostics).²

Despite an initial rapid and progressive viremic response in the first 2 weeks, viral loads stabilized at values <1000 IU/mL from week 3 onward in both patients, without achieving viremic suppression. During week 3 and week 4 of maribavir therapy, viral load remained below 1000 IU/mL, but it did not reach undetectable levels (Figure 1, Figure 2).

Given the clinical recovery and the stable viral load below 1000 IU/mL, maribavir treatment was discontinued after 28 days in patient 1 (Figure 1) and after 23 days in patient 2 (Figure 2). Close monitoring of the viral load in both patients was continued as a form of secondary preemptive therapy (Figure 1, Figure 2). Viral load was monitored every 96 hours for 2 weeks after cessation of treatment, then weekly for the next month, and subsequently every 2 to 4 weeks (Figure 1, Figure 2).

During the 4-month posttherapy follow-up period, no increase in viral load was shown, and both patients maintained viremia levels below 1000 IU/mL (Figure 1, Figure 2). In addition, both patients showed no recurrence of CMV disease during the follow-up period.

Our experience supports the efficacy and safety of maribavir for management of refractory CMV infection, although this conclusion was based on only 2 cases. Furthermore, our experience prompts further consideration and evaluation regarding the management of CMV infection with maribavir. Specifically, our results raise questions about the optimal timing and duration of antiviral therapy with maribavir, as well as the necessity of continuing treatment with the goal to achieve viremia clearance.

In our 2 cases treated with maribavir, both clinical improvement and viremic response were observed, with a stable viral load below 1000 IU/mL after at least 2 weeks of antiviral therapy. However, viremia clearance was not achieved by week 3 or week 4 of therapy (Figure 1, Figure 2). This raises the question of whether complete viremia clearance is a realistic endpoint for all patients treated with maribavir and whether complete viremia clearance truly serves as a surrogate marker for clinical response and lack of relapse.

The failure to achieve viremia clearance during antiviral therapy with maribavir is not unpre-cedented. In the SOLSTICE trial, only 55.7% of patients treated with maribavir achieved viremia clearance by the end of 8 weeks of therapy. Among patients with refractory (nonresistant) CMV infection, only 43.8% reached viremia clearance within 8 weeks. In contrast, 62.8% of patients with baseline genotypic resistance to other antivirals achieved clearance after 8 weeks of treatment with maribavir. Additionally, the same trial showed that, after 8 weeks of posttherapy follow-up, only 18.7% of patients maintained viremia clearance and symptom control, whereas clinically manifest recurrent infections occurred in 26% of those treated with maribavir.⁸

Our data highlight not only the challenge to achieve viremia clearance in some cases but also the importance of considering the risks of prolonged antiviral therapy, such as the potential for resistance. Indeed, mutations in the virus DNA at the UL97 gene (F342Y, T409M, H411Y, C480F) and the UL27 gene (L193F) have been identified to confer reduced susceptibility to maribavir.⁹ According to the SOLSTICE trial drug resistance analysis by Chou and colleagues, baseline maribavir resistance mutations were rare, occurring in just 1.7% of patients.¹⁰ However, most maribavir resistance mutations developed during treatment, with 26% of patients (60/234) randomized to maribavir showing resistance, including 48% of nonresponders and 86% of relapsers, who experienced viral rebound after initial clearance.^8,10 These mutations typically emerged between 26 days and 130 days (average 56 days) after the initiation of maribavir therapy.^8,10

These findings suggest that, although maribavir is a valuable tool for management of resistant or refractory CMV infections, the long-term use of maribavir may present certain limitations, particularly regarding the development of resistance.

Given this context, in our 2 cases, we opted to discontinue maribavir therapy once clinical recovery was achieved and viral load remained stable below 1000 IU/mL for at least 2 weeks. This decision was made with close clinical and viral load monitoring to ensure patient safety after treatment. During the 4 months of follow-up, there were no recurrences or increases in viral load, with viral levels remaining stable below 1000 IU/mL.

No adverse events were observed in our cases, whether mild, moderate, or severe. However, it is important to note that the median duration of maribavir exposure in our patients was only 25.5 days, significantly shorter than the 57-day duration in the SOLSTICE trial.⁸

Although our case series has important limitations, including a small sample size and a retrospective design, it highlights the need for careful consi-deration for management and continuance of maribavir therapy. Specifically, our study suggests that the goal to achieve complete viremia clearance may not always be necessary if clinical resolution and stable viremic responses (ie, viral load <1000 IU/mL) are achieved. In such cases, discontinuation of therapy with close monitoring could be a viable option.

Ongoing research on long-term viremic response and in particular the need to achieve viremia clearance with maribavir is critical to optimize its clinical application and improve patient outcomes.

Volume: 23 Issue: 4 April 2025

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